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An ultrasound image demonstrating a blood clot in the left common femoral vein.
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Thrombophilia (sometimes called hypercoagulability or a prothrombotic state) is an abnormality of blood coagulation that increases the risk of thrombosis (blood clots in blood vessels). [1] [2] 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. [3] A significant proportion of the population has a detectable thrombophilic abnormality, but most of these develop thrombosis only in the presence of an additional risk factor. [2]


There is no specific treatment for most thrombophilias, but recurrent episodes of thrombosis may be an indication for long-term preventive anticoagulation. [2] The first major form of thrombophilia to be identified by medical science, antithrombin deficiency, was identified in 1965, while the most common abnormalities (including factor V Leiden) were described in the 1990s. [4] [5]

Signs and symptoms

A right-sided acute deep vein thrombosis (to the left in the image). The leg is swollen and red due to venous outflow obstruction. Deep vein thrombosis of the right leg.jpg
A right-sided acute deep vein thrombosis (to the left in the image). The leg is swollen and red due to venous outflow obstruction.

The most common conditions associated with thrombophilia are deep vein thrombosis (DVT) and pulmonary embolism (PE), which are referred to collectively as venous thromboembolism (VTE). DVT usually occurs in the legs, and is characterized by pain, swelling and redness of the limb. It may lead to long-term swelling and heaviness due to damage to valves in the veins. [6] The clot may also break off and migrate (embolize) to arteries in the lungs. Depending on the size and the location of the clot, this may lead to sudden-onset shortness of breath, chest pain, palpitations and may be complicated by collapse, shock and cardiac arrest. [2] [7]

Venous thrombosis may also occur in more unusual places: in the veins of the brain, liver (portal vein thrombosis and hepatic vein thrombosis), mesenteric vein, kidney (renal vein thrombosis) and the veins of the arms. [2] Whether thrombophilia also increases the risk of arterial thrombosis (which is the underlying cause of heart attacks and strokes) is less well established. [2] [8] [9] However, more recent data suggest some forms of inherited thrombophilia are associated with increased risk for arterial ischemic stroke. [10]

Thrombophilia has been linked to recurrent miscarriage, [11] and possibly various complications of pregnancy such as intrauterine growth restriction, stillbirth, severe pre-eclampsia and abruptio placentae. [2]

Protein C deficiency may cause purpura fulminans, a severe clotting disorder in the newborn that leads to both tissue death and bleeding into the skin and other organs. The condition has also been described in adults. Protein C and protein S deficiency have also been associated with an increased risk of skin necrosis on commencing anticoagulant treatment with warfarin or related drugs. [2] [12]


Thrombophilia can be congenital or acquired. Congenital thrombophilia refers to inborn conditions (and usually hereditary, in which case "hereditary thrombophilia" may be used) that increase the tendency to develop thrombosis, while, on the other hand, acquired thrombophilia refers to conditions that arise later in life.


The most common types of congenital thrombophilia are those that arise as a result of overactivity of coagulation factors. They are relatively mild, and are therefore classified as "type II" defects. [13] [14] The most common ones are factor V Leiden (a mutation in the F5 gene at position 1691) and prothrombin G20210A, a mutation in prothrombin (at position 20210 in the 3' untranslated region of the gene). [1] [15]

The rare forms of congenital thrombophilia are typically caused by a deficiency of natural anticoagulants. They are classified as "type I" and are more severe in their propensity to cause thrombosis. [13] The main ones are antithrombin III deficiency, protein C deficiency and protein S deficiency. [1] [15] Milder rare congenital thrombophilias are factor XIII mutation [15] and familial dysfibrinogenemia (an abnormal fibrinogen). [15] It is unclear whether congenital disorders of fibrinolysis (the system that destroys clots) are major contributors to thrombosis risk. [13] Congenital deficiency of plasminogen, for instance, mainly causes eye symptoms and sometimes problems in other organs, but the link with thrombosis has been more uncertain. [16]

Blood group determines thrombosis risk to a significant extent. Those with blood groups other than type O are at a 2- to 4-fold relative risk. O blood group is associated with reduced levels of von Willebrand factor – because of increased clearance – and factor VIII, which is related to thrombotic risk . [5]


A number of acquired conditions augment the risk of thrombosis. A prominent example is antiphospholipid syndrome, [1] [15] which is caused by antibodies against constituents of the cell membrane, particularly lupus anticoagulant (first found in people with the disease systemic lupus erythematosus but often detected in people without the disease), anti-cardiolipin antibodies, and anti-β2-glycoprotein 1 antibodies; it is therefore regarded as an autoimmune disease. In some cases, antiphospholipid syndrome can cause arterial as well as venous thrombosis. It is also more strongly associated with miscarriage, and can cause a number of other symptoms (such as livedo reticularis of the skin and migraine). [17]

Heparin-induced thrombocytopenia (HIT) is due to an immune system reaction against the anticoagulant drug heparin (or its derivatives). [1] Though it is named for associated low platelet counts, HIT is strongly associated with risk of venous and arterial thrombosis. [18] Paroxysmal nocturnal hemoglobinuria (PNH) is a rare condition resulting from acquired alterations in the PIGA gene, which plays a role in the protection of blood cells from the complement system. PNH increases the risk of venous thrombosis but is also associated with hemolytic anemia (anemia resulting from destruction of red blood cells). [19] Both HIT and PNH require particular treatment. [18] [19]

Hematologic conditions associated with sluggish blood flow can increase risk for thrombosis. For example, sickle-cell disease (caused by mutations of hemoglobin) is regarded as a mild prothrombotic state induced by impaired flow. [1] Similarly, myeloproliferative disorders, in which the bone marrow produces too many blood cells, predispose to thrombosis, particularly in polycythemia vera (excess red blood cells) and essential thrombocytosis (excess platelets). Again, these conditions usually warrant specific treatment when identified. [20]

Cancer, particularly when metastatic (spread to other places in the body), is a recognised risk factor for thrombosis. [2] [15] A number of mechanisms have been proposed, such as activation of the coagulation system by cancer cells or secretion of procoagulant substances. Furthermore, particular cancer treatments (such as the use of central venous catheters for chemotherapy) may increase the risk of thrombosis further. [21]

Nephrotic syndrome, in which protein from the bloodstream is released into the urine due to kidney diseases, can predispose to thrombosis; [1] this is particularly the case in more severe cases (as indicated by blood levels of albumin below 25 g/L) and if the syndrome is caused by the condition membranous nephropathy. [22] Inflammatory bowel disease (ulcerative colitis and Crohn's disease) predispose to thrombosis, particularly when the disease is active. Various mechanisms have been proposed. [2] [23]

Pregnancy is associated with an increased risk of thrombosis of 2- to 7-fold. [24] This probably results from a physiological hypercoagulability in pregnancy that protects against postpartum hemorrhage. [25] This hypercoagulability in turn is likely related to the high levels of estradiol and progesterone that occur during pregnancy. [26]

Estrogens, when used in combined hormonal birth control and in menopausal hormone therapy (in combination with progestogens), have been associated with a 2- to 6-fold increased risk of venous thrombosis. The risk depends on the types of hormones used, the dose of estrogen, and the presence of other thrombophilic risk factors. [27] Various mechanisms, such as deficiency of protein S and tissue factor pathway inhibitor, are said to be responsible. [28]

Obesity has long been regarded as a risk factor for venous thrombosis. It more than doubles the risk in numerous studies, particularly in combination with the use of oral contraceptives or in the period after surgery. Various coagulation abnormalities have been described in the obese. Plasminogen activator inhibitor-1, an inhibitor of fibrinolysis, is present in higher levels in people with obesity. Obese people also have larger numbers of circulating microvesicles (fragments of damaged cells) that bear tissue factor. Platelet aggregation may be increased, and there are higher levels of coagulation proteins such as von Willebrand factor, fibrinogen, factor VII and factor VIII. Obesity also increases the risk of recurrence after an initial episode of thrombosis. [29]


A number of conditions that have been linked with venous thrombosis are possibly genetic and possibly acquired. [15] These include: elevated levels of factor VIII, factor IX, factor XI, fibrinogen and thrombin-activatable fibrinolysis inhibitor, and decreased levels of tissue factor pathway inhibitor. Activated protein C resistance that is not attributable to factor V mutations is probably caused by other factors and remains a risk factor for thrombosis. [15]

There is an association between the blood levels of homocysteine and thrombosis, [15] although this has not been reported consistently in all studies. [5] Homocysteine levels are determined by mutations in the MTHFR and CBS genes, but also by levels of folic acid, vitamin B6 and vitamin B12, which depend on diet. [13]


The coagulation system, often described as a "cascade", consists of a group of proteins that interact in the formation of a fibrin-rich clot. Coagulation full.svg
The coagulation system, often described as a "cascade", consists of a group of proteins that interact in the formation of a fibrin-rich clot.

Thrombosis is a multifactorial problem because there are often multiple reasons why a person might develop thrombosis. These risk factors may include any combination of abnormalities in the blood vessel wall, abnormalities in the blood flow (as in immobilization), and abnormalities in the consistency of the blood. Thrombophilia is caused by abnormalities in blood consistency, which is determined by the levels of coagulation factors and other circulating blood proteins that participate in the "coagulation cascade". [15]

Normal coagulation is initiated by the release of tissue factor from damaged tissue. Tissue factor binds to circulating factor VIIa. The combination activates factor X to factor Xa and factor IX to factor IXa. Factor Xa (in the presence of factor V) activates prothrombin into thrombin. Thrombin is a central enzyme in the coagulation process: it generates fibrin from fibrinogen, and activates a number of other enzymes and cofactors (factor XIII, factor XI, factor V and factor VIII, TAFI) that enhance the fibrin clot. [13] The process is inhibited by TFPI (which inactivates the first step catalyzed by factor VIIa/tissue factor), antithrombin (which inactivates thrombin, factor IXa, Xa and XIa), protein C (which inhibits factors Va and VIIIa in the presence of protein S), and protein Z (which inhibits factor Xa). [13]

In thrombophilia, the balance between "procoagulant" and "anticoagulant" activity is disturbed. The severity of the imbalance determines the likelihood that someone develops thrombosis. Even small perturbances of proteins, such as the reduction of antithrombin to only 70–80% of the normal level, can increase the thrombosis risk; this is in contrast with hemophilia, which only arises if levels of coagulation factors are markedly decreased. [13]

In addition to its effects on thrombosis, hypercoagulable states may accelerate the development of atherosclerosis, the arterial disease that underlies myocardial infarction and other forms of cardiovascular disease. [30] [31]


A mutation of coagulation factor V (schematic representation drawn here) is much more common in people with thrombosis than in those without, but is only regarded as a weak risk factor. Protein F5 PDB 1czs.png
A mutation of coagulation factor V (schematic representation drawn here) is much more common in people with thrombosis than in those without, but is only regarded as a weak risk factor.

Tests for thrombophilia include complete blood count (with examination of the blood film), prothrombin time, partial thromboplastin time, thrombodynamics test, thrombin time and reptilase time, lupus anticoagulant, anti-cardiolipin antibody, anti-β2 glycoprotein 1 antibody, activated protein C resistance, fibrinogen tests, factor V Leiden and prothrombin mutation, and basal homocysteine levels. [2] Testing may be more or less extensive depending on clinical judgement and abnormalities detected on initial evaluation. [2]

For hereditary cases, the patient must have at least two abnormal tests plus family history.


There are divergent views as to whether everyone with an unprovoked episode of thrombosis should be investigated for thrombophilia. Even those with a form of thrombophilia may not necessarily be at risk of further thrombosis, while recurrent thrombosis is more likely in those who have had previous thrombosis even in those who have no detectable thrombophilic abnormalities. [8] [12] [32] Recurrent thromboembolism, or thrombosis in unusual sites (e.g. the hepatic vein in Budd-Chiari syndrome), is a generally accepted indication for screening. It is more likely to be cost-effective in people with a strong personal or family history of thrombosis. [33] In contrast, the combination of thrombophilia with other risk factors may provide an indication for preventive treatment, which is why thrombophilia testing may be performed even in those who would not meet the strict criteria for these tests. [32] Searching for a coagulation abnormality is not normally undertaken in patients in whom thrombosis has an obvious trigger. For example, if the thrombosis is due to immobilization after recent orthopedic surgery, it is regarded as "provoked" by the immobilization and the surgery and it is less likely that investigations will yield clinically important results. [12] [32]

When venous thromboembolism occurs when a patient is experiencing transient major risk factors such as prolonged immobility, surgery, or trauma, testing for thrombophilia is not appropriate because the outcome of the test would not change a patient's indicated treatment. [34] [35] In 2013, the American Society of Hematology, as part of recommendations in the Choosing Wisely campaign, cautioned against overuse of thrombophilia screening; false positive results of testing would lead to people inappropriately being labeled as having thrombophilia, and being treated with anticoagulants without clinical need [34]

In the United Kingdom, professional guidelines give specific indications for thrombophilia testing. It is recommended that testing be done only after appropriate counseling, and hence the investigations are usually not performed at the time when thrombosis is diagnosed but at a later time. [12] In particular situations, such as retinal vein thrombosis, testing is discouraged altogether because thrombophilia is not regarded as a major risk factor. In other rare conditions generally linked with hypercoagulability, such as cerebral venous thrombosis and portal vein thrombosis, there is insufficient data to state for certain whether thrombophilia screening is helpful, and decisions on thrombophilia screening in these conditions are therefore not regarded as evidence-based. [12] If cost-effectiveness (quality-adjusted life years in return for expenditure) is taken as a guide, it is generally unclear whether thrombophilia investigations justify the often high cost, [36] unless the testing is restricted to selected situations. [37]

Recurrent miscarriage is an indication for thrombophilia screening, particularly antiphospholipid antibodies (anti-cardiolipin IgG and IgM, as well as lupus anticoagulant), factor V Leiden and prothrombin mutation, activated protein C resistance and a general assessment of coagulation through an investigation known as thromboelastography. [11]

Women who are planning to use oral contraceptives do not benefit from routine screening for thrombophilias, as the absolute risk of thrombotic events is low. If either the woman or a first-degree relative has had thrombosis, the risk of developing thrombosis is increased. Screening this selected group may be beneficial, [28] but even when negative may still indicate residual risk. [12] Professional guidelines therefore suggest that alternative forms of contraception be used rather than relying on screening. [12]

Thrombophilia screening in people with arterial thrombosis is generally regarded as unrewarding and is generally discouraged, [12] except possibly for unusually young patients (especially when precipitated by smoking or use of estrogen-containing hormonal contraceptives) and those in whom revascularization, such as coronary arterial bypass, fails because of rapid occlusion of the graft. [9]


People considered to be at a high risk of repeated thrombosis due to thrombophilia are often advised to take warfarin for prolonged periods of time or even indefinitely. Warfarintablets5-3-1.jpg
People considered to be at a high risk of repeated thrombosis due to thrombophilia are often advised to take warfarin for prolonged periods of time or even indefinitely.

There is no specific treatment for thrombophilia, unless it is caused by an underlying medical illness (such as nephrotic syndrome), where the treatment of the underlying disease is needed. In those with unprovoked and/or recurrent thrombosis, or those with a high-risk form of thrombophilia, the most important decision is whether to use anticoagulation medications, such as warfarin, on a long-term basis to reduce the risk of further episodes. [3] This risk needs to weighed against the risk that the treatment will cause significant bleeding, as the reported risk of major bleeding is over 3% per year, and 11% of those with major bleeding may die as a result. [3]

Apart from the abovementioned forms of thrombophilia, the risk of recurrence after an episode of thrombosis is determined by factors such as the extent and severity of the original thrombosis, whether it was provoked (such as by immobilization or pregnancy), the number of previous thrombotic events, male sex, the presence of an inferior vena cava filter, the presence of cancer, symptoms of post-thrombotic syndrome, and obesity. [3] These factors tend to be more important in the decision than the presence or absence of a detectable thrombophilia. [12] [38]

Those with antiphospholipid syndrome may be offered long-term anticoagulation after a first unprovoked episode of thrombosis. The risk is determined by the subtype of antibody detected, by the antibody titer (amount of antibodies), whether multiple antibodies are detected, and whether it is detected repeatedly or only on a single occasion. [17]

Women with a thrombophilia who are contemplating pregnancy or are pregnant usually require alternatives to warfarin during pregnancy, especially in the first 13 weeks, when it may produce abnormalities in the unborn child. Low molecular weight heparin (LMWH, such as enoxaparin) is generally used as an alternative. [39] Warfarin and LMWH may safely be used in breastfeeding. [39]

When women experience recurrent pregnancy loss secondary to thrombophilia, some studies have suggested that low molecular weight heparin reduces the risk of miscarriage. When the results of all studies are analysed together, no statistically significant benefit could be demonstrated. [40]


In people without a detectable thrombophilia, the cumulative risk of developing thrombosis by the age of 60 is about 12%. About 60% of people who are deficient in antithrombin will have experienced thrombosis at least once by age 60, as will about 50% of people with protein C deficiency and about a third of those with protein S deficiency. People with activated protein C resistance (usually resulting from factor V Leiden), in contrast, have a slightly raised absolute risk of thrombosis, with 15% having had at least one thrombotic event by the age of sixty. [13] In general, men are more likely than women to experience repeated episodes of venous thrombosis. [5]

People with factor V Leiden are at a relatively low risk of thrombosis, but may develop thrombosis in the presence of an additional risk factor, such as immobilization. Most people with the prothrombin mutation (G20210A) never develop thrombosis. [13]


The major ("type 1") thrombophilias are rare. Antithrombin deficiency is present in 0.2% of the general population and 0.5–7.5% of people with venous thrombosis. Protein C deficiency, too, is present in 0.2% of the population, and can be found in 2.5–6% of people with thrombosis. The exact prevalence of protein S deficiency in the population is unknown; it is found 1.3–5% of people with thrombosis. [13]

The minor ("type 2") thrombophilias are much more common. Factor V Leiden is present in 5% of the population of Northern European descent, but much rarer in those of Asian or African extraction. In people with thrombosis, 10% have factor V Leiden. In those who are referred for thrombophilia testing, 30–50% have the defect. The prothrombin mutation occurs at rates of 1–4% in the general population, 5–10% of people with thrombosis, and 15% of people referred for thrombophilia testing. Like factor V Leiden, this abnormality is uncommon in Africans and Asians. [13]

The exact prevalence of antiphospholipid syndrome is not well known, as different studies employ different definitions of the condition. Antiphospholipid antibodies are detected in 24% of those referred to thrombophilia testing. [17]


Rudolf Virchow, the German pathologist who distinguished the various causes of thrombosis, and whose work led to the development of thrombophilia as a concept Rudolf Virchow.jpg
Rudolf Virchow, the German pathologist who distinguished the various causes of thrombosis, and whose work led to the development of thrombophilia as a concept

German physician Rudolf Virchow categorized abnormalities in the consistency of the blood as a factor in the development of thrombosis in 1856. The exact nature of these abnormalities remained elusive until the first form of thrombophilia, antithrombin deficiency, was recognized in 1965 by the Norwegian hematologist Olav Egeberg. [41] Protein C deficiency followed in 1981, when described by researchers from the Scripps Research Institute and the U.S. Centers of Disease Control. [42] Protein S deficiency followed in 1984, described by researchers at the University of Oklahoma. [4] [5] [43]

Antiphospholipid syndrome was described in full in the 1980s, after various previous reports of specific antibodies in people with systemic lupus erythematosus and thrombosis. [17] [44] The syndrome is often attributed to the British rheumatologist Graham R.V. Hughes, and is often referred to as Hughes syndrome for that reason. [45]

The more common genetic thrombophilias were described in the 1990s. Many studies had previously indicated that many people with thrombosis showed resistance activated protein C. In 1994 a group in Leiden, The Netherlands, identified the most common underlying defect—a mutation in factor V that made it resistant to the action of activated protein C. The defect was called factor V Leiden, as genetic abnormalities are typically named after the place where they are discovered. [46] Two years later, the same group described a common mutation in the prothrombin gene that caused elevation of prothrombin levels and a mild increase in thrombosis risk. [4] [5] [47]

It is suspected that other genetic abnormalities underlying familial thrombosis will in future be discovered through studies of the entire genetic code, looking for small alternations in genes. [4] [5]

Related Research Articles

<span class="mw-page-title-main">Venous thrombosis</span> Blood clot (thrombus) that forms within a vein

Venous thrombosis is the blockage of a vein caused by a thrombus. A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to lodge there, it becomes a pulmonary embolism (PE), a blood clot in the lungs. The conditions of DVT only, DVT with PE, and PE only, are all captured by the term venous thromboembolism (VTE).

<span class="mw-page-title-main">Coagulation</span> Process of formation of blood clots

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. 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, as well as deposition and maturation of fibrin.

<span class="mw-page-title-main">Antiphospholipid syndrome</span> Medical condition

Antiphospholipid syndrome, or antiphospholipid antibody syndrome, is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS can lead to blood clots (thrombosis) in both arteries and veins, pregnancy-related complications, and other symptoms like low platelets, kidney disease, heart disease, and rash. Although the exact etiology of APS is still not clear, genetics is believed to play a key role in the development of the disease. Diagnosis is made based on symptoms and testing, but sometimes research criteria are used to aid in diagnosis. The research criteria for definite APS requires one clinical event and two positive blood test results spaced at least three months apart that detect lupus anticoagulant, anti-apolipoprotein antibodies, and/or anti-cardiolipin antibodies.

Factor V Leiden is a variant of human factor V, which causes an increase in blood clotting (hypercoagulability). Due to this mutation, protein C, an anticoagulant protein that normally inhibits the pro-clotting activity of factor V, is not able to bind normally to factor V, leading to a hypercoagulable state, i.e., an increased tendency for the patient to form abnormal and potentially harmful blood clots. Factor V Leiden is the most common hereditary hypercoagulability disorder amongst ethnic Europeans. It is named after the Dutch city of Leiden, where it was first identified in 1994 by Rogier Maria Bertina under the direction of Pieter Hendrick Reitsma. Despite the increased risk of venous thromboembolisms, people with one copy of this gene have not been found to have shorter lives than the general population. It is an autosomal dominant genetic disorder with incomplete penetrance.

<span class="mw-page-title-main">Thrombin</span> Enzyme involved in blood coagulation in humans

Thrombin is a serine protease, an enzyme that, in humans, is encoded by the F2 gene. During the clotting process, prothrombin is proteolytically cleaved by the prothrombinase enzyme complex to form thrombin. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.

<span class="mw-page-title-main">Deep vein thrombosis</span> Formation of a blood clot (thrombus) in a deep vein

Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enlarged veins in the affected area, but some DVTs have no symptoms. The most common life-threatening concern with DVT is the potential for a clot to embolize, travel as an embolus through the right side of the heart, and become lodged in a pulmonary artery that supplies blood to the lungs. This is called a pulmonary embolism (PE). DVT and PE comprise the cardiovascular disease of venous thromboembolism (VTE). About two-thirds of VTE manifests as DVT only, with one-third manifesting as PE with or without DVT. The most frequent long-term DVT complication is post-thrombotic syndrome, which can cause pain, swelling, a sensation of heaviness, itching, and in severe cases, ulcers. Recurrent VTE occurs in about 30% of those in the ten years following an initial VTE.

<span class="mw-page-title-main">Budd–Chiari syndrome</span> Medical condition

Budd–Chiari syndrome is a very rare condition, affecting one in a million adults. The condition is caused by occlusion of the hepatic veins that drain the liver. The symptoms are non-specific and vary widely, but it may present with the classical triad of abdominal pain, ascites, and liver enlargement. It is usually seen in younger adults, with the median age at diagnosis between the ages of 35 and 40, and it has a similar incidence in males and females. The syndrome can be fulminant, acute, chronic, or asymptomatic. Subacute presentation is the most common form.

<span class="mw-page-title-main">Partial thromboplastin time</span> Test for coagulation of blood

The partial thromboplastin time (PTT), also known as the activated partial thromboplastin time, is a blood test that characterizes coagulation of the blood. A historical name for this measure is the kaolin-cephalin clotting time (KCCT), reflecting kaolin and cephalin as materials historically used in the test. Apart from detecting abnormalities in blood clotting, partial thromboplastin time is also used to monitor the treatment effect of heparin, a widely prescribed drug that reduces blood's tendency to clot.

Lupus anticoagulant is an immunoglobulin that binds to phospholipids and proteins associated with the cell membrane. Its name is a partial misnomer, as it is actually a prothrombotic antibody in vivo. Lupus anticoagulant in living systems causes a decrease in clotting time. The name derives from their properties in vitro, as these antibodies increase coagulation times in laboratory tests such as the activated partial thromboplastin time (aPTT). Investigators speculate that the antibodies interfere with phospholipids used to induce in vitro coagulation. In vivo, the antibodies are thought to interact with platelet membrane phospholipids, increasing adhesion and aggregation of platelets, which accounts for the in vivo prothrombotic characteristics.

<span class="mw-page-title-main">Protein S deficiency</span> Medical condition

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 activate protein C in the degradation of factor Va and factor VIIIa.

<span class="mw-page-title-main">Factor V</span> Mammalian protein found in humans

Factor V is a protein of the coagulation system, rarely referred to as proaccelerin or labile 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 predispose for thrombosis.

<span class="mw-page-title-main">Dilute Russell's viper venom time</span>

Dilute Russell's viper venom time (dRVVT) is a laboratory test often used for detection of lupus anticoagulant (LA).

The prothrombinase enzyme complex consists of factor Xa (a serine protease) and factor Va (a protein cofactor). 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, to thrombin (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.

<span class="mw-page-title-main">Renal vein thrombosis</span> Medical condition

Renal vein thrombosis (RVT) is the formation of a clot in the vein that drains blood from the kidneys, ultimately leading to a reduction in the drainage of one or both kidneys and the possible migration of the clot to other parts of the body. First described by German pathologist Friedrich Daniel von Recklinghausen in 1861, RVT most commonly affects two subpopulations: newly born infants with blood clotting abnormalities or dehydration and adults with nephrotic syndrome.

<span class="mw-page-title-main">Activated protein C resistance</span> Medical condition

Activated protein C resistance (APCR) is a hypercoagulability characterized by a lack of a response to activated protein C (APC), which normally helps prevent blood from clotting excessively. This results in an increased risk of venous thrombosis, which resulting in medical conditions such as deep vein thrombosis and pulmonary embolism. The most common cause of hereditary APC resistance is factor V Leiden mutation.

<span class="mw-page-title-main">Protein C deficiency</span> Medical condition

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, whereas no association with arterial thrombotic disease has been found.

Antithrombin III deficiency is a deficiency of antithrombin III. This deficiency may be inherited or acquired. 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). Hereditary antithrombin deficiency results in a state of increased coagulation which may lead to venous thrombosis. Inheritance is usually autosomal dominant, though a few recessive cases have been noted. The disorder was first described by Egeberg in 1965. The causes of acquired antithrombin deficiency are easier to find than the hereditary deficiency.

Hypercoagulability in pregnancy is the propensity of pregnant women to develop thrombosis. Pregnancy itself is a factor of hypercoagulability, as a physiologically adaptive mechanism to prevent post partum bleeding. However, when combined with an additional underlying hypercoagulable states, the risk of thrombosis or embolism may become substantial.

Prothrombin G20210A is a genetic condition that increases the risk of blood clots including from deep vein thrombosis, and of pulmonary embolism. One copy of the mutation increases the risk of a blood clot from 1 in 1,000 per year to 2.5 in 1,000. Two copies increases the risk to up to 20 in 1,000 per year. Most people never develop a blood clot in their lifetimes.

Prothrombin fragment 1+2 (F1+2), also written as prothrombin fragment 1.2 (F1.2), is a polypeptide fragment of prothrombin generated by the in vivo cleavage of prothrombin into thrombin by the enzyme prothrombinase. It is released from the N-terminus of prothrombin. F1+2 is a marker of thrombin generation and hence of coagulation activation. It is considered the best marker of in vivo thrombin generation.


  1. 1 2 3 4 5 6 7 Mitchell RS, Kumar V, Abbas AK, Fausto N (2007). "Chapter 4". Robbins Basic Pathology (Eighth ed.). Philadelphia: Saunders. ISBN   978-1-4160-2973-1.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 Heit JA (2007). "Thrombophilia: common questions on laboratory assessment and management". Hematology Am. Soc. Hematol. Educ. Program. 2007 (1): 127–35. doi: 10.1182/asheducation-2007.1.127 . PMID   18024620.
  3. 1 2 3 4 Kyrle PA, Rosendaal FR, Eichinger S (December 2010). "Risk assessment for recurrent venous thrombosis". Lancet. 376 (9757): 2032–9. doi:10.1016/S0140-6736(10)60962-2. PMID   21131039. S2CID   31610364.
  4. 1 2 3 4 Dahlbäck B (July 2008). "Advances in understanding pathogenic mechanisms of thrombophilic disorders". Blood. 112 (1): 19–27. doi: 10.1182/blood-2008-01-077909 . PMID   18574041.
  5. 1 2 3 4 5 6 7 Rosendaal FR, Reitsma PH (July 2009). "Genetics of venous thrombosis". J. Thromb. Haemost. 7 (Suppl 1): 301–4. doi: 10.1111/j.1538-7836.2009.03394.x . PMID   19630821.
  6. Scarvelis D, Wells PS (October 2006). "Diagnosis and treatment of deep-vein thrombosis". CMAJ. 175 (9): 1087–92. doi:10.1503/cmaj.060366. PMC   1609160 . PMID   17060659.
  7. Agnelli G, Becattini C (July 2010). "Acute pulmonary embolism". N. Engl. J. Med. 363 (3): 266–74. doi:10.1056/NEJMra0907731. PMID   20592294.
  8. 1 2 Middeldorp S, van Hylckama Vlieg A (August 2008). "Does thrombophilia testing help in the clinical management of patients?". Br. J. Haematol. 143 (3): 321–35. doi: 10.1111/j.1365-2141.2008.07339.x . PMID   18710381.
  9. 1 2 de Moerloose P, Boehlen F (April 2007). "Inherited thrombophilia in arterial disease: a selective review". Semin. Hematol. 44 (2): 106–13. doi:10.1053/j.seminhematol.2007.01.008. PMID   17433903.
  10. Chiasakul T, De Jesus E, Tong J, Chen Y, Crowther M, Garcia D, Chai-Adisaksopha C, Messé SR, Cuker A (October 2019). "Inherited Thrombophilia and the Risk of Arterial Ischemic Stroke: A Systematic Review and Meta-Analysis". Journal of the American Heart Association. 8 (19): e012877. doi:10.1161/JAHA.119.012877. ISSN   2047-9980. PMC   6806047 . PMID   31549567.
  11. 1 2 Rai R, Regan L (August 2006). "Recurrent miscarriage". Lancet. 368 (9535): 601–11. doi:10.1016/S0140-6736(06)69204-0. PMID   16905025. S2CID   42968924.
  12. 1 2 3 4 5 6 7 8 9 Baglin T, Gray E, Greaves M, et al. (April 2010). "Clinical guidelines for testing for heritable thrombophilia". Br. J. Haematol. 149 (2): 209–20. doi: 10.1111/j.1365-2141.2009.08022.x . PMID   20128794.
  13. 1 2 3 4 5 6 7 8 9 10 11 Crowther MA, Kelton JG (2003). "Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system". Ann. Intern. Med. 138 (2): 128–34. doi:10.7326/0003-4819-138-2-200301210-00014. PMID   12529095. S2CID   43161448.
  14. "Congenital Causes of Venous Thrombosis—A Classification System". Annals of Internal Medicine. American College of Physicians. 138 (2): I. January 21, 2003. doi:10.7326/0003-4819-138-2-200301210-00005. S2CID   53089216.
  15. 1 2 3 4 5 6 7 8 9 10 Rosendaal FR (2005). "Venous thrombosis