Category: DICTIONARY

Activated clotting time

Activated clotting time (ACT), also known as activated coagulation time is a test of coagulation.

The ACT test can be used to monitor anticoagulation effects, such as high-dose heparin before, during, and shortly after procedures that require intense anticoagulant administration, such as cardiac bypass, cardiac angioplasty, thrombolysis, extra-corporeal membrane oxygenation (ECMO) and continuous dialysis. It measures the seconds needed for whole blood to clot upon exposure to an activator of an intrinsic pathway by the addition of factor XII activators.

The clotting time is based on a relative scale and requires a baseline value for a point of comparison due to inconsistencies between the source and formulation of the activator being used. It is usually ordered in situations where the partial thromboplastin time (PTT) test may take an excessive amount of time to process or is not clinically useful. Prolongation of the ACT may indicate a deficiency in coagulation factors, thrombocytopenia or platelet dysfunction. Clotting time measurements can be affected by other drugs that such as Warfarin, aprotinin and GPIIb/IIIa inhibitors.

Activated partial thromboplastin time

The partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT or APTT) is a medical test that characterizes blood coagulation. Apart from detecting abnormalities in blood clotting, it is also used to monitor the treatment effects with heparin, a major anticoagulant. PTT is a performance indicator of the efficacy of both the “intrinsic” (now referred to as the contact activation pathway) and the common coagulation pathways. It is used in conjunction with the prothrombin time (PT) which measures the extrinsic pathway. Kaolin cephalin clotting time (KccT) is a historic name for the activated partial thromboplastin time.

Activated protein C resistance

Activated protein C resistance (APCR) is a hemostatic disorder characterized by a poor anticoagulant response to activated protein C (APC). This results in an increased risk of venous thrombosis, which can cause problems with circulation, such as pulmonary embolism.

The disorder can be acquired or inherited, the hereditary form having an autosomal dominant inheritance pattern.

Activated protein C (with protein S as a cofactor) degrades Factor Va and Factor VIIIa. Activated protein C resistance is the inability of protein C to cleave Factor Va and/or Factor VIIIa, which allows for longer duration of thrombin generation and may lead to a hypercoagulable state. This may be hereditary or acquired. The best known and most common hereditary form is Factor V Leiden. Acquired forms occur in the presence of elevated Factor VIII concentrations.

Alpha 2-antiplasmin

Alpha 2-antiplasmin (or α2-antiplasmin or plasmin inhibitor) is a serine protease inhibitor (serpin) responsible for inactivating plasmin, an important enzyme that participates in fibrinolysis and degradation of various other proteins. This protein is encoded by the SERPINF2 gene.

American Society of Hematology

The American Society of Hematology (ASH) is the world’s largest professional society serving both clinicians and scientists around the world who are working to conquer blood diseases.

The Society’s mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting the blood, bone marrow, and the immunologic, hemostatic and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.

Anticoagulant

Anticoagulants (antithrombics, fibrinolytic, and thrombolytics) are a class of drugs that work to prevent the coagulation(clotting) of blood. Such substances occur naturally in leeches and blood-sucking insects. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis equipment.

Antiphospholipid syndrome

Antiphospholipid syndrome or antiphospholipid antibody syndrome (APS or APLS), or often also Hughes syndrome, is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS provokes blood clots (thrombosis) in both arteries and veins as well as pregnancy-related complications such as miscarriage, stillbirth, preterm delivery, and severe preeclampsia.

The diagnostic criteria require one clinical event, i.e. thrombosis or pregnancy complication, and two positive blood testsspaced at least three months apart. These antibodies are: lupus anticoagulant, anti-cardiolipin and anti-β2-glycoprotein-I.

Antiphospholipid syndrome can be primary or secondary. Primary antiphospholipid syndrome occurs in the absence of any other related disease. Secondary antiphospholipid syndrome occurs with other autoimmune diseases, such assystemic lupus erythematosus (SLE). In rare cases, APS leads to rapid organ failure due to generalised thrombosis; this is termed “catastrophic antiphospholipid syndrome” (CAPS) and is associated with a high risk of death.

Antiphospholipid syndrome often requires treatment with anticoagulant medication such as heparin to reduce the risk of further episodes of thrombosis and improve the prognosis of pregnancy. Warfarin/Coumadin is not used during pregnancy because it can cross the placenta, unlike heparin, and is teratogenic.

Antiplatelets

An antiplatelet drug (antiaggregant) is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effective in the arterial circulation, where anticoagulants have little effect.

They are widely used in primary and secondary prevention of thrombotic cerebrovascular or cardiovascular disease.

Antithrombin

Antithrombin (AT) is a small protein molecule that inactivates several enzymes of the coagulation system. Antithrombin is a glycoprotein produced by the liver and consists of 432 amino acids. It contains three disulfide bonds and a total of four possible glycosylation sites. α-Antithrombin is the dominant form of antithrombin found in blood plasma and has an oligosaccharide occupying each of its four glycosylation sites. A single glycosylation site remains consistently un-occupied in the minor form of antithrombin, β-antithrombin. Its activity is increased manyfold by the anticoagulant drug heparin, which enhances the binding of antithrombin to factor IIand factor X.

Antithrombin III deficiency

Antithrombin III deficiency (abbreviated ATIII deficiency) is a deficiency of antithrombin III. It is a rare hereditary disorder that generally comes to light when a patient suffers recurrent venous thrombosis and pulmonary embolism, and repetitive intrauterine fetal death (IUFD). Inheritance is usually autosomal dominant, though a few recessive cases have been noted.

The patients are treated with anticoagulants or, more rarely, with antithrombin concentrate.

In kidney failure, especially nephrotic syndrome, antithrombin is lost in the urine, leading to a higher activity of Factor II and Factor X and in increased tendency to thrombosis.

Antithrombotics

An antithrombotic agent is a drug that reduces the formation of blood clots (thrombi). Antithrombotics can be used therapeutically for prevention (primary prevention, secondary prevention) or treatment of a dangerous blood clot (acute thrombus).

Argatroban

Argatroban is an anticoagulant that is a small molecule direct thrombin inhibitor. Argatroban was licensed by the Food and Drug Administration (FDA) for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT). It was also approved for use during percutaneous coronary interventions in patients who have HIT or are at risk for developing it.

Arterial thrombosis

Arterial thrombosis is the formation of a thrombus within an artery. In most cases, arterial thrombosis follows rupture of atheroma, and is therefore referred to asatherothrombosis.

Another common cause of arterial occlusion is atrial fibrillation, which causes a blood stasis within the atria with easy thrombus formation. In addition, it is well known that the direct current cardioversion of atrial fibrillation carries a great risk of thromboembolism, especially if persisting more than 48 hours. Thromboembolism strikes approximately 5% of cases not receiving anticoagulant therapy. When cardiac rhythm is restored clots are pushed out from atria to ventricles and from these to the aorta and its branches.

Arterial thrombosis can embolize and is a major cause of arterial embolism, potentially causing infarction of almost any organ in the body.

Artery

Arteries (from Greek ἀρτηρία (artēria), meaning “windpipe, artery”) are blood vessels that carry blood away from the heart. While most arteries carry oxygenated blood, there are two exceptions to this, the pulmonary and the umbilical arteries. The effective arterial blood volume is that extracellular fluid which fills the arterial system.

The circulatory system is vital for sustaining life. Its normal functioning is responsible for the delivery of oxygen andnutrients to all cells, as well as the removal of carbon dioxide and waste products, the maintenance of optimum pH, and the circulation of proteins and cells of the immune system. In developed countries, the two leading causes of death,myocardial infarction (heart attack), and stroke, may each directly result from an arterial system that has been slowly and progressively compromised by years of deterioration.

Aspirin

Aspirin (BAN, USAN), also known as acetylsalicylic acid [ASA], is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. Aspirin also has an antiplatelet effect by inhibiting the production of thromboxane, which under normal circumstances binds platelet molecules together to create a patch over damaged walls of blood vessels. Because the platelet patch can become too large and also block blood flow, locally and downstream, aspirin is also used long-term, at low doses, to help prevent heart attacks, strokes, and blood clot formation in people at high risk of developing blood clots. Also, low doses of aspirin may be given immediately after a heart attack to reduce the risk of another heart attack or of the death of cardiac tissue. Aspirin may be effective at preventing certain types of cancer, particularly colorectal cancer.

The main side effects of aspirin are gastrointestinal ulcers, stomach bleeding, and ringing in the ears, especially with higher doses. In children and adolescents, aspirin is not recommended for flu-like symptoms or viral illnesses, because of the risk of Reye’s syndrome.

Aspirin is part of a group of medications called nonsteroidal anti-inflammatory drugs (NSAIDs), but differs from most other NSAIDs in the mechanism of action. Though it and others with similar structure, called the salicylates, have similar effects (antipyretic, anti-inflammatory, analgesic) to the other NSAIDs and inhibit the same enzyme cyclooxygenase (COX), aspirin does so in an irreversible manner and, unlike others, affects more the COX-1 variant than the COX-2 variant of the enzyme.

Bernard–Soulier syndrome

Bernard–Soulier syndrome (BSS), also called hemorrhagiparous thrombocytic dystrophy, is a rare autosomal recessive coagulopathy (bleeding disorder) that causes a deficiency of glycoprotein Ib (GpIb), the receptor for von Willebrand factor, an important glycoprotein involved in hemostasis.

The incidence of BSS is estimated to be less than 1 case per million persons, based on cases reported from Europe, North America, and Japan.

BSS is a giant platelet disorder, meaning that it is characterized by abnormally large platelets.

Bleeding

Bleeding, technically known as hemorrhaging or haemorrhaging (see American and British spelling differences), is blood escaping from the circulatory system. Bleeding can occur internally, where blood leaks from blood vessels inside the body, or externally, either through a natural opening such as the mouth, nose, ear, urethra, vagina or anus, or through a break in the skin. Hypovolemia is a massive decrease in blood volume, and death by excessive loss of blood is referred to as exsanguination. Typically, a healthy person can endure a loss of 10–15% of the total blood volume without seriousmedical difficulties (by comparison, blood donation typically takes 8–10% of the donor’s blood volume). The stopping or controlling of bleeding is called hemostasis and is an important part of both first aid and surgery.

Blood

Blood is a bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells. When it reaches the lungs, gas exchange occurs when carbon dioxide is diffused out of the blood into the pulmonary alveoli and oxygen is diffused into the blood. This oxygenated blood is pumped to the left hand side of the heart in the pulmonary vein and enters the left atrium. From here it passes through the mitral valve, through the ventricle and taken all around the body by the aorta. Blood containsantibodies, nutrients, oxygen and much more to help the body work.

In vertebrates, it is composed of blood cells suspended in blood plasma. Plasma, which constitutes 55% of blood fluid, is mostly water (92% by volume), and contains dissipated proteins, glucose, mineral ions, hormones, carbon dioxide (plasma being the main medium for excretory product transportation), and blood cells themselves. Albumin is the main protein in plasma, and it functions to regulate the colloidal osmotic pressure of blood. The blood cells are mainly red blood cells (also called RBCs or erythrocytes) and white blood cells, including leukocytes and platelets. The most abundant cells in vertebrate blood are red blood cells. These contain hemoglobin, an iron-containing protein, which facilitates oxygen transport by reversibly binding to this respiratory gas and greatly increasing its solubility in blood. In contrast, carbon dioxide is almost entirely transported extracellularly dissolved in plasma as bicarbonate ion.

Vertebrate blood is bright red when its hemoglobin is oxygenated and dark red when it is deoxygenated. Some animals, such as crustaceans and mollusks, use hemocyanin to carry oxygen, instead of hemoglobin. Insects and some mollusks use a fluid called hemolymph instead of blood, the difference being that hemolymph is not contained in a closedcirculatory system. In most insects, this “blood” does not contain oxygen-carrying molecules such as hemoglobin because their bodies are small enough for their tracheal system to suffice for supplying oxygen.

Jawed vertebrates have an adaptive immune system, based largely on white blood cells. White blood cells help to resist infections and parasites. Platelets are important in the clotting of blood. Arthropods, using hemolymph, have hemocytesas part of their immune system.

Blood is circulated around the body through blood vessels by the pumping action of the heart. In animals with lungs,arterial blood carries oxygen from inhaled air to the tissues of the body, and venous blood carries carbon dioxide, a waste product of metabolism produced by cells, from the tissues to the lungs to be exhaled.

Medical terms related to blood often begin with hemo- or hemato- (also spelled haemo- and haemato-) from the Greekword αἷμα (haima) for “blood”. In terms of anatomy and histology, blood is considered a specialized form of connective tissue, given its origin in the bones and the presence of potential molecular fibers in the form of fibrinogen.

Blood cell

A blood cell, also called a hematocyte, is a cell produced by hematopoiesis and normally found in blood. In mammals, these fall into three general categories:

  • Red blood cells – Erythrocytes
  • White blood cells – Leukocytes
  • Platelets – Thrombocytes.

Together, these three kinds of blood cells add up to a total 45% of the blood tissue by volume, with the remaining 55% of the volume composed of plasma, the liquid component of blood. This volume percentage (e.g., 45%) of cells to total volume is called hematocrit, determined by centrifuge or flow cytometry. Hemoglobin (the main component of red blood cells) is an iron-containing protein that facilitates transportation of oxygen from the lungs to tissues and carbon dioxide from tissues to the lungs.

