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Glossary

I have tried to cover as much as possible within the glossary and thus at times is does get scientific, unfortunately there is no other way to explain some of the terminology you may come across. If I have left anything out, please do not hesitate to contact me. A lot of this information has been taken from Wikipedia,(The Web's free Encylopedia) so should you not understand anything it maybe worth looking at their website, under the title headings.

Antithrombin deficiency is a rare hereditary disorder that generally comes to light when a patient suffers recurrent venous thrombosis and pulmonary embolism. This was first described by Egeberg in 1965. The patients are treated with anticoagulants or, more rarely, with antithrombin concentrate.

Antithrombin is a small molecule that inactivates several enzymes of the coagulation system. It is a glycoprotein produced by the liver.

Antithrombin is a serpin (serine protease inhibitor) that inactivates a number of enzymes from the coagulation system, namely the activated forms of Factor X, Factor IX, Factor II (thrombin), Factor VII, Factor XI, and Factor XII. The rate of its reaction with these molecules (i.e. its effectivity) is greatly enhanced by heparin.

In renal 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.

Heparin is a highly sulfated glycosaminoglycan widely used as an injectable anticoagulant. It is also used to form an inner anticoagulant surface on various experimental and medical devices such as test tubes and renal dialysis machines. Pharmaceutical grade heparin is commonly derived from mucosal tissues of slaughtered meat animals such as porcine intestine or bovine lung

INR: International normalized ratio, a system established by the World Health Organisation (WHO) and the International Committee on Thrombosis and Hemostasis for reporting the results of blood coagulation (clotting) tests. All results are standardized using the international sensitivity index for the particular thromboplastin reagent and instrument combination utilized to perform the test. The average person's INR normally sits between 0.8 and 1. A Patient taking anticoagulants (Bloodthinners) like Warfarin or Heparin may optimally maintain a prothrombin time of between 2 and 3. The idea behind the system is that whereever you test is done worldwide, the result should be the same allowing patients on anticoagulants to travel and still obtain the same result.

Factor V (Five) Leiden (sometimes Factor VLeiden) is the name given to a variant of human factor V that causes a hypercoagulability disorder. In this disorder the Leiden variant of factor V, cannot be inactivated by activated protein C. Factor V Leiden is the most common hereditary hypercoagulability disorder amongst Eurasians. It is named after the city Leiden (The Netherlands), where it was first identified in 1994 by Prof R. Bertina et al.

In the normal person, factor V functions as a cofactor to allow factor X to generate the active form of an enzyme called thrombin. Thrombin in turn cleaves fibrinogen to fibrin, which polymerises to form the dense meshwork that makes up the majority of a clot. Activated protein C (aPC) is a natural anticoagulant that acts to limit the extent of clotting by cleaving and degrading factor V.

Factor V Leiden is an autosomal dominant condition in which the coagulation factor cannot be destroyed by aPC. Mutation of the gene encoding factor V—a single nucleotide substitution of adenine for guanine—changes the protein's 506th amino acid from arginine to glutamine. Since this amino acid is normally the cleavage site for aPC, the mutation prevents efficient inactivation of factor V. When factor V remains active, it facilitates overproduction of thrombin leading to excess fibrin generation and excess clotting.

The excessive clotting that occurs in this disorder is almost always restricted to the veins, where the clotting may cause a deep vein thrombosis (DVT). Women with the disorder have an increased risk of miscarriage and stillbirth. This disorder does not increase the formation of clots in arteries that can lead to stroke or heart attack, though a "mini-stroke" known as a transient ischemic attack may occur.

Protein C deficiency is a rare genetic trait that predisposes to thrombolitic disease. It was first described in 1981. The disease belongs to a group of genetic disorders know as thrombophilias.
The prevalence of protein C deficiency has been estimated to about 0,2% of the general population.

Protein C deficiency is associated with an increased incidence of venous thromboembolism (relative risk 7), whereas no association with arterial thrombotic disease has been found.

The main function of protein C is its anticoagulant property as an inhibitor of coagulation factors V and VIII. There are two main types of protein C mutations that lead to protein C deficiency:

  • Type I: Quantitative defects of protein C (low production or short protein halflife)
  • Type II: Qualitative defects, in which interaction with other molecules is abnormal. Defects in interaction with thrombomodulin, phospholipids, factors V/VIII and others have been described.

Homozygous protein C mutations often causes a severe thrombotic disorder known as purpura fulminans. Protein C deficiency has only had 16 cases prior 1999

Primary phrophylaxis with aspirin, heparin or warfarin should be considered in known familial cases.
Anticoagulant prophylaxis is given to all who develop a venous clot regardless of underlying cause. Studies have demonstrated an increased risk of recurrent venous thromboembolic events in patients with protein C deficiency. Therefore, long-term anticoagulation therapy with warfairn should be considered in these patients.

Homozygous protein C defect constitutes a potentially life-threatening disease, and warrants the use of supplemental protein C concentrates.

Protein S deficiency is a disorder associated with increased risk of thrombosis. Decreased levels or impaired function of protein S, a Vitamin K-dependent physiological anticoagulant, leads to decreased degradation of factor Va and factor VIIIa and an increased propensity to venous thrombosis.

There are three types of hereditary protein S deficiency:

  • Type I - decreased protein S activity: low levels of free proteins S, normal levels of bound protein S
  • Type IIa - decreased protein S activity: low levels of free protein S, low levels of bound protein S
  • Type IIb - decreased protein S activity: normal levels of free protein S, normal levels of bound protein S

Decreased activity is present in an acquired form in vitamin K deficiency or treatment with warfarin. This generally also impairs the coagulation system itself (factors II, VII, IX and X), and therefore predisposes to bleeding rather than thrombosis. Protein S levels are also lower in pregnancy and liver disease.

Protein S deficiency is the underlying cause of a small proportion of cases of disseminated intravascular coagulation (DIC), deep vein thrombosis (DVT) and pulmonary embolism (PE).

Hereditary PSD is an autosomal dominant condition, resulting in a 50 percent chance of passing the disease to offspring. Less than half of those diagnosed with PSD will experience thrombosis, and those who do usually are affected only from the age of the late teens onwards. Screening of young children is usually deferred because early testing is often inaccurate, and it is better to wait until they are old enough to decide for themselves whether they want to be tested.

Prothrombin time: A clotting test, the prothrombin time is done to test the integrity of part of the clotting scheme. The prothrombin time is commonly used as a method of monitoring the accuracy of blood thinning treatment (anticoagulation). Familiarly called the "pro time," the test is the time needed for clot formation after a substance called thromboplastin (+ calcium) has been added to plasma. Prothrombin is a coagulation (clotting) factor needed for the normal clotting of blood. There is a cascade of biochemical events that leads to the formation of the final clot. In this cascade, prothrombin is a precursor to thrombin. Because prothrombin comes before thrombin, it is called prothrombin.

Prothrombin Mutation (activated Factor II (IIa)) is a coagulation protein that has many effects in the coagulation cascade. It is a serine protease(EC 3.4.21.5) that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalysing many other coagulation-related reactions.

The prothrombin gene is located on the eleventh chromosome (11p11-q12). The molecular weight of prothrombin is approximately 72000. Once activated, the catalytic domain of prothrombin (i.e. thrombin, molecular weight 36000) is released from prothrombin fragment 1.2. There are an estimated 30 people in the world who have been diagnosed with the congenital form of Factor II. The prothrombin gene is called a Factor II mutation. Most people who have a Factor II mutation acquire it later on in life, unlike the few who have obtained it congenitally. The Factor II mutated gene is not always accompanied by other factors (i.e. the most common Factor V). In most cases, it is viewed as a homozygous gene (unless otherwise) diagnosed as heterozygous. If you are on oral contraceptives or you have accompanying conditions (i.e. Crohn's disease or Ulcerative Colitis) it is best to be tested for all clotting factors.

Thrombin is produced by the enzymatic cleavage of two sites on prothrombin by activated Factor X (Xa). The activity of factor Xa is greatly enhanced by binding to activated Factor V (Va), termed the prothrombinase complex. Prothrombin is produced in the liver and is post-translationally modified in a vitamin K-dependent reaction that converts ten glutamic acids on prothrombin to gamma-carboxyglutamic acid (Gla). In the presence of calcium, the gamma-carboxyglutamic acid residues promote the binding of thrombin to phospholipid bilayers. Deficiency of vitamin K or administration of the anticoagulant warfarin inhibits the production of gamma-carboxyglutamic acid residues, slowing the activation of the coagulation cascade.

Thrombin converts fibrinogen to an active form that assembles into fibrin. Thrombin also activates factor XI, factor V and factor VIII. This positive feedback accelerates the production of thrombin.

Factor XIII is also activated by thrombin. Factor XIIIa is a transglutaminase that catalyzes the formation of covalent bonds between lysine and glutamine residues in fibrin. The covalent bonds increase the stability of the fibrin clot.

In addition to its activity in the coagulation cascades, thrombin also promotes platelet activation, via activation of protease-activated receptors on the platelet.

Thrombin activates protein C, an inhibitor of the coagulation cascade. The activation of protein C is greatly enhanced following the binding of thrombin to thrombomodulin, an integral membrane protein expressed by endothelial cells. Activated protein C inactivates factors Va and VIIIa. Binding of activated protein C to protein S leads to a modest increase in its activity.

Activation of prothrombin is crucial in physiological and pathological coagulation. Various rare diseases involving prothrombin have been described (e.g. hypoprothrombinemia).

An apparently quite common disorder (up to 5% in Western patients) is the substitution of adenine for guanine at position 20210 of the prothrombin gene. Although this falls outside the reading frame for the protein, it leads to high levels of prothrombin and a possibly increased risk of thrombosis (Poort et al 1996).

Thrombolytic Agents:Thrombolytic Agents actually help to dissolve clots. Administered by intravenous infusion or directly into the clot via catheter, they target the fibrin mesh that binds clots together, causing it to disintegrate. Hospitalisation is required, and the risk of bleeding complications is greater than with anticoagulants. These agents include streptokinase and tissue plasminogen activator (TPA). At present, most thrombolytic therapy is reserved for patients with new large clots especially large pulmonary emboli and those who are at high risk of long-term complications due to a clotting disorder or other predisposing condition.

Thrombophilia is the propensity to develop thrombosis (blood clots) due to an abnormality in the system of coagulation.

Searching for a coagulation abnormality is not normally undertaken in patients in whom thrombosis has an obvious other cause. For example, if the thrombosis is due to immobilisation after recent surgery or a long flight, it is unlikely that an underlying cause is found.

Conversely, although thrombosis itself may occur in any person, repeated (two or more) unprovoked episodes of thrombosis and unusual sites and types of thrombosis (e.g. Budd-Chiari Syndrome) may point towards a coagulation disorder.

Increasingly, recurrent miscarriage is seen as an indication for thrombophilia screening. (Dawood et al, 2004)

Thrombophilia can be classified in various forms.

  • The most common classification is by the nature of the thrombosis: arterial, venous or combined.
  • Crowther & Kelton (2003) propose to classify the abnormality by the molecular deficiency, type I being the (severe) deficiencies of inhibitors, and type II being the less severe elevation of coagulation factors.
  • Acquired vs. congenital

Common types:

  • Factor V, Leiden (5% of the population are heterozygous for FVL).
  • Prothrombin mutation (G20210A, 5'UTR).
  • High homocysteine levels due to MTHFR mutation or vitamin deficiency (vitamins B6, B12 and folic acid).
  • Antiphospholipid antibodies
    • anticardiolipin antibodies and/or
    • lupus anticoagulants
  • Renal disease (renal loss of antithrombin)

Rare forms:

  • Plasminogen and fibrinolysis disorders.
  • Paroxysmal nocturnal hemoglobinuria
  • Protein C deficiency.
  • Protein S deficiency.
  • Antithrombin III deficiency.

Tests for thrombophilia include prothrombin time and INR, partial thromboplastin time, thrombin time, fibrinogen levels, antiphospholipid antibody levels (IgG- and IgM-anticardiolipin, dilute Russell viper venom time and lupus anticoagulant), protein C, protein S and antithrombin (both levels and activity), activated protein C resistance (APC resistance), Factor V Leiden and prothrombin mutation. Many laboratories add on various other tests, depending on local policy and guidelines.

Virchow's Triad:The following are considered the contributors of Virchow's Triad:

  1. Alterations in blood flow ( Hemostasis)
  2. Injury to the vascular endothelium
  3. Alterations in the constitution of blood (hypercoaqulability)

The origin of the term Virchow's Triad is of historical interest. Rudolf Virchow elucidated the etiology of pulmonary thromboembolism, whereby thrombi occurring within the veins -- particularly those of the extremities -- become dislodged and migrate to the pulmonary vasculature. In detailing the pathophysiology surrounding pulmonary embolism, Virchow alluded to many of the factors known to contribute to venous thrombosis. While these factors had already been previously established in the medical literature by others, for unclear reasons they ultimately became known as Virchow's Triad.

Thus, the elements comprising Virchow's Triad were neither proposed by Virchow, nor did he ever suggest a triad to describe the pathogenesis of venous thrombosis. In fact, it was decades following Virchow's death before a consensus was reached proposing that thrombosis is the result of alterations in blood flow, vascular endothelial injury, or alterations in the constitution of the blood. Moreover, the eponym Virchow's Triad did not emerge in the literature until almost 150 years after his original work. Its nebulous origins notwithstanding, Virchow's Triad remains a useful concept for clinicians and pathologists alike in understanding the contributors to venous, and perhaps arterial, thrombosis.

Warfarin (also known under the brand names of Coumadin®, Jantoven®, Marevan®, and Waran®) is ananticoagulant medication that is administered orally or, very rarely, by injection. It is used for the prophlaxis of thrombosis and embolism in many disorders. Its activity has to be monitored by frequent blood testing for the international normalised ratio (INR). It is named for the Wisconsin Alumni Research Foundation.

Warfarin is a synthetic derivative of coumarin, a chemical found naturally in many plants, notably woodruff (Galium odoratum, Rubiaceae), and at lower levels in liquorice, lavender and various other species. Warfarin was originally developed as a rat poison, but it is no longer used for that purpose as modern poisons are much more potent and toxic (e.g. brodifacoum). However, warfarin and contemporary rodenticides belong to the same class of drugs (coumarins) and both decrease blood coagulation by interfering with vitamin K metabolism.