Blood plasma

Blood plasma is the pale yellow liquid component of blood that normally holds the blood cells in whole blood in suspension; this makes plasma the extracellular matrix of blood cells. It makes up about 55% of the body’s total blood volume. It is the intravascular fluid part of extracellular fluid (all body fluid outside of cells). It is mostly water (up to 95% by volume), and contains dissolved proteins (6–8%) (i.e.—serum albumins, globulins, and fibrinogen), glucose, clotting factors, electrolytes (Na+, Ca2+, Mg2+, HCO3−, Cl−, etc.), hormones, and carbon dioxide (plasma being the main medium for excretory product transportation). Plasma also serves as the protein reserve of the human body. It plays a vital role in an intravascular osmotic effect that keeps electrolytes in balanced form and protects the body from infection and other blood disorders.

Blood plasma is prepared by spinning a tube of fresh blood containing an anticoagulant in a centrifuge until the blood cells fall to the bottom of the tube. The blood plasma is then poured or drawn off. Blood plasma has a density of approximately 1025 kg/m3, or 1.025 g/ml.

Blood serum is blood plasma without clotting factors; in other words, “pure” blood. Plasmapheresis is a medical therapy that involves blood plasma extraction, treatment, and reintegration.

Blood vessel

Blood vessels are the part of the circulatory system that transports blood throughout the human body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and the tissues; and the veins, which carry blood from the capillaries back toward the heart. The word vascular, meaning relating to the blood vessels, is derived from the Latin vas, meaning vessel. Avascular refers to being without (blood) vessels.

Blood vessels

The blood vessels are the part of the circulatory system that transports blood throughout the human body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and the tissues; and the veins, which carry blood from the capillaries back toward the heart. The word vascular, meaning relating to the blood vessels, is derived from the Latin vas, meaning vessel. Avascular refers to being without (blood) vessels.

C1-inhibitor

C1-inhibitor (C1-inh, C1 esterase inhibitor) is a protease inhibitor belonging to the serpin superfamily. Its main function is the inhibition of the complement system to prevent spontaneous activation. C1-inhibitor is an acute-phase protein that circulates in blood at levels of around 0.25 g/L. The levels rise ~2-fold during inflammation. C1-inhibitor irreversibly binds to and inactivates C1r and C1s proteases in the C1 complex of classical pathway of complement. MASP-1 and MASP-2 proteases in MBL complexes of the lectin pathway are also inactivated. This way, C1-inhibitor prevents the proteolytic cleavage of later complement components C4 and C2 by C1 and MBL. Although named after its complement inhibitory activity, C1-inhibitor also inhibits proteases of the fibrinolytic, clotting, and kinin pathways. Note that C1-inhibitor is the most important physiological inhibitor of plasma kallikrein, fXIa, and fXIIa.

Capillary

Capillaries are the smallest of a body’s blood vessels (and lymph vessels) that make up the microcirculation. Their endothelial linings are only one cell layer thick. These microvessels, measuring around 5 to 10 micrometres (µm) in diameter, connect arterioles and venules, and they help to enable the exchange ofwater, oxygen, carbon dioxide, and many other nutrients and waste chemical substances between blood and thetissues surrounding them. Lymph capillaries interconnect with larger lymph vessels to drain lymph collected in the microcirculation.

During early embryonic development new capillaries are formed through vasculogenesis, the process of blood vesselformation that occurs through a de novo production of endothelial cells followed by their forming into vascular tubes. The term angiogenesis denotes the formation of new capillaries from pre-existing blood vessels and already present endothelium which divides.

Cardiology

Cardiology (from Greek καρδίᾱ kardiā, “heart” and -λογία -logia, “study”) is a branch of medicine dealing with disorders of the heart be it human or animal. The field includes medical diagnosis and treatment of congenital heart defects, coronary artery disease, heart failure, valvular heart disease and electrophysiology. Physicians who specialize in this field of medicine are called cardiologists, a specialty of internal medicine. Pediatric cardiologists are pediatricians who specialize in cardiology. Physicians who specialize in cardiac surgery are called cardiothoracic surgeons or cardiac surgeons, a specialty of general surgery.

Cardiovascular disease

Cardiovascular disease is a class of diseases that involve the heart, the blood vessels (arteries, capillaries, and veins) or both.

Cardiovascular disease refers to any disease that affects the cardiovascular system, principally cardiac disease, vascular diseases of the brain and kidney, and peripheral arterial disease. The causes of cardiovascular disease are diverse butatherosclerosis and hypertension are the most common. In addition, with aging come a number of physiological and morphological changes that alter cardiovascular function and lead to increased risk of cardiovascular disease, even in healthy asymptomatic individuals.

Cardiovascular diseases are the leading cause of deaths on the globally. According to a World Bank analysis, cardiovascular mortality has been declining in many high-income countries since 1970s. At the same time, cardiovascular deaths and disease have increased at a fast rate in low- and middle-income countries. Although cardiovascular disease usually affects older adults, the antecedents of cardiovascular disease, notably atherosclerosis, begin in early life, making primary prevention efforts necessary from childhood. Consequently, there is increased emphasis on preventing atherosclerosis by modifying risk factors, for example by healthy eating, exercise, and avoidance of smoking tobacco and excessive alcohol intake.

Coagulation

Coagulation (also known as clotting) is the process by which blood changes from a liquid to a gel. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism of coagulation involves activation, adhesion, and aggregation of platelets along with deposition and maturation of fibrin. Disorders of coagulation are disease states which can result in bleeding (hemorrhage or bruising) or obstructive clotting (thrombosis).

Coagulation is highly conserved throughout biology; in all mammals, coagulation involves both a cellular (platelet) and a protein (coagulation factor) component. The system in humans has been the most extensively researched and is the best understood.

Coagulation begins almost instantly after an injury to the blood vessel has damaged the endothelium lining the vessel. Exposure of blood to the space under the endothelium initiates two processes: changes in platelets, and the exposure of subendothilial tissue factor to plasma Factor VII, which ultimately leads to fibrinformation. Platelets immediately form a plug at the site of injury; this is called primary hemostasis. Secondary hemostasis occurs simultaneously: Additionalcoagulation factors or clotting factors beyond Factor VII (listed below) respond in a complex cascade to form fibrin strands, which strengthen the platelet plug.

Coagulation cascade

The coagulation cascade of secondary hemostasis has two initial pathways which lead to fibrin formation. These are the contact activation pathway (also known as the intrinsic pathway), and the tissue factor pathway (also known as the extrinsic pathway) which both lead to the same fundamental reactions that produce fibrin. It was previously thought that the two pathways of coagulation cascade were of equal importance, but it is now known that the primary pathway for the initiation of blood coagulation is the tissue factor pathway. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin. Coagulation factors are generally indicated by Roman numerals, with a lowercase a appended to indicate an active form.

The coagulation factors are generally serine proteases (enzymes), which act by cleaving downstream proteins. There are some exceptions. For example, FVIII and FV are glycoproteins, and Factor XIII is atransglutaminase. The coagulation factors circulate as inactive zymogens. The coagulation cascade is therefore classically divided into three pathways. The tissue factor and contact activation pathways both activate the “final common pathway” of factor X, thrombin and fibrin

Coagulopathy

Coagulopathy (also called clotting disorder and bleeding disorder) is a condition in which the blood’s ability to clot (coagulate) is impaired. This condition can cause prolonged or excessive bleeding, which may occur spontaneously or following an injury or medical and dental procedures.

Collagen

Collagen is the main structural protein of the various connective tissues in animals. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole-body protein content.

Collagen, in the form of elongated fibrils, is mostly found in fibrous tissues such as tendons, ligaments and skin. It is also abundant in corneas, cartilage, bones, blood vessels, the gut, intervertebral discs and the dentin in teeth. In muscle tissue, it serves as a major component of theendomysium. Collagen constitutes one to two percent of muscle tissue, and accounts for 6% of the weight of strong, tendinous muscles. Thefibroblast is the most common cell that creates collagen.

Gelatin, which is used in food and industry, is collagen that has been irreversibly hydrolyzed. Collagen also has many medical uses in treating complications of the bones and skin.

The name collagen comes from the Greek κολλα, kolla meaning “glue” and suffix -γέν, -gen denoting “producing.” This refers to the compound’s early use in the process of boiling the skin and sinews of horses and other animals to obtain glue.

Collagen Binding Assay

The Collagen Binding Assay (vWF:CBA) is a test procedure that measures the binding of vWF to collagen. Collagen binding of vWF is associated with the functionally more important HMW forms of vWF. Therefore, vWF:CBA may correlate more closely with vWF function and bleeding problems than vWF antigen assay (vWF: Ag) which measures total vWF multimers. When used in conjunction with the vWF: Ag assay, vWF:CBA can be used to differentiate between vWD type 1 and type 2 (A and B subtypes) by calculating a ratio of the two assay results (ratio = vWF:CBA/vWFAg).

Common Pathway

A part of the coagulation system where the intrinsic and extrinsic pathways converge to activate factor X. Coagulation factors X, V, II, and fibrinogen are part of this pathway; both the APTT and PT measure the integrity of this system.

Congenital afibrinogenemia

Congenital afibrinogenemia is a rare inherited blood disorder in which the blood does not clot normally due to a lack of or a malfunction involving fibrinogen, a protein necessary for coagulation.

Fibrinogen is also known as Factor I. Its lack is inherited in an autosomic recessive way. It can express itself with excessive bleeding since birth (bleeding from umbilical cord, easy bruising, bleeding after circumcision).

Coronary artery disease

Coronary artery disease (CAD) also known as atherosclerotic heart disease, atherosclerotic cardiovascular disease, coronary heart disease, or ischemic heart disease (IHD), is the most common type of heart disease and cause of heart attacks. The disease is caused by plaque building up along the inner walls of the arteries of the heart, which narrows the lumen of arteries and reduces blood flow to the heart.

While the symptoms and signs of coronary artery disease are noted in the advanced state of disease, most individuals with coronary artery disease show no evidence of disease for decades as the disease progresses before the first onset of symptoms, often a “sudden” heart attack, finally arises. Symptoms of stable ischaemic heart disease include angina(characteristic chest pain on exertion) and decreased exercise tolerance.

Unstable IHD presents itself as chest pain or other symptoms at rest, or rapidly worsening angina. The risk of artery narrowing increases with age, smoking, high blood cholesterol, diabetes, high blood pressure, and is more common in men and those who have close relatives with CAD. Other causes include coronary vasospasm, a spasm of the blood vessels of the heart, it is usually called Prinzmetal’s angina.

Diagnosis of IHD is with an electrocardiogram, blood tests (cardiac markers), cardiac stress testing or a coronary angiogram. Depending on the symptoms and risk, treatment may be with medication, percutaneous coronary intervention(angioplasty) or coronary artery bypass surgery (CABG).

It was as of 2012 the most common cause of death in the world, and a major cause of hospital admissions. There is limited evidence for population screening, but prevention (with a healthy diet and sometimes medication for diabetes, cholesterol and high blood pressure) is used both to prevent IHD and to decrease the risk of complications.

Cytokines

Cytokines (Greek:Cyto from Greek “κύτταρο” kyttaro “cell” + Kines from Greek “κίνηση” kinisi “movement”) are a broad and loose category of small proteins (~5–20kDa) that are important in cell signaling. They are released by cells and affect the behavior of other cells, and sometimes the releasing cell itself. Cytokines includechemokines, interferons, interleukins, lymphokines, tumour necrosis factor but generally not hormones or growth factors (despite some terminologic overlap). Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells,fibroblasts, and various stromal cells; a given cytokine may be produced by more than one type of cell.

They act through receptors, and are especially important in the immune system; cytokines modulate the balance between humoral and cell-based immune responses, and they regulate the maturation, growth, and responsiveness of particular cell populations. Some cytokines enhance or inhibit the action of other cytokines in complex ways.

They are different from hormones, which are also important cell signaling molecules, in that hormones circulate in much lower concentrations and hormones tend to be made by specific kinds of cells.

They are important in health and disease, specifically in host responses to infection, immune responses, inflammation, trauma, sepsis, cancer, and reproduction.

D-dimer

D-dimer (or D dimer) is a fibrin degradation product (or FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is so named because it contains two crosslinked D fragments of the fibrin protein.

D-dimer concentration may be determined by a blood test to help diagnose thrombosis. Since its introduction in the 1990s, it has become an important test performed in patients with suspected thrombotic disorders. While a negative result practically rules out thrombosis, a positive result can indicate thrombosis but does not rule out other potential causes. Its main use, therefore, is to exclude thromboembolic disease where the probability is low. In addition, it is used in the diagnosis of the blood disorder disseminated intravascular coagulation.

Dabigatran

Dabigatran is an oral anticoagulant from the class of the direct thrombin inhibitors. It is being studied for various clinical indications and in some cases it offers an alternative to warfarin as the preferred orally administered anticoagulant (“blood thinner”) since it does not require blood tests for international normalized ratio (INR) monitoring while offering similar results in terms of efficacy.

Deep Vein Thrombosis

Deep vein thrombosis, or deep venous thrombosis, (DVT) is the formation of a blood clot (thrombus) within a deep vein, predominantly in the legs. Non-specific signs may include pain, swelling, redness, warmness, and engorgedsuperficial veins. Pulmonary embolism, a potentially life-threatening complication, is caused by the detachment (embolization) of a clot that travels to the lungs. Together, DVT and pulmonary embolism constitute a single disease process known as venous thromboembolism. Post-thrombotic syndrome, another complication, significantly contributes to the health-care cost of DVT. Prevention options for at-risk individuals include early and frequent walking, calf exercises, anticoagulants, aspirin, graduated compression stockings, and intermittent pneumatic compression.

In 1856, German pathologist Rudolf Virchow postulated the interplay of three processes resulting in venous thrombosis, now known as Virchow’s triad: a decreased blood flow rate (venous stasis), increased tendency to clot (hypercoagulability), and changes to the blood vessel wall. DVT formation typically begins inside the valves of the calfveins, where the blood is relatively oxygen deprived, which activates certain biochemical pathways. Several medical conditions increase the risk for DVT, including cancer, trauma, and antiphospholipid syndrome. Other risk factors include older age, surgery, immobilization (as with bed rest, orthopedic casts, and sitting on long flights), combined oral contraceptives, pregnancy, the postnatal period, and genetic factors such as a non-O blood type. The frequency of occurrence (incidence) increases dramatically from childhood to old age; in adulthood, about 1 in 1000 adults develops DVT annually.

Individuals suspected of having DVT may be assessed using a clinical prediction rule such as the Wells score. A D-dimertest may also be used to assist with excluding the diagnosis (because of its high sensitivity) or to signal a need for further testing. Diagnosis is most commonly done with ultrasound of the suspected veins. Anticoagulation is the standard treatment; typical medications include a low-molecular-weight heparin and a vitamin K antagonist. Wearing graduated compression stockings appears to reduce the risk of post-thrombotic syndrome.

Dicoumarol

Dicoumarol is a naturally occurring anticoagulant that functions as a functional vitamin K depleter (similar to warfarin, a drug that dicoumarol inspired). It is also used in biochemical experiments as an inhibitor of reductases.

Dicoumarol is a natural chemical substance of combined plant and fungal origin. It is a derivative of coumarin, a substance that does not itself affect coagulation, but which is transformed into active dicoumarol. Dicoumarol does affect coagulation.

Direct thrombin inhibitors

Direct thrombin inhibitors (DTIs) are a class of medication that act as anticoagulants (delaying blood clotting) by directly inhibiting the enzyme thrombin (factor II). Some are in clinical use, while others are undergoing clinical development. Several members of the class are expected to replace heparin (and derivatives) and warfarin in various clinical scenarios.

Disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC), also known as disseminated intravascular coagulopathy or less commonly as consumptive coagulopathy, is a pathological process characterized by the widespread activation of the clotting cascade that results in the formation of blood clots in the small blood vessels throughout the body. This leads to compromise of tissue blood flow and can ultimately lead to multiple organ damage. In addition, as the coagulation process consumes clotting factors and platelets, normal clotting is disrupted and severe bleeding can occur from various sites. DIC does not occur by itself but only as a complicating factor from another underlying condition, usually in those with a critical illness. The combination of widespread tissue ischemia and simultaneous bleeding carry an increased risk of death in addition to that posed by the underlying disease. DIC can be overt and severe in some cases, but milder and insidious in others. The diagnosis of DIC depends on the findings of characteristic laboratory tests and clinical background. Treatment is mainly geared towards the underlying condition.

Embolism

In medicine, an embolism is the lodging of an embolus, which may be a blood clot, fat globule, gas bubble, in the bloodstream. This can cause a blockage in a blood vessel. Such a blockage (vascular occlusion) may affect a part of the body distanced from the actual site of the embolism. This is in contrast to a thrombus, which causes a blockage at the site of origin.

Endotheilium

The endothelium is the thin layer of simple squamous cells that lines the interior surface of blood vessels and lymphatic vessels, forming an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. The cells that form the endothelium are called endothelial cells. Endothelial cells in direct contact with blood are called vascular endothelial cells, whereas those in direct contact with lymph are known as lymphatic endothelial cells.

Vascular endothelial cells line the entire circulatory system, from the heart to the smallest capillaries. These cells have unique functions in vascular biology. These functions include fluid filtration, such as in the glomeruli of the kidney, blood vessel tone, hemostasis, neutrophil recruitment, and hormone trafficking. Endothelium of the interior surfaces of the heart chambers is called endocardium.

Enzyme

Enzymes are macromolecular biological catalysts. They are responsible for thousands of metabolic processes that sustain life. The study of enzymes is called enzymology. Enzymes are highly selective catalysts, greatly accelerating both the rate and the specificity of metabolic chemical reactions: from the digestion of food to the synthesis of DNA. Most enzymes are proteins, although a few are catalytic RNA molecules, such as theribosome. Enzymes fold into a specific three-dimensional structure, and may use organic (e.g. biotin) and inorganic (e.g. magnesium ion) cofactors to aid catalysis.

Enzymes work by converting starting molecules (substrates) into different molecules (products). Almost all chemical reactions in a biological cell need enzymes to happen at rates high enough to sustain life. Because enzymes are selective for their substrates, they speed up only a few reactions from among many possibilities. The set of enzymes made in a cell determines which metabolic pathways occur in that cell.

Like all catalysts, enzymes increase the rate of a reaction by lowering its activation energy. Most enzyme reaction rates are millions of times faster than the un-catalyzed reactions, and some are so fast that they are limited only by how fast substrates can diffuse to the enzyme. As with all catalysts, enzymes are not consumed by the reactions they catalyze, nor do they alter the equilibrium of these reactions. However, enzymes do differ from most other catalysts in that they are highly specific for their substrates. Enzymes are known to catalyze about 4,000 biochemical reactions.

Enzyme activity can be affected by other molecules: decreased by inhibitors or increased by activators. Manydrugs and poisons are enzyme inhibitors. Activity is also affected by temperature, pressure, chemical environment (e.g., pH), and the concentration of substrate. Some enzymes are used commercially, for example, in the synthesis of antibiotics. In addition, some household products use enzymes to speed up biochemical reactions (e.g., enzymes in biological washing powders break down protein or fat stains on clothes; enzymes in meat tenderizers break down proteins into smaller molecules, making the meat easier to chew).

Extrinsic Pathway

The main role of the tissue factor pathway is to generate a “thrombin burst”, a process by which thrombin, the most important constituent of the coagulation cascade in terms of its feedback activation roles, is released very rapidly. FVIIa circulates in a higher amount than any other activated coagulation factor. The process includes the following steps:

  • Following damage to the blood vessel, FVII leaves the circulation and comes into contact with tissue factor (TF) expressed on tissue-factor-bearing cells (stromal fibroblasts and leukocytes), forming an activated complex (TF-FVIIa).
  • TF-FVIIa activates FIX and FX.
  • FVII is itself activated by thrombin, FXIa, FXII and FXa.
  • The activation of FX (to form FXa) by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor (TFPI).
  • FXa and its co-factor FVa form the prothrombinase complex, which activates prothrombin to thrombin.
  • Thrombin then activates other components of the coagulation cascade, including FV and FVIII (which activates FXI, which, in turn, activates FIX), and activates and releases FVIII from being bound to vWF.
  • FVIIIa is the co-factor of FIXa, and together they form the “tenase” complex, which activates FX; and so the cycle continues. (“Tenase” is a contraction of “ten” and the suffix “-ase” used for enzymes.)

Factor IX

Factor IX (or Christmas factor) (EC 3.4.21.22) is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to hemophilia.

Factor V

Factor V (pronounced factor five) is a protein of the coagulation system, rarely referred to as proaccelerin orlabile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor. Deficiency leads to predisposition for hemorrhage, while some mutations (most notably factor V Leiden) predispose for thrombosis.

Factor V Leiden

Factor V Leiden thrombophilia is a genetically inherited disorder of blood clotting. Factor V Leiden is a variant (mutated form) of human factor V that causes an increase in blood clotting (hypercoagulability). In this disorder, the Leiden variant (form) of factor V cannot be inactivated (switched off) by activated protein C, and so clotting is encouraged. Factor V Leiden is the most common hereditary hypercoagulability (prone to clotting) disorder amongst European Caucasians.

Factor VII

Factor VII (EC 3.4.21.21, blood-coagulation factor VIIa, activated blood coagulation factor VII, formerly known as proconvertin) is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class.

Factor VIII

Factor VIII (FVIII) is an essential blood-clotting protein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the F8 gene. Defects in this gene results in hemophilia A, a recessive X-linked coagulation disorder. Factor VIII is produced in liver sinusoidal cells and endothelial cells outside of the liver throughout the body. This protein circulates in the bloodstream in an inactive form, bound to another molecule called von Willebrand factor, until an injury that damages blood vessels occurs. In response to injury, coagulation factor VIII is activated and separates from von Willebrand factor. The active protein (sometimes written as coagulation factor VIIIa) interacts with another coagulation factor called factor IX. This interaction sets off a chain of additional chemical reactions that form a blood clot.

Factor VIII participates in blood coagulation; it is a cofactor for factor IXa which, in the presence of Ca2+ andphospholipids forms a complex that converts factor X to the activated form Xa. The factor VIII gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity.

People with high levels of factor VIII are at increased risk for deep vein thrombosis and pulmonary embolism. Copper is a required cofactor for factor VIII and copper deficiency is known to increase levels of factor VIII.

Factor X

Factor X, also known by the eponym Stuart–Prower factor or as prothrombinase, thrombokinase orthromboplastin, is an enzyme (EC 3.4.21.6) of the coagulation cascade. It is a serine endopeptidase (protease group S1).

Factor Xa

The active site of factor Xa is divided into four sub pockets as S1, S2, S3 and S4. The S1 subpocket determines the major component of selectivity and binding. The S2 sub-pocket is small, shallow and not well defined. It merges with the S4 subpocket. The S3 sub-pocket is located on the rim of the S1 pocket and is quite exposed to solvent. The S4 sub-pocket has three ligand binding domains: the “hydrophobic box”, the “cationic hole” and the water site. Factor Xa inhibitors generally bind in an L-shaped conformation, where one group of the ligand occupies the anionic S1 pocket lined by residues Asp189, Ser195, and Tyr228, and another group of the ligand occupies the aromatic S4 pocket lined by residues Tyr99, Phe174, and Trp215. Typically, a fairly rigid linker group bridges these two interaction sites.

Factor XI

Factor XI or plasma thromboplastin antecedent is the zymogen form of factor XIa, one of the enzymes of thecoagulation cascade. Like many other coagulation factors, it is a serine protease. In humans, Factor XI is encoded by the F11 gene.

 

Factor XII

Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme (EC 3.4.21.38) of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the F12 gene.

Fibrin

Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen which causes the latter to polymerize. The polymerized fibrin together with platelets forms ahemostatic plug or clot over a wound site.

When the lining of a blood vessel is broken, platelets are attracted forming a platelet plug. These platelets express thrombin receptors on their surfaces that bind serum thrombin molecules which in turn convert soluble fibrinogen in the serum into fibrin at the wound site. Fibrin forms long strands of tough insoluble protein that are laid down and are bound to the platelets.Factor XIII completes the cross-linking of fibrin so that it hardens and contracts. The cross-linked fibrin forms a mesh overlying the platelet plug that completes the clot.

Fibrin degradation product

Fibrin degradation product (FDPs), also known as fibrin split products, are components of the blood produced by clot degeneration. Clotting, also called coagulation, at the wound site produces a mass of fibrin threads called a net that remains in place until the cut is healed. As a cut heals, the clotting slows down. Eventually the clot is broken down and dissolved by plasmin. When the clot and fibrin net dissolve, fragments of protein are released into the body. These fragments are fibrin degradation products or FDPs. If your body is unable to dissolve a clot, you may have abnormal levels of FDPs. The most notable subtype of fibrin degradation products is D-dimer.

The levels of these FDPs rise after any thrombotic event.

Fibrin and fibrinogen degradation product (FDP) testing is commonly used to diagnose disseminated intravascular coagulation.

Fibrinogen

Fibrinogen (factor I) is a glycoprotein in vertebrates that helps in the formation of blood clots. It consists of a linear array of three nodules held together by a very thin thread which is estimated to have a diameter between 8 and 15 A. The two end nodules are alike but the center one is slightly smaller. Measurements of shadow lengths indicate that nodule diameters are in the range 50 to 70 A. The length of the dried molecule is 475 ± 25 A.

The fibrinogen molecule is a soluble, large, and complex glycoprotein, 340 kDa plasma glycoprotein, that is converted bythrombin into fibrin during blood clot formation. It has a rod-like shape with dimensions of 9 × 47.5 × 6 nm and it shows a negative net charge at physiological pH (IP at pH 5.2). Fibrinogen is synthesized in the liver by the hepatocytes. The concentration of fibrinogen in the blood plasma is 200–400 mg/dL (normally measured using the Clauss method).

During normal blood coagulation, a coagulation cascade activates the zymogen prothrombin by converting it into theserine protease thrombin. Thrombin then converts the soluble fibrinogen into insoluble fibrin strands. These strands are then cross-linked by factor XIII to form a blood clot. FXIIa stabilizes fibrin further by incorporation of the fibrinolysisinhibitors alpha-2-antiplasmin and TAFI (thrombin activatable fibrinolysis inhibitor, procarboxypeptidase B), and binding to several adhesive proteins of various cells. Both the activation of factor XIII by thrombin and plasminogen activator (t-PA) are catalyzed by fibrin. Fibrin specifically binds the activated coagulation factors factor Xa and thrombin and entraps them in the network of fibers, thus functioning as a temporary inhibitor of these enzymes, which stay active and can be released during fibrinolysis. Research from 2011 has shown that fibrin plays a key role in the inflammatory response and development of rheumatoid arthritis.

Fibrinolysis

Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. This process has two types: primary fibrinolysis and secondary fibrinolysis. The primary type is a normal body process, whereas secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other cause.

In fibrinolysis, a fibrin clot, the product of coagulation, is broken down. Its main enzyme plasmin cuts the fibrin mesh at various places, leading to the production of circulating fragments that are cleared by other proteases or by the kidney and liver.

Fibronectin

Fibronectin is a high-molecular weight (~440kDa) glycoprotein of the extracellular matrix that binds tomembrane-spanning receptor proteins called integrins. Similar to integrins, fibronectin binds extracellular matrix components such as collagen, fibrin, and heparan sulfate proteoglycans (e.g. syndecans).

Fibronectin exists as a protein dimer, consisting of two nearly identical monomers linked by a pair of disulfide bonds. The fibronectin protein is produced from a single gene, but alternative splicing of its pre-mRNA leads to the creation of several isoforms.

Two types of fibronectin are present in vertebrates:

  • soluble plasma fibronectin (formerly called “cold-insoluble globulin”, or CIg) is a major protein component ofblood plasma (300 μg/ml) and is produced in the liver by hepatocytes.
  • insoluble cellular fibronectin is a major component of the extracellular matrix. It is secreted by various cells, primarily fibroblasts, as a soluble protein dimer and is then assembled into an insoluble matrix in a complex cell-mediated process.

Fibronectin plays a major role in cell adhesion, growth, migration, and differentiation, and it is important for processes such as wound healing and embryonic development. Altered fibronectin expression, degradation, and organization has been associated with a number of pathologies, including cancer and fibrosis.

Flow cytometry

In biotechnology, flow cytometry is a laser-based, biophysical technology employed in cell counting, cell sorting, biomarker detection and protein engineering, by suspending cells in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and chemical characteristics of up to thousands of particles per second.

Flow cytometry is routinely used in the diagnosis of health disorders, especially blood cancers, but has many other applications in basic research, clinical practice and clinical trials. A common variation is to physically sort particles based on their properties, so as to purify populations of interest.

Fondaparinux

Fondaparinux is an anticoagulant medication chemically related to low molecular weight heparins. Fondaparinux is given subcutaneously daily for the prevention of deep vein thrombosis in patients who have had orthopedic surgery as well as for the treatment of deep vein thrombosis and pulmonary embolism.

Fondaparinux is a synthetic pentasaccharide factor Xa inhibitor. Apart from the O-methyl group at the reducing end of the molecule, the identity and sequence of the five monomeric sugar units contained in fondaparinux is identical to a sequence of five monomeric sugar units that can be isolated after either chemical or enzymatic cleavage of the polymericglycosaminoglycans heparin and heparin sulfate (HS). Within heparin and heparin sulfate this monomeric sequence is thought to form the high-affinity binding site for the anti-coagulant factor antithrombin III (ATIII). Binding of heparin/HS to ATIII has been shown to increase the anti-coagulant activity of antithrombin III 1000 fold. In contrast to heparin, fondaparinux does not inhibit thrombin.

Glanzmann’s thrombasthenia

Glanzmann’s thrombasthenia is an abnormality of platelets. It is an extremely rare coagulopathy (bleeding disorder due to a blood abnormality), in which the platelets contain defective or low levels of glycoprotein IIb/IIIa (GpIIb/IIIa), which is a receptor for fibrinogen. As a result, no fibrinogen bridging of platelets to other platelets can occur, and the bleeding time is significantly prolonged.

Glycoprotein

Glycoproteins are proteins that contain oligosaccharide chains (glycans) covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known asglycosylation. Secreted extracellular proteins are often glycosylated. In proteins that have segments extending extracellularly, the extracellular segments are also glycosylated. Glycoproteins are often important integral membrane proteins, where they play a role in cell–cell interactions. Glycoproteins are also formed in the cytosol, but their functions and the pathways producing these modifications in this compartment are less well understood.

Glycoprotein Ib

Glycoprotein Ib (GPIb), also known as CD42, is a component of the GPIb-V-IX complex on platelets. The GPIb-V-IX complex binds von Willebrand factor, allowing platelet adhesion and platelet plug formation at sites of vascular injury.

It is deficient in the Bernard-Soulier syndrome. A gain-of-function mutation causes platelet-type von Willebrand’s disease.

Autoantibodies against Ib/IX can be produced in immune thrombocytopenic purpura.

Components include GP1BA and GP1BB.

It complexes with Glycoprotein IX.

Glycoprotein IIb/IIIa

Glycoprotein IIb/IIIa (GPIIb/IIIa, also known as integrin αIIbβ3) is an integrin complex found on platelets. It is a receptor for fibrinogen and von Willebrand factor and aids in platelet activation. The complex is formed via calcium-dependent association of gpIIb and gpIIIa, a required step in normal platelet aggregation and endothelial adherence. Platelet activation by ADP (blocked by clopidogrel) leads to a conformational change in platelet gpIIb/IIIa receptors that induces binding to fibrinogen. The gpIIb/IIIa receptor is a target of several drugs including abciximab, eptifibatide, tirofiban.

Heart

The heart is a muscular organ in both humans and other animals, which pumps blood through the blood vessels of the circulatory system. Blood provides the body with oxygen and nutrients, and also assists in the removal of metabolic wastes. The heart is located in the middle compartment of the mediastinum in the chest.

In humans, other mammals and birds the heart is divided into four chambers: upper left and right atria; and lower left and right ventricles. Commonly the right atrium and ventricle are referred together as the right heart and their left counterparts as the left heart. Fish in contrast have two chambers, an atrium and a ventricle, while reptiles have three chambers. In a healthy heart blood flows one way through the heart due to heart valves, which prevent backflow. The heart is enclosed in a protective sac, the pericardium, which also contains a small amount of fluid. The wall of the heart is made up of three layers: epicardium; myocardium; and endocardium.

The heart pumps blood through both circulatory systems. Blood low in oxygen from the systemic circulation enters the right atrium from the superior and inferior vena cavae and passes to the right ventricle. From here it is pumped into thepulmonary circulation, through the lungs where it receives oxygen and gives off carbon dioxide. Oxygenated blood then returns to the left atrium, passes through the left ventricle and is pumped out through the aorta to the systemic circulation−where the oxygen is used and metabolized to carbon dioxide. In addition the blood carries nutrients from the liver and gastrointestinal tract to various organs of the body, while transporting waste to the liver and kidneys. Normally with each heartbeat, the right ventricle pumps the same amount of blood into the lungs as the left ventricle pumps out into the body. Veins transport blood to the heart, while arteries transport blood away from the heart. Veins normally have lower pressures than arteries. The heart contracts at a rate of around 72 beats per minute, at rest. Exercise temporarily increases this rate, but lowers resting heart rate in the long term, and is good for heart health.

Cardiovascular diseases (CVD) were the most common cause of death globally in 2008. CVD accounted for 30% of death cases during this year alone. Of these deaths more than three quarters were due to coronary artery disease and stroke. Risk factors include: smoking, being overweight, not enough exercise, high cholesterol, high blood pressure, and poorly controlled diabetes among others. Diagnosis of CVD is often done by listening to the heart-sounds with astethoscope, ECG or by ultrasound. Diseases of the heart are primarily treated by cardiologists, although many specialties of medicine may be involved.

Hematocrit

The hematocrit (Ht or HCT, British English spelling haematocrit), also known as packed cell volume (PCV) orerythrocyte volume fraction (EVF), is the volume percentage (%) of red blood cells in blood. It is normally 45% for men and 40% for women. It is considered an integral part of a person’s complete blood count results, along with hemoglobinconcentration, white blood cell count, and platelet count. Because the purpose of red blood cells is to transfer oxygen from the lungs to body tissues, a blood sample’s hematocrit—the red blood cell volume percentage—can become a point of reference of its capability of delivering oxygen. Additionally, the measure of a subject’s blood sample’s hematocrit levels may expose possible diseases in the subject. Anemia refers to an abnormally low hematocrit, as opposed topolycythemia, which refers to an abnormally high hematocrit. For a condition such as anemia that goes unnoticed, one way it can be diagnosed is by measuring the hematocrit levels in the blood. Both are potentially life-threatening disorders.

Hematology

Hematology, also spelled haematology (from the Greek αἷμα, haima “blood” and -λoγία), is the branch of medicine concerned with the study, diagnosis, treatment, and prevention of diseases related to the blood. Hematology includes the study of etiology. It involves treating diseases that affect the production of blood and its components, such as blood cells, hemoglobin, blood proteins, and the mechanism of coagulation. The laboratory work that goes into the study of blood is frequently performed by a medical technologist. Hematologists also conduct studies in oncology—the medical treatment of cancer.

Physicians specialized in hematology are known as hematologists or haematologists. Their routine work mainly includes the care and treatment of patients with hematological diseases, although some may also work at the hematology laboratory viewing blood films and bone marrow slides under the microscope, interpreting various hematological test results and blood clotting test results. In some institutions, hematologists also manage the hematology laboratory. Physicians who work in hematology laboratories, and most commonly manage them, are pathologists specialized in the diagnosis of hematological diseases, referred to as hematopathologists or haematopathologists. Hematologists and hematopathologists generally work in conjunction to formulate a diagnosis and deliver the most appropriate therapy if needed. Hematology is a distinct subspecialty of internal medicine, separate from but overlapping with the subspecialty of medical oncology. Hematologists may specialize further or have special interests, for example, in:

  • treating bleeding disorders such as hemophilia and idiopathic thrombocytopenic purpura
  • treating hematological malignacies such as lymphoma and leukemia
  • treating hemoglobinopathies
  • in the science of blood transfusion and the work of a blood bank
  • in bone marrow and stem cell transplantation

Hemoglobin

Hemoglobin (also spelled haemoglobin and abbreviated Hb or Hgb), is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates (with the exception of the fish family Channichthyidae) as well as the tissues of some invertebrates. Hemoglobin in the blood carries oxygen from the respiratory organs (lungs or gills) to the rest of the body (i.e. the tissues). There it releases the oxygen to permitaerobic respiration to provide energy to power the functions of the organism in the process called metabolism.

In mammals, the protein makes up about 96% of the red blood cells’ dry content (by weight), and around 35% of the total content (including water). Hemoglobin has an oxygen-binding capacity of 1.34 mL O2 per gram, which increases the total blood oxygen capacity seventy-fold compared to dissolved oxygen in blood. The mammalian hemoglobin molecule can bind (carry) up to four oxygen molecules.

Hemoglobin is involved in the transport of other gases: It carries some of the body’s respiratory carbon dioxide (about 10% of the total) as carbaminohemoglobin, in which CO2 is bound to the globin protein. The molecule also carries the important regulatory molecule nitric oxide bound to a globin protein thiol group, releasing it at the same time as oxygen.

Hemoglobin is also found outside red blood cells and their progenitor lines. Other cells that contain hemoglobin include the A9 dopaminergic neurons in the substantia nigra, macrophages, alveolar cells, and mesangial cells in the kidney. In these tissues, hemoglobin has a non-oxygen-carrying function as an antioxidant and a regulator of iron metabolism.

Hemoglobin and hemoglobin-like molecules are also found in many invertebrates, fungi, and plants. In these organisms, hemoglobins may carry oxygen, or they may act to transport and regulate other things such as carbon dioxide, nitric oxide, hydrogen sulfide and sulfide. A variant of the molecule, called leghemoglobin, is used to scavenge oxygen away from anaerobic systems, such as the nitrogen-fixing nodules of leguminous plants, before the oxygen can poison the system.

Hemophilia

Haemophilia (also spelled hemophilia in North America) is a group of hereditary genetic disorders that impair the body’s ability to control blood clotting, which is used to stop bleeding when a blood vessel is broken.

Haemophilia A (clotting factor VIII deficiency) is the most common form of the disorder, present in about 1 in 5,000–10,000 male births.

Haemophilia B (factor IX deficiency) occurs in around 1 in about 20,000–34,000 male births.

Like most recessive sex-linked, X chromosome disorders, haemophilia is more likely to occur in males than females. This is because females have two X chromosomes while males have only one, so the defective gene is guaranteed to manifest in any male who carries it. Because females have two X chromosomes and haemophilia is rare, the chance of a female having two defective copies of the gene is very remote, so females are almost exclusively asymptomatic carriersof the disorder. Female carriers can inherit the defective gene from either their mother or father, or it may be a new mutation. Although it is not impossible for a female to have haemophilia, it is unusual: a female with haemophilia A or B would have to be the daughter of both a male haemophiliac and a female carrier, while the non-sex-linked haemophilia C due to coagulant factor XI deficiency, which can affect either sex, is more common in Jews of Ashkenazi (east European) descent but rare in other population groups.

Haemophilia patients have lower clotting factor level of blood plasma or impaired activity of the coagulation factors needed for a normal clotting process. Thus when a blood vessel is injured, a temporary scab does form, but the missing coagulation factors prevent fibrin formation, which is necessary to maintain the blood clot. A haemophiliac does not bleed more intensely than a person without it, but can bleed for a much longer time. In severe haemophiliacs even a minor injury can result in blood loss lasting days or weeks, or even never healing completely. In areas such as the brain or inside joints, this can be fatal or permanently debilitating.

Hemophilia A

Hemophilia A (also known as haemophilia A) is a genetic deficiency in clotting factor VIII, which causes increased bleeding and usually affects males. About 70% of the time it is inherited as an X-linked recessive trait, but around 30% of cases arise from spontaneous mutations.

Hemophilia A is inherited as an X-linked recessive trait, and thus occurs in males and in homozygous females. However, mild hemophilia A (and B) is known to occur in heterozygous females due to X-inactivation, so it is recommended that levels of factor VIII and IX be measured in all known or potential carriers prior to surgery and in the event of clinically significant bleeding.

5-10% of patients with hemophilia A are affected because they make a dysfunctional version of the factor VIII protein (qualitative deficiency), while the remainder are affected because they produced factor VIII in insufficient amounts (quantitative deficiency). Of those who have severe deficiency (defined as <1% activity of factor VIII), 45-50% have the same mutation, an inversion within the factor VIII gene that results in total elimination of protein production. However, since both forms of hemophilia can be caused by a variety of different mutations, initial diagnosis and classification is done by measurement of protein activity rather than by genetic tests, though genetic tests are recommended for testing of family members once a known case of hemophilia B is identified.

Hemophilia B

Haemophilia B (or hemophilia B) is a blood clotting disorder caused by a mutation of the factor IX gene, leading to a deficiency of factor IX. It is the second-most common form of hemophilia, rarer than hemophilia A. It is sometimes called Christmas disease, named after Stephen Christmas, the first patient described with this disease. In addition, the first report of its identification was published in the Christmas edition of the British Medical Journal.

The factor IX gene is located on the X chromosome (Xq27.1-q27.2). It is an X-linked recessive trait, which explains why, as in hemophilia A, usually only males are affected. One in 20,000–30,000 males are affected.

Hemostasis

Hemostasis or haemostasis is a process which causes bleeding to stop, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves blood changing from a liquid to a gel. Intact blood vessels are central to moderating blood’s tendency to clot. The endothelial cells of intact vessels prevent blood clotting with a heparin-like molecule andthrombomodulin and prevent platelet aggregation with nitric oxide and prostacyclin. When endothelial injury occurs, the endothelial cells stop secretion of coagulation and aggregation inhibitors and instead secrete von Willebrand factor which initiate the maintenance of hemostasis after injury. Hemostasis has three major steps: 1) vasoconstriction, 2) temporary blockage of a break by a platelet plug, and 3) blood coagulation, or formation of a fibrin clot. These processes seal the hole until tissues are repaired.

PROCESS

Hemostasis occurs when blood is present outside of the body or blood vessels. It is the instinctive response for the body to stop bleeding and loss of blood. During hemostasis three steps occur in a rapid sequence. Vascular spasm is the first response as the blood vessels constrict to allow less blood to be lost. In the second step, platelet plug formation, platelets stick together to form a temporary seal to cover the break in the vessel wall. The third and last step is called coagulation or blood clotting. Coagulation reinforces the platelet plug with fibrin threads that act as a “molecular glue”. Platelets are a large factor in the hemostatic process. They allow for the creation of the “platelet plug” that forms almost directly after a blood vessel has been ruptured. Within seconds of a blood vessel’s epithelial wall being disrupted platelets begin to adhere to the sub-endotheliumsurface. It takes approximately sixty seconds until the first fibrin strands begin to intersperse among the wound. After several minutes the platelet plug is completely formed by fibrin. Hemostasis is maintained in the body via three mechanisms:

1. Vascular spasm – Damaged blood vessels constrict. Vascular spasm is the blood vessels’ first response to injury. The damaged vessels will constrict (vasoconstrict) which reduces the amount of blood flow through the area and limits the amount of blood loss. This response is triggered by factors such as a direct injury to vascular smooth muscle, chemicals released by endothelial cells and platelets, and reflexes initiated by local pain receptors. The spasm response becomes more effective as the amount of damage is increased. Vascular spasm is much more effective in smaller blood vessels.

2. Platelet plug formation – Platelets adhere to damaged endothelium to form platelet plug (primary hemostasis) and then degranulate. This process is regulated through thromboregulation. Platelets play one of the biggest factors in the hemostatic process. Being the second step in the sequence they stick together (aggregation) to form a plug that temporarily seals the break in the vessel wall. As platelets adhere to the collagen fibers of a wound they become spiked and much stickier. They then release chemical messengers such as adenosine diphosphate (ADP), serotonin and thromboxane A2. These chemicals are released to cause more platelets to stick to the area and release their contents and enhance vascular spasms. As more chemicals are released more platelets stick and release their chemicals; creating a platelet plug and continuing the process in a positive feedback loop. Platelets alone are responsible for stopping the bleeding of unnoticed wear and tear of our skin on a daily basis.

The second stage of hemostasis involves platelets that move throughout the blood. When the platelets find an exposed area or an injury, they begin to form what is called a platelet plug. The platelet plug formation is activated by a glycoprotein called the Von Willebrand factor (vWF), which are found in the body’s blood plasma. When the platelets in the blood are activated, they then become very sticky so allowing them to stick to other platelets and adhere to the injured area.

There are a dozen proteins that travel along the blood plasma in an inactive state and are known as clotting factors. Once the platelet plug has been formed by the platelets, the clotting factors begin creating the Blood Clot. When this occurs the clotting factors begin to form a collagen fiber called fibrin. Fibrin mesh is then produced all around the platelet plug, which helps hold the fibrin in place. Once this begins, red and white blood cells become caught up in the fibrin mesh which causes the clot to become even stronger.

3. Blood coagulation – Clots form upon the conversion of fibrinogen to fibrin, and its addition to the platelet plug (secondary hemostasis). Coagulation: The third and final step in this rapid response reinforces the platelet plug. Coagulation or blood clotting uses fibrin threads that act as a glue for the sticky platelets. As the fibrin mesh begins to form the blood is also transformed from a liquid to a gel like substance through involvement of clotting factors and pro-coagulants. The coagulation process is useful in closing up and maintaining the platelet plug on larger wounds. The release of Prothrombin also plays an essential part in the coagulation process because it allows for the formation of a thrombus, or clot, to form. This final step forces blood cells and platelets to stay trapped in the wounded area. Though this is often a good step for wound healing, it has the ability to cause severe health problems if the thrombus becomes detached from the vessel wall and travels through the circulatory system; If it reaches the brain, heart or lungs it could lead to stroke, heart attack, or pulmonary embolism respectively. However, without this process the healing of a wound would not be possible.

DISORDERS

The body’s hemostasis system requires careful regulation in order to work properly. If the blood does not clot sufficiently, it may be due to bleeding disorders such ashemophilia; this requires careful investigation. Over-active clotting can also cause problems; thrombosis, where blood clots form abnormally, can potentially causeembolisms, where blood clots break off and subsequently become lodged in a vein or artery.

Hemostasis disorders can develop for many different reasons. They may be congenital, due to a deficiency or defect in an individual’s platelets or clotting factors. A number of disorders can be acquired as well.

Heparan sulfate

Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (HSPG) in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. It is in this form that HS binds to a variety of protein ligands and regulates a wide variety of biological activities, including developmental processes, angiogenesis, blood coagulation, abolishing detachment activity by GrB (Granzyme B), and tumor metastasis. HS has been shown to serve as cellular receptor for a number of viruses including the respiratory syncytial virus.

Heparin

Heparin, also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule. It can also be used to form an inner anticoagulant surface on various experimental and medical devices such as test tubes and renal dialysis machines.

Although it is used principally in medicine for anticoagulation, its true physiological role in the body remains unclear, because blood anticoagulation is achieved mostly by heparan sulfate proteoglycans derived from endothelial cells. Heparin is usually stored within the secretory granules of mast cells and released only into the vasculature at sites of tissue injury. It has been proposed that, rather than anticoagulation, the main purpose of heparin is defense at such sites against invading bacteria and other foreign materials. In addition, it is observed across a number of widely different species, including some invertebrates that do not have a similar blood coagulation system.

It is on the World Health Organization’s List of Essential Medicines, a list of the most important medication needed in a basic health system.

Heparin cofactor II

Heparin cofactor II (HCII), a protein encoded by the SERPIND1 gene, is a coagulation factor that inhibits IIa, and is a cofactor for heparin and dermatan sulfate (“minor antithrombin”).

The product encoded by this gene is a serine proteinase inhibitor which rapidly inhibits thrombin in the presence of dermatan sulfate or heparin. The gene contains five exons and four introns. This protein shares homology with antithrombin III and other members of the alpha 1-antitrypsin superfamily. Mutations in this gene are associated with heparin cofactor II deficiency. Heparin Cofactor II deficiency can lead to increased thrombin generation and a hypercoagulable state.

Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is the development of thrombocytopenia (a low platelet count), due to the administration of various forms of heparin, an anticoagulant. HIT predisposes to thrombosis, the abnormal formation of blood clots inside a blood vessel, and when thrombosis is identified the condition is called heparin-induced thrombocytopenia and thrombosis (HITT). HIT is caused by the formation of abnormal antibodies that activate platelets. If someone receiving heparin develops new or worsening thrombosis, or if the platelet count falls, HIT can be confirmed with specific blood tests.

The treatment of HIT requires both protection from thrombosis and choice of an agent that will not reduce the platelet count further. Several agents exist for this purpose, mainly lepirudin and argatroban. While heparin was discovered in the 1930s, HIT was not reported until the 1960s and 1970s.

Hereditary angioedema

Hereditary angioedema (types I, II and III) (also known as “HAE”) is a rare, autosomal dominantly inherited blood disorder that causes episodic attacks of swelling that may affect the face, extremities, genitals, gastrointestinal tract and upper airways. Swellings of the intestinal mucosa may lead to vomiting and painful, colic-like intestinal spasms that may mimic intestinal obstruction. Airway edema may be life-threatening. Episodes may be triggered by trauma, surgery, dental work, menstruation, some medications, viral illness and stress; however, this is not always readily determined. This disorder affects approximately one in 10,000–50,000 people.

HAE type I primarily caused because of abnormally low concentration some complex blood proteins (C1 esterase inhibitors), also called complements. These help to control various body functions such as the flow of body fluids in and out of cells. It is responsible for approximately 80-85% of this disorder.

HAE type II is a more infrequent form of this disorder. It occurs due to the fabrication of atypical complement proteins and accounts for about 15-20% of this disorder . Type III is not common and was documented recently. This type mainly afflicts females and it is influenced by contact with estrogens and also by hormone replacement therapy (e.g. oral contraceptives and pregnancy) and this is not connected with the deficiency of C1-INH.

HAE type III is not necessarily caused by C1-INH deficiency; it is credited to a rise in the action of the enzyme kininogenase’s and this then leads to rise in the levels of bradykinin. Some patients who have the type III HAE will have an alteration in the F12 gene and this produces a protein which participates in the clotting of blood . Some patients with type III HAE have a mutation in the F12 gene which produces a protein involved in blood clotting.

The underlying cause of HAE is attributed to autosomal dominant inheritance of mutations in the C1 inhibitor (C1-INH gene or SERPING1 gene), which is mapped to chromosome 11 (11q12-q13.1).To date there are over 300 known genetic mutations that result in a deficiency of functional C1 Inhibitor. 2-4 The majority of HAE patients have a family history; however, 25% are the result of new mutations. The low level of C1 inhibitor in the plasma leads to increased activation of pathways that release bradykinin, the chemical responsible for the angioedema due to increased vascular permeability, and the pain seen in individuals with HAE.

High molecular weight kininogen

High molecular weight kininogen (HMWK or HK) is a circulating plasma protein which participates in the initiation of blood coagulation, and in the generation of the vasodilator bradykinin via the Kallikrein-kinin system. HMWK is inactive until it either adheres to binding proteins beneath an endothelium disrupted by injury, thereby initiating coagulation; or it binds to intact endothelial cells or platelets for functions other than coagulation.

Hirudin

Hirudin is a naturally occurring peptide in the salivary glands of medicinal leeches that has a blood anticoagulant property. This is fundamental for the leeches’ alimentary habit of hematophagy, since it keeps the blood flowing after the initial phlebotomy performed by the worm on the host’s skin.

A key event in the final stages of blood coagulation is the conversion of fibrinogen into fibrin by the serine protease enzyme thrombin. Thrombin is produced from prothrombin, by the action of an enzyme, prothrombinase (Factor Xa along with Factor Va as a cofactor), in the final states of coagulation. Fibrin is then cross linked by factor XIII (Fibrin Stabilizing Factor) to form a blood clot. The principal inhibitor of thrombin in normal blood circulation is antithrombin. Similar to antithrombin III, the anticoagulatant activity of hirudin is based on its ability to inhibit the procoagulant activity of thrombin.

Hirudin is the most potent natural inhibitor of thrombin. Unlike antithrombin, hirudin binds to and inhibits only the activity of thrombin, with a specific activity on fibrinogen. Therefore, hirudin prevents or dissolves the formation of clots and thrombi (i.e., it has a thrombolytic activity), and has therapeutic value in blood coagulation disorders, in the treatment of skin hematomas and of superficial varicose veins, either as an injectable or a topical application cream. In some aspects, hirudin has advantages over more commonly used anticoagulants and thrombolytics, such as heparin, as it does not interfere with the biological activity of other serum proteins, and can also act on complexed thrombin.

It is difficult to extract large amounts of hirudin from natural sources, so a method for producing and purifying this protein using recombinant biotechnology has been developed. This has led to the development and marketing of a number of hirudin-based anticoagulant pharmaceutical products. Several other direct thrombin inhibitors are derived chemically from hirudin.

Hyperfibrinolysis

The fibrinolysis system is responsible for removing blood clots. Hyperfibrinolysis describes a situation with markedly enhanced fibrinolytic activity, resulting in increased, sometimes catastrophic bleeding. Hyperfibrinolysis can be caused by acquired or congenital reasons. Among the congenital conditions for hyperfibrinolysis, deficiency of alpha-2-antiplasmin (alpha-2-plasmin inhibitor) or plasminogen activator inhibitor type 1 (PAI-1) are very rare. The affected individuals show ahemophilia-like bleeding phenotype. Acquired hyperfibrinolysis is found in liver disease, in patients with severe trauma, during major surgical procedures, and other conditions. A special situation with temporarily enhanced fibrinolysis is thrombolytic therapy with drugs which activate plasminogen, e.g. for use in acute ischemicevents or in patients with stroke. In patients with severe trauma, hyperfibrinolysis is associated with poor outcome.

Bleeding is caused by the generation of fibrinogen degradation products which interfere with regular fibrin polymerization and inhibit platelet aggregation. Moreover, plasmin which is formed in excess in hyperfibrinolysis can proteolytically activate or inactivate many plasmatic or cellular proteins involved in hemostasis. Especially the degradation of fibrinogen, an essential protein for platelet aggregation and clot stability, may be a major cause for clinical bleeding.

International Society on Thrombosis and Haemostasis

The International Society on Thrombosis and Haemostasis (ISTH) is a global not-for-profit organization advancing the understanding, prevention, diagnosis and treatment of thrombotic and bleeding disorders. The ISTH has body of experts in this field which has regular members’ meetings, sets standards for the laboratory testing of blood clotting, and publishes a medical journal, the Journal of Thrombosis and Haemostasis.

Intrinsic Pathway

The contact activation pathway begins with formation of the primary complex on collagen by high-molecular-weight kininogen(HMWK), prekallikrein, and FXII (Hageman factor). Prekallikrein is converted to kallikrein and FXII becomes FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa. The minor role that the contact activation pathway has in initiating clot formation can be illustrated by the fact that patients with severe deficiencies of FXII, HMWK, and prekallikrein do not have a bleeding disorder. Instead, contact activation system seems to be more involved in inflammation.

Kallikrein

Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein (KLKB1) has no known homologue, while tissue kallikrein-related peptidases (KLKs) encode a family of fifteen closely related serine proteases. These genes are localised to chromosome19q13, forming the largest contiguous cluster of proteases within the human genome. Kallikreins are responsible for the coordination of various physiological functions including blood pressure, semen liquefaction and skin desquamation.

Low molecular weight heparin

Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. These drugs are used for treating deep vein thrombosis, pulmonary embolism when it is located in the veins, or heart attacks and strokes when located in the arteries.

Heparin is a naturally occurring polysaccharide that inhibits coagulation, the process that leads to thrombosis. Natural heparin consists of molecular chains of varying lengths, or molecular weights. Chains of varying molecular weights, from 5000 to over 40,000 Daltons, make up polydisperse pharmaceutical-grade heparin. LMWHs, in contrast, consist of only short chains of polysaccharide. LMWHs are defined as heparin salts having an average molecular weight of less than 8000 Da and for which at least 60% of all chains have a molecular weight less than 8000 Da. These are obtained by various methods of fractionation or depolymerisation of polymeric heparin.

Heparin derived from natural sources, mainly porcine intestine or bovine lung, can be administered therapeutically to prevent thrombosis. However, the effects of natural, or unfractionated heparin are more unpredictable than LMWH.

Lupus anticoagulant

Lupus anticoagulant (also known as lupus antibody, LA, LAC, or lupus inhibitors) is an immunoglobulin that binds to phospholipids and proteins associated with the cell membrane. Lupus anticoagulant is a misnomer, as it is actually a prothrombotic agent. That is, Lupus anticoagulant antibodies in living systems cause an increase in inappropriate blood clotting. Their name derives from their properties in vitro, since in laboratory tests, these antibodies cause an increase in aPTT. It is speculated that the antibodies interfere with phospholipids utilized to induce in vitro coagulation. In vivo, it is thought to interact with platelet membrane phospholipids, increasing adhesion and aggregation of platelets; thus its in vivo prothrombotic characteristics.

Phospholipid

Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such ascholine; one exception to this rule is sphingomyelin, which is derived from sphingosine instead of glycerol. The first phospholipid identified as such in biological tissues was lecithin, or phosphatidylcholine, in the egg yolk. The structure of the phospholipid molecule generally consists of hydrophobic tails and a hydrophilic head. Biological membranes in eukaryotes also contain another class of lipid, sterol, interspersed among the phospholipids and together they provide membrane fluidity and mechanical strength. Purified phospholipids are produced commercially and have found applications in nanotechnology and materials science.

Plasmin

Plasmin is an important enzyme (EC 3.4.21.7) present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.

Plasminogen activator inhibitor-1

Plasminogen activator inhibitor-1 (PAI-1) also known as endothelial plasminogen activator inhibitor orserpin E1 is a protein that in humans is encoded by the SERPINE1 gene.

PAI-1 is a serine protease inhibitor (serpin) that functions as the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), the activators of plasminogen and hence fibrinolysis (the physiological breakdown of blood clots). It is a serine protease inhibitor (serpin) protein (SERPINE1).

The other PAI, plasminogen activator inhibitor-2 (PAI-2) is secreted by the placenta and only present in significant amounts during pregnancy. In addition, protease nexin acts as an inhibitor of tPA and urokinase. PAI-1, however, is the main inhibitor of the plasminogen activators.

Plasminogen activator inhibitor-2

Plasminogen activator inhibitor-2 (placental PAI) is a coagulation factor that inactivates tPA and urokinase. It is present in most cells, especially monocytes/macrophages. PAI-2 exists in two forms, a 60-kDa extracellular glycosylated form and a 43-kDa intracellular form.

It is present only at detectable quantities in blood during pregnancy, as it is produced by the placenta, and may explain partially the increased rate of thrombosis during pregnancy. The majority of expressed PAI-2 remains unsecreted due to the presence of an inefficient internal signal peptide.

Platelets

Platelets, also called “thrombocytes”, are blood cells whose function (along with the coagulation factors) is to stop bleeding. Platelets have no nucleus: they are fragments of cytoplasm which are derived from the megakaryocytes of the bone marrow, and then enter the circulation. These unactivated platelets are biconvex discoid structures shaped like a lens, 2–3 µm in greatest diameter. Platelets are found only in mammals, an adaptation that may have evolved to offset the risk of death from hemorrhage at childbirth – a risk unique to mammals.

On a stained blood smear, platelets appear as dark purple spots, about 20% the diameter of red blood cells. The smear is used to examine platelets for size, shape, qualitative number, and clumping. The ratio of platelets to red blood cells in a healthy adult is 1:10 to 1:20.

The main function of platelets is to contribute to hemostasis: the process of stopping bleeding at the site of interruptedendothelium. They gather at the site and unless the interruption is physically too large, they plug the hole. First, platelets attach to substances outside the interrupted endothelium: adhesion. Second, they change shape, turn on receptors and secrete chemical messengers: activation. Third, they connect to each other through receptor bridges: aggregation. Formation of this platelet plug (primary hemostasis) is associated with activation of the coagulation cascade with resultant fibrin deposition and linking (secondary hemostasis). These processes may overlap: the spectrum is from a predominantly platelet plug, or “white clot” to a predominantly fibrin clot, or “red clot” or the more typical mixture. The final result is theclot. Some would add the subsequent clot retraction and platelet inhibition as fourth and fifth steps to the completion of the process and still others a sixth step wound repair.

Low platelet concentration is thrombocytopenia and is due to either decreased production or increased destruction. Elevated platelet concentration is thrombocytosis and is either congenital, reactive (to cytokines), or due to unregulated production: one of the myeloprolerative neoplasms or certain other myeloid neoplasms. A disorder of platelet function is a thrombocytopathy.

Normal platelets can respond to an abnormality on the vessel wall rather than to hemorrhage, resulting in inappropriate platelet adhesion/activation and thrombosis: the formation of a clot within an intact vessel. These arise by different mechanisms than a normal clot. Examples are: extending the fibrin clot of venous thrombosis; extending an unstable or ruptured arterial plaque, causing arterial thrombosis; and microcirculatory thrombosis. An arterial thrombus may partially obstruct blood flow, causing downstream ischemia; or completely obstruct it, causing downstream infarction.

Prekallikrein

Prekallikrein (PK), also known as Fletcher factor, is an 85,000 Mr serine protease that complexes with high-molecular-weight kininogen. PK is the precursor of plasmakallikrein, which is a serine protease that activates kinins. PK is cleaved to produce kallikrein by activated Factor XII (Hageman factor).

Procoagulants

The use of adsorbent chemicals, such as zeolites, and other hemostatic agents are also used for sealing severe injuries quickly (such as in traumatic bleeding secondary to gunshot wounds). Thrombin and fibrin glue are used surgically to treat bleeding and to thrombose aneurysms.

Desmopressin is used to improve platelet function by activating arginine vasopressin receptor 1A.

Coagulation factor concentrates are used to treat hemophilia, to reverse the effects of anticoagulants, and to treat bleeding in patients with impaired coagulation factor synthesis or increased consumption. Prothrombin complex concentrate, cryoprecipitate and fresh frozen plasma are commonly used coagulation factor products.Recombinant activated human factor VII is increasingly popular in the treatment of major bleeding.

Tranexamic acid and aminocaproic acid inhibit fibrinolysis, and lead to a de facto reduced bleeding rate. Before its withdrawal, aprotinin was used in some forms of major surgery to decrease bleeding risk and need for blood products.

Protein

Proteins are large biological molecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within living organisms, including catalyzing metabolic reactions, replicating DNA, responding to stimuli, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in folding of the protein into a specific three-dimensional structure that determines its activity.

A linear chain of amino acid residues is called a polypeptide. A protein contains at least one long polypeptide. Short polypeptides, containing less than about 20-30 residues, are rarely considered to be proteins and are commonly calledpeptides, or sometimes oligopeptides. The individual amino acid residues are bonded together by peptide bonds and adjacent amino acid residues. The sequence of amino acid residues in a protein is defined by the sequence of a gene, which is encoded in the genetic code. In general, the genetic code specifies 20 standard amino acids; however, in certain organisms the genetic code can include selenocysteine and—in certain archaea—pyrrolysine. Shortly after or even during synthesis, the residues in a protein are often chemically modified by posttranslational modification, which alters the physical and chemical properties, folding, stability, activity, and ultimately, the function of the proteins. Sometimes proteins have non-peptide groups attached, which can be called prosthetic groups or cofactors. Proteins can also work together to achieve a particular function, and they often associate to form stable protein complexes.

Once formed, proteins only exist for a certain period of time and are then degraded and recycled by the cell’s machinery through the process of protein turnover. A protein’s lifespan is measured in terms of its half-life and covers a wide range. They can exist for minutes or years with an average lifespan of 1–2 days in mammalian cells. Abnormal and or misfolded proteins are degraded more rapidly either due to being targeted for destruction or due to being unstable.

Like other biological macromolecules such as polysaccharides and nucleic acids, proteins are essential parts of organisms and participate in virtually every process within cells. Many proteins are enzymes that catalyze biochemical reactions and are vital to metabolism. Proteins also have structural or mechanical functions, such asactin and myosin in muscle and the proteins in the cytoskeleton, which form a system of scaffolding that maintains cell shape. Other proteins are important in cell signaling, immune responses, cell adhesion, and the cell cycle. Proteins are also necessary in animals’ diets, since animals cannot synthesize all the amino acids they need and must obtain essential amino acids from food. Through the process of digestion, animals break down ingested protein into free amino acids that are then used in metabolism.

Proteins may be purified from other cellular components using a variety of techniques such as ultracentrifugation, precipitation, electrophoresis, and chromatography; the advent of genetic engineering has made possible a number of methods to facilitate purification. Methods commonly used to study protein structure and function include immunohistochemistry, site-directed mutagenesis, X-ray crystallography, nuclear magnetic resonance and mass spectrometry.

Protein C

Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogen, the activated form of which plays an important role in regulating anticoagulation, inflammation, cell death, and maintaining the permeability of blood vessel walls in humans and other animals. Activated protein C (APC) performs these operations primarily by proteolytically inactivating proteins Factor Va and Factor VIIIa. APC is classified as a serine protease as it contains a residue of serine in its active site. In humans, protein C is encoded by the PROC gene, which is found on chromosome 2. The zymogenic form of protein C is a vitamin K-dependent glycoprotein that circulates in blood plasma. Its structure is that of a two-chain polypeptide consisting of a light chain and a heavy chain connected by a disulfide bond. The protein C zymogen is activated when it binds to thrombin, another protein heavily involved in coagulation, and protein C’s activation is greatly promoted by the presence of thrombomodulin and endothelial protein C receptors (EPCRs). Because of EPCR’s role, activated protein C is found primarily near endothelial cells (i.e., those that make up the walls of blood vessels), and it is these cells and leukocytes (white blood cells) that APC affects. Because of the crucial role that protein C plays as an anticoagulant, those with deficiencies in protein C, or some kind of resistance to APC, suffer from a significantly increased risk of forming dangerous blood clots (thrombosis).

Protein C deficiency

Protein C deficiency is a rare genetic trait that predisposes to thrombotic disease. It was first described in 1981. The disease belongs to a group of genetic disorders known as thrombophilias. Protein C deficiency is associated with an increased incidence of venous thromboembolism (relative risk 8–10), whereas no association with arterial thrombotic disease has been found.

Protein S

Protein S (also known as S-Protein) is a vitamin K-dependent plasma glycoprotein synthesized in the endothelium. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In humans, protein S is encoded by the PROS1 gene.

Protein S deficiency

Protein S deficiency is a disorder associated with increased risk of venous thrombosis. Protein S, a vitamin K-dependent physiological anticoagulant, acts as a nonenzymatic cofactor to activated protein C in the proteolytic degradation of factor Va and factor VIIIa. Decreased (antigen) levels or impaired function (activity) of protein S leads to decreased degradation of factor Va and factor VIIIa and an increased propensity to venous thrombosis. Protein S circulates in human plasma in two forms: approximately 60 percent is bound to complement component C4b β-chain while the remaining 40 percent is free. Only free protein S has activated protein C cofactor activity.

Protein S deficiency

Protein S deficiency is a disorder associated with increased risk of venous thrombosis. Protein S, a vitamin K-dependent physiological anticoagulant, acts as a nonenzymatic cofactor to activated protein C in the proteolytic degradation of factor Va and factor VIIIa. Decreased (antigen) levels or impaired function (activity) of protein S leads to decreased degradation of factor Va and factor VIIIa and an increased propensity to venous thrombosis. Protein S circulates in human plasma in two forms: approximately 60 percent is bound to complement component C4b β-chain while the remaining 40 percent is free. Only free protein S has activated protein C cofactor activity.

Protein Z

Protein Z (PZ or PROZ) is a protein which in humans is encoded by the PROZ gene.

Protein Z is a member of the coagulation cascade, the group of blood proteins that leads to the formation of blood clots. It is a gla domain protein and thus vitamin K-dependent, and its functionality is therefore impaired in warfarin therapy. It is aglycoprotein.

Protein Z-dependent protease inhibitor

Protein Z-dependent protease inhibitor is a protein circulating in the blood which inhibits factors Xa and XIa of thecoagulation cascade. It is a member of the class of the serine protease inhibitors (serpins). Its name implies that it requires protein Z, another circulating protein, to function properly, but this only applies to its inhibition of factor X.

It is about 72 kDa heavy and 444 amino acids large. It is produced by the liver.

Prothrombin

Prothrombin (coagulation factor II) is proteolytically cleaved to form thrombin in the coagulation cascade, which ultimately results in the reduction of blood loss. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands offibrin, as well as catalyzing many other coagulation-related reactions.

Prothrombin time

The prothrombin time (PT) and its derived measures of prothrombin ratio (PR) and international normalized ratio(INR) are measures of the extrinsic pathway of coagulation. This test is also called “ProTime INR” and “PT/INR”. They are used to determine the clotting tendency of blood, in the measure of warfarin dosage, liver damage, and vitamin K status. PT measures factors I (fibrinogen), II (prothrombin), V, VII, and X. It is used in conjunction with the activated partial thromboplastin time (aPTT) which measures the intrinsic pathway and common pathway.

Prothrombinase

The prothrombinase complex consists of the serine proteins, Factor Xa, and the protein cofactor, Factor Va. The complex assembles on negatively charged phospholipid membranes in the presence of calcium ions. The prothrombinase complex catalyzes the conversion of prothrombin (Factor II), an inactive zymogen, tothrombin (Factor IIa), an active serine protease. The activation of thrombin is a critical reaction in the coagulation cascade, which functions to regulate hemostasis in the body. To produce thrombin, the prothrombinase complex cleaves two peptide bonds in prothrombin, one after Arg271 and the other after Arg320. Although it has been shown that Factor Xa can activate prothrombin when unassociated with the prothrombinase complex, the rate of thrombin formation is severely decreased under such circumstances. The prothrombinase complex can catalyze the activation of prothrombin at a rate 3 x 105-fold faster than can Factor Xa alone. Thus, the prothrombinase complex is required for the efficient production of activated thrombin and also for adequate hemostasis.

Pulmonary embolism

Pulmonary embolism (PE) is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream (embolism). PE most commonly results from deep vein thrombosis (a blood clot in the deep veins of the legs or pelvis) that breaks off and migrates to the lung, a process termed venous thromboembolism (VTE). A small proportion of cases are caused by the embolization of air, fat, or talc in drugs of intravenous drug abusers or amniotic fluid. The obstruction of the blood flow through the lungs and the resultant pressure on the right ventricle of the heart lead to the symptoms and signs of PE. The risk of PE is increased in various situations, such as cancer or prolonged bed rest.

Symptoms of pulmonary embolism include difficulty breathing, chest pain on inspiration, and palpitations. Clinical signsinclude low blood oxygen saturation and cyanosis, rapid breathing, and a rapid heart rate. Severe cases of PE can lead tocollapse, abnormally low blood pressure, and sudden death.

Diagnosis is based on these clinical findings in combination with laboratory tests (such as the D-dimer test) and imaging studies, usually CT pulmonary angiography. Treatment is typically with anticoagulant medication, including heparin andwarfarin. Severe cases may require thrombolysis using medication such as tissue plasminogen activator (tPA), or may require surgical intervention via pulmonary thrombectomy.

Purpura

Purpura (from Latin: purpura, meaning “purple”) are red or purple discolorations on the skin that do not blanch on applying pressure. They are caused by bleeding underneath the skin usually secondary to vasculitis or dietary deficiency of vitamin C (scurvy). Purpura measure 0.3–1 cm (3–10 mm), whereas petechiae measure less than 3 mm, andecchymoses greater than 1 cm.

This is common with typhus and can be present with meningitis caused by meningococci or septicaemia. In particular, meningococcus (Neisseria meningitidis), a Gram-negative diplococcus organism, releases endotoxin when it lyses. Endotoxin activates the Hageman factor (clotting factor XII), which causes disseminated intravascular coagulation (DIC). The DIC is what appears as a rash on the affected individual.

Red blood cells

Red blood cells (RBCs), also called erythrocytes, are the most common type of blood cell and the vertebrate organism’s principal means of delivering oxygen (O2) to the body tissues–via blood flow through the circulatory system. RBCs take up oxygen in the lungs or gills and release it into tissues while squeezing through the body’s capillaries.

The cytoplasm of erythrocytes is rich in hemoglobin, an iron-containing biomolecule that can bind oxygen and is responsible for the red color of the cells. The cell membrane is composed of proteins and lipids, and this structure provides properties essential for physiologicalcell function such as deformability and stability while traversing the circulatory system and specifically the capillary network.

In humans, mature red blood cells are flexible and oval biconcave disks. They lack a cell nucleus and most organelles, in order to accommodate maximum space for hemoglobin. Approximately 2.4 million new erythrocytes are produced per second in human adults. The cells develop in the bone marrow and circulate for about 100–120 days in the body before their components are recycled bymacrophages. Each circulation takes about 20 seconds. Approximately a quarter of the cells in the human body are red blood cells.

Red blood cells are also known as RBCs, red cells, red blood corpuscles (an archaic term), haematids, erythroid cells orerythrocytes (from Greek erythros for “red” and kytos for “hollow vessel”, with -cyte translated as “cell” in modern usage). Packed red blood cells (pRBC) are red blood cells that have been donated, processed, and stored in a blood bank for blood transfusion.

Rivaroxaban

Rivaroxaban is an oral anticoagulant and the first available orally active direct factor Xa inhibitor. Rivaroxaban is well absorbed from the gut and maximum inhibition of factor Xa occurs four hours after a dose. The effects last approximately 8–12 hours, but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible.

Scientific and Standardization Committee

SSC History

  • Scientific and Standardization Committee (current name)
  • International Committee for the Standardization of the Nomenclature of the Blood Clotting Factors (previous name)
  • International Committee on Thrombosis and Haemostasis (ICTH) (previous name)
  • International Society on Thrombosis and Haemostasis (ISTH) (founder)

The SSC adopted the Roman numeral system for labeling blood clotting factors, which became the standard in professional literature. The group changed its name over various incarnations, expanding its interests in the fields of blood coagulation and haemorrhagic disorders, eventually founding the ISTH.

The SSC is a permanent committee of the ISTH and is its scientific working arm. Conducted through subcommittees and working groups, SSC activities promote cooperation among leading international scientists.

Serine protease

Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins, in which serineserves as the nucleophilic amino acid at the (enzyme’s) active site. They are found ubiquitously in both eukaryotes andprokaryotes. Serine proteases fall into two broad categories based on their structure: chymotrypsin-like (trypsin-like) orsubtilisin-like. In humans, they are responsible for co-ordinating various physiological functions, including digestion, immune response, blood coagulation and reproduction.

Serpin

Serpins are a group of proteins with similar structures that were first identified as a set of proteins able to inhibit proteases. The acronym serpin was originally coined because many serpins inhibit chymotrypsin-like serine proteases (serine protease inhibitors).

The first members of the serpin superfamily to be extensively studied were the human plasma proteins antithrombin andantitrypsin, which play key roles in controlling blood coagulation and inflammation, respectively. Initially, research focused upon their role in human disease: antithrombin deficiency results in thrombosis and antitrypsin deficiency causes emphysema. In 1980 Hunt and Dayhoff made the surprising discovery that both these molecules share significant amino acid sequence similarity to the major protein in chicken egg white, ovalbumin, and they proposed a new protein superfamily. Over 1000 serpins have now been identified, these include 36 human proteins, as well as molecules in plants, fungi, bacteria, archaea and certain viruses. Serpins are thus the largest and most diverse family of protease inhibitors.

While most serpins control proteolytic cascades, certain serpins do not inhibit enzymes, but instead perform diverse functions such as storage (ovalbumin, in egg white), hormone carriage proteins (thyroxine-binding globulin, cortisol-binding globulin) and molecular chaperones (HSP47). The term serpin is used to describe these latter members as well, despite their noninhibitory function.

As serpins control processes such as coagulation and inflammation, these proteins are the target of medical research. However, serpins are also of particular interest to the structural biology and protein folding communities, because they undergo a unique and dramatic change in shape (or conformational change) when they inhibit target proteases. This is unusual — most classical protease inhibitors function as simple “lock and key” molecules that bind to and block access to the protease active site (see, for example, bovine pancreatic trypsin inhibitor). While the serpin mechanism of protease inhibition confers certain advantages, it also has drawbacks, and serpins are vulnerable to mutations that result in protein misfolding and the formation of inactive long-chain polymers (serpinopathies). Serpin polymerisation reduces the amount of active inhibitor, as well as accumulation of serpin polymers, causing cell death and organ failure. For example, the serpin antitrypsin is primarily produced in the liver, and antitrypsin polymerisation causes liver cirrhosis. Understanding serpinopathies also provides insights on protein misfolding in general, a process common to many human diseases, such as Alzheimer’s and Creutzfeldt-Jakob disease.

Streptokinase

Streptokinase (SK) is an enzyme secreted by several species of streptococci that can bind and activate humanplasminogen. SK is used as an effective and inexpensive thrombolysis medication in some cases of myocardial infarction(heart attack) and pulmonary embolism. Streptokinase belongs to a group of medications known as fibrinolytics, and complexes of streptokinase with human plasminogen can hydrolytically activate other unbound plasminogen by activating through bond cleavage to produce plasmin. There are three domains to Streptokinase, denoted α (residues 1–150), β (residues 151–287), and γ (residues 288–414). Each domain binds plasminogen, although none can activate plasminogen independently.

It is on the World Health Organization’s List of Essential Medicines, a list of the most important medication needed in a basic health system.

Thrombin Time

The thrombin time (TT), also known as the thrombin clotting time (TCT) is a blood test that measures the time it takes for a clot to form in the plasma of a blood sample containing anticoagulant, after an excess of thrombin has been added. It is used to diagnose blood coagulation disorders and to assess the effectiveness of fibrinolytic therapy. This test is repeated with pooled plasma from normal patients. The difference in time between the test and the ‘normal’ indicates an abnormality in the conversion of fibrinogen (a soluble protein) to fibrin, an insoluble protein.

The thrombin time compares the rate of clot formation to that of a sample of normal pooled plasma. Thrombin is added to the samples of plasma. If the time it takes for the plasma to clot is prolonged, a quantitative (fibrinogen deficiency) or qualitative (dysfunctional fibrinogen) defect is present. In blood samples containing heparin, a substance derived from snake venom called batroxobin (formerly reptilase) is used instead of thrombin. Batroxobin has a similar action to thrombin but unlike thrombin it is not inhibited by heparin.

Normal values for thrombin time are 12 to 14 seconds. If batroxobin is used, the time should be between 15 and 20 seconds. Thrombin time can be prolonged by heparin, fibrin degradation products, and fibrinogen deficiency or abnormality.

Thrombocyte

Platelets, also called “thrombocytes”, are blood cells whose function (along with the coagulation factors) is to stop bleeding. Thrombocytes have no nucleus: they are fragments of cytoplasm which are derived from the megakaryocytes of the bone marrow, and then enter the circulation. These unactivated platelets are biconvex discoid structures shaped like a lens, 2–3 µm in greatest diameter. Platelets are found only in mammals, an adaptation that may have evolved to offset the risk of death from hemorrhage at childbirth – a risk unique to mammals.

On a stained blood smear, thrombocytes appear as dark purple spots, about 20% the diameter of red blood cells. The smear is used to examine platelets for size, shape, qualitative number, and clumping. The ratio of platelets to red blood cells in a healthy adult is 1:10 to 1:20.

The main function of thrombocytes is to contribute to hemostasis: the process of stopping bleeding at the site of interrupted endothelium. They gather at the site and unless the interruption is physically too large, they plug the hole. First, platelets attach to substances outside the interrupted endothelium: adhesion. Second, they change shape, turn on receptors and secrete chemical messengers: activation. Third, they connect to each other through receptor bridges: aggregation. Formation of this platelet plug (primary hemostasis) is associated with activation of the coagulation cascade with resultant fibrin deposition and linking (secondary hemostasis). These processes may overlap: the spectrum is from a predominantly platelet plug, or “white clot” to a predominantly fibrin clot, or “red clot” or the more typical mixture. The final result is theclot. Some would add the subsequent clot retraction and thrombocyte inhibition as fourth and fifth steps to the completion of the process and still others a sixth step wound repair.

Low thrombocyte concentration is thrombocytopenia and is due to either decreased production or increased destruction. Elevated thrombocyte concentration is thrombocytosis and is either congenital, reactive (to cytokines), or due to unregulated production: one of the myeloprolerative neoplasms or certain other myeloid neoplasms. A disorder of platelet function is a thrombocytopathy.

Normal thrombocytes can respond to an abnormality on the vessel wall rather than to hemorrhage, resulting in inappropriate thrombocyte adhesion/activation and thrombosis: the formation of a clot within an intact vessel. These arise by different mechanisms than a normal clot. Examples are: extending the fibrin clot of venous thrombosis; extending an unstable or ruptured arterial plaque, causing arterial thrombosis; and microcirculatory thrombosis. An arterial thrombus may partially obstruct blood flow, causing downstream ischemia; or completely obstruct it, causing downstream infarction.

Thrombocytopenia

The terms thrombocytopenia and thrombopenia refer to a disorder in which there is a relative decrease of thrombocytes, commonly known as platelets, present in the blood.

A normal human platelet count ranges from 150,000 to 450,000 platelets per microlitre of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease. One common definition of thrombocytopenia is a platelet count below 50,000 per microlitre.

Thrombolysis

Thrombolysis is the breakdown (lysis) of blood clots by pharmacological means, and commonly called clot busting. It works by stimulating secondary fibrinolysis by plasmin through infusion of analogs of tissue plasminogen activator (tPA), the protein that normally activates plasmin.

Thrombolytics

Thrombolytic drugs are used in medicine to dissolve blood clots in a procedure termed thrombolysis. They limit the damage caused by the blockage or occlusion of a blood vessel.

Thrombolytic agents are used for the treatment of myocardial infarction (heart attack), thromboembolic strokes, deep vein thrombosis and pulmonary embolism to clear a blocked artery and avoid permanent damage to the perfused (see perfusion) tissue (e.g. myocardium, brain, leg) and death. They may also be used to clear blocked catheters that are used in long-term medical therapy.

Thrombolytic therapy in hemorrhagic strokes is contraindicated, as its use in that situation would prolong bleeding into the intracranial space and cause further damage.

Thrombomodulin

Thrombomodulin (TM), CD141 or BDCA-3 is an integral membrane protein expressed on the surface of endothelial cells and serves as a cofactor for thrombin. It reduces blood coagulation by converting thrombin to an anticoagulant enzyme from a procoagulant enzyme. Thrombomodulin is also expressed on human mesothelial cell, monocyte and a dendritic cell subset.

Thrombophilia

Thrombophilia (sometimes hypercoagulability or a prothrombotic state) is an abnormality of blood coagulation that increases the risk of thrombosis (blood clots in blood vessels). Such abnormalities can be identified in 50% of people who have an episode of thrombosis (such as deep vein thrombosis in the leg) that was not provoked by other causes. A significant proportion of the population has a detectable abnormality, but most of these only develop thrombosis in the presence of an additional risk factor.

There is no specific treatment for most thrombophilias, but recurrent episodes of thrombosis may be an indication for long-term preventative anticoagulation. The first major form of thrombophilia, antithrombin deficiency, was identified in 1965, while the most common abnormalities (including factor V Leiden) were described in the 1990s.

Thrombosis

Thrombosis is the formation of a blood clot (thrombus) inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets(thrombocytes) and fibrin to form a blood clot to prevent blood loss. Even when a blood vessel is not injured, blood clots may form in the body under certain conditions. A clot that breaks free and begins to travel around the body is known as an embolus.

When a thrombus is significantly large enough to reduce the blood flow to a tissue, hypoxia (oxygen deprivation) can occur and metabolic products such as lactic acid can accumulate. A larger thrombus causing a much greater obstruction to the blood flow may result in anoxia, the complete deprivation of oxygen and infarction, tissue death. There are also a number of other conditions that can arise according to the location of the thrombus and the organs affected.

Thromboembolism is the combination of thrombosis and its main complication, embolism.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP or Moschcowitz syndrome) is a rare disorder of the blood-coagulation system, causing extensive microscopic clots to form in the small blood vessels throughout the body. These small blood clots, called thrombi, can damage many organs including the kidneys, heart and brain. In the era before effective treatment with plasma exchange, the fatality rate was about 90%. With plasma exchange, this has dropped to 10% at six months. Immunosuppressants, such as glucocorticoids, rituximab, cyclophosphamide, vincristine, or cyclosporine, may also be used if a relapse or recurrence follows plasma exchange.

Most cases of TTP arise from inhibition of the enzyme ADAMTS13, a metalloprotease responsible for cleaving large multimers of von Willebrand factor (vWF) into smaller units. The increase in circulating multimers of vWF increase platelet adhesion to areas of endothelial injury, particularly at arteriole-capillary junctions.

A rarer form of TTP, called Upshaw-Schülman syndrome, is genetically inherited as a dysfunction of ADAMTS13. If large vWF multimers persist, a tendency for increased coagulation exists.

Red blood cells passing the microscopic clots are subjected to shear stress which damages their membranes, leading to intravascular hemolysis, which in turn leads to anaemia and schistocyte formation. Reduced blood flow due to thrombosisand cellular injury results in end organ damage. Current therapy is based on support and plasmapheresis to reducecirculating antibodies against ADAMTS13 and replenish blood levels of the enzyme.

Thrombus

A thrombus, or colloquially a blood clot, is the final product of the blood coagulation step in hemostasis. Note, a thrombus is a solid or semi-solid mass formed from the constituents of blood within the vascular system during life, whereas a blood clot refers to one that is formed post-mortem. There are two components to a thrombus, aggregated platelets that form a platelet plug, and a mesh of cross-linked fibrin protein. A thrombus is a healthy response to injury intended to prevent bleeding, but can be harmful in thrombosis, when clots obstruct blood flow through healthy blood vessels.

Mural thrombi are thrombi that adhere to the wall of a blood vessel. They occur in large vessels such as heart and aorta, and can restrict blood flow but usually do not block it entirely. They appear grey-red with alternating light and dark lines (known as lines of Zahn) which represent bands of fibrin (lighter) with entrapped white blood cells and red blood cells (darker).

Tissue Factor

Tissue factor, also called platelet tissue factor, factor III, thromboplastin, or CD142 is a protein present in subendothelial tissue and leukocytes necessary for the initiation of thrombin formation from the zymogen prothrombin.

Tissue factor pathway inhibitor

Tissue factor pathway inhibitor (or TFPI) is a single-chain polypeptide which can reversibly inhibit Factor Xa(Xa). While Xa is inhibited, the Xa-TFPI complex can subsequently also inhibit the FVIIa-tissue factor complex. TFPI contributes significantly to the inhibition of Xa in vivo, despite being present at concentrations of only 2.5 nM.

Tissue plasminogen activator

Tissue plasminogen activator (tPA, PLAT) is a protein involved in the breakdown of blood clots. It is a serine protease (EC 3.4.21.68) found on endothelial cells, the cells that line the blood vessels. As an enzyme, it catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown. Because it works on the clotting system, tPA is used in clinical medicine to treat embolic orthrombotic stroke. Use is contraindicated in hemorrhagic stroke and head trauma. The antidote for tPA in case of toxicity is aminocaproic acid.

tPA may be manufactured using recombinant biotechnology techniques. tPA created this way may be referred to as recombinant tissue plasminogen activator (rtPA).

Unfractionated heparin

Heparin, also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule. It can also be used to form an inner anticoagulant surface on various experimental and medical devices such as test tubes and renal dialysis machines.

Although it is used principally in medicine for anticoagulation, its true physiological role in the body remains unclear, because blood anticoagulation is achieved mostly by heparan sulfate proteoglycans derived from endothelial cells. Heparin is usually stored within the secretory granules of mast cells and released only into the vasculature at sites of tissue injury. It has been proposed that, rather than anticoagulation, the main purpose of heparin is defense at such sites against invading bacteria and other foreign materials. In addition, it is observed across a number of widely different species, including some invertebrates that do not have a similar blood coagulation system.

It is on the World Health Organization’s List of Essential Medicines, a list of the most important medication needed in a basic health system.

Urokinase

Urokinase (trade name Abbokinase), also called urokinase-type plasminogen activator (uPA), is a serine protease (EC3.4.21.73). It was discovered in 1947 by McFarlane. Urokinase was originally isolated from human urine, but is present in several physiological locations, such as blood stream and the extracellular matrix. The primary physiological substrate is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolysis cascade that, depending on the physiological environment, participates in thrombolysis orextracellular matrix degradation. This links urokinase to vascular diseases and cancer.

Vein

In the circulatory system, veins (from the Latin vena) are blood vessels that carry blood toward the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are the pulmonary and umbilical veins, both of which carry oxygenated blood to the heart. In contrast to veins, arteries carry blood away from the heart. Veins are less muscular than arteries and are often closer to the skin. There are valves in most veins to prevent backflow.

Venous thrombosis

A venous thrombus is a blood clot (thrombus) that forms within a vein. Thrombosis is a term for a blood clot occurring inside a blood vessel. A common type of venous thrombosis is a deep vein thrombosis (DVT), which is a blood clot in the deep veins of the leg. If the thrombus breaks off (embolizes) and flows towards the lungs, it can become a life-threateningpulmonary embolism (PE), a blood clot in the lungs.

When a blood clot breaks loose and travels in the blood, this is called a venous thromboembolism (VTE). The abbreviation DVT/PE refers to a VTE where a deep vein thrombosis (DVT) has moved to the lungs (PE or pulmonary embolism).

An inflammatory reaction is usually present, mainly in the superficial veins and, for this reason this pathology is called most of the time thrombophlebitis. In fact, the inflammatory reaction and the white blood cells play a role in the resolution of venous clots.

Vitamin K

Vitamin K refers to a group of structurally similar, fat-soluble vitamins the human body needs for complete synthesis of certain proteins that are required for blood coagulation. Without vitamin K, blood coagulation is seriously impaired, and uncontrolled bleeding occurs. Low levels of vitamin K also weaken bones and promote calcification of arteries and other soft tissues.

Vitamin K1 is active as a vitamin in animals and performs the classic functions of vitamin K, including its activity in the production of blood-clotting proteins.

Vitamin K deficiency

Vitamin K deficiency is a form of avitaminosis resulting from insufficient vitamin K1 or vitamin K2 or both.

Vitamin K1 Deficiency

Vitamin K1-deficiency may occur by disturbed intestinal uptake (such as would occur in a bile duct obstruction), by therapeutic or accidental intake of a vitamin K1-antagonist such as warfarin, or, very rarely, by nutritional vitamin K1 deficiency. As a result, Gla-residues are inadequately formed and the Gla-proteins are insufficiently active.

Von Willebrand disease

Von Willebrand disease (vWD) is the most common hereditary coagulation abnormality described in humans, although it can also be acquired as a result of other medical conditions. It arises from a qualitative or quantitative deficiency of von Willebrand factor (vWF), a multimeric protein that is required for platelet adhesion. It is known to affect humans and dogs (notably Doberman Pinschers), and rarely swine, cattle, horses, and cats. There are three forms of vWD: hereditary, acquired, and pseudo or platelet type. There are three types of hereditary vWD: vWD Type I, vWD Type II, and vWD Type III. Within the three inherited types of vWD there are various subtypes. Platelet type vWD is also an inherited condition.

vWD Type I is the most common type of the disorder and those that have it are typically asymptomatic or may experience mild symptoms such as nosebleeds although there may be severe symptoms in some cases. There are various factors that affect the presentation and severity of symptoms of vWD such as blood type.

vWD is named after Erik Adolf von Willebrand, a Finnish pediatrician who first described the disease in 1926.

Von Willebrand factor

Von Willebrand factor (vWF) is a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic thrombocytopenic purpura, Heyde’s syndrome, and possibly hemolytic-uremic syndrome. Increased plasma levels in a large number of cardiovascular, neoplastic, and connective tissue diseases are presumed to arise from adverse changes to the endothelium, and may contribute to an increased risk of thrombosis.

Warfarin

Warfarin is an anticoagulant normally used in the prevention of thrombosis and thromboembolism, the formation of blood clots in the blood vessels and their migration elsewhere in the body, respectively. It was initially introduced in 1948 as a pesticide against rats and mice, and is still used for this purpose, although more potent poisons such as brodifacoum have since been developed. In the early 1950s, warfarin was found to be effective and relatively safe for preventing thrombosis and thromboembolism in many disorders. It was approved for use as a medication in 1954, and has remained popular ever since. Warfarin is the most widely prescribed oral anticoagulant drug in North America.

Despite its effectiveness, treatment with warfarin has several shortcomings. Many commonly used medications interact with warfarin, as do some foods (particularly leaf vegetable foods or “greens,” since these typically contain large amounts of vitamin K1) and its activity has to be monitored by blood testing for the international normalized ratio (INR) to ensure an adequate yet safe dose is taken. A high INR predisposes patients to an increased risk of bleeding, while an INR below the therapeutic target indicates the dose of warfarin is insufficient to protect against thromboembolic events.

Warfarin and related 4-hydroxycoumarin-containing molecules decrease blood coagulation by inhibiting vitamin K epoxide reductase, an enzyme that recycles oxidized vitamin K1 to its reduced form after it has participated in the carboxylation of several blood coagulation proteins, mainly prothrombin and factor VII. Despite being labeled a vitamin K antagonist, warfarin does not antagonize the action of vitamin K1, but rather antagonizes vitamin K1 recycling, depleting active vitamin K1. Thus, the pharmacologic action may always be reversed by fresh vitamin K1. When administered, these drugs do not anticoagulate blood immediately. Instead, onset of their effect requires about two to three days before remaining active clotting factors have had time to naturally disappear in metabolism, and the duration of action of a single dose of warfarin is 2 to 5 days. Reversal of warfarin’s effect when it is discontinued or vitamin K1 is administered, requires a similar time.

Zymogen

A zymogen (or proenzyme) is an inactive enzyme precursor. A zymogen requires a biochemical change (such as a hydrolysis reaction revealing the active site, or changing the configuration to reveal the active site) for it to become an active enzyme. The biochemical change usually occurs in a lysosome where a specific part of the precursor enzyme is cleaved in order to activate it. The inactivating piece which is cleaved off can be a peptide unit, or can be independently folding domains comprising more than 100 residues. Although they limit the enzyme’s ability, these n-terminal extensions of the enzyme or a “prosegment” often aid in the stabilizing and folding of the enzyme they inhibit.

The pancreas secretes zymogens partly to prevent the enzymes from digesting proteins in the cells in which they are synthesised. Enzymes like pepsin are created in the form of pepsinogen, an inactive zymogen. Pepsinogen is activated when chief cells release it into HCl which partially activates it. Another partially activated pepsinogen completes the activation by removing the peptide turning the pepsinogen into pepsin. Accidental activation of zymogens can happen when the secretion duct in the pancreas is blocked by a gallstone resulting in acute pancreatitis.

Fungi also secrete digestive enzymes into the environment as zymogens. The external environment has a different pH than inside the fungal cell and this changes the zymogen’s structure into an active enzyme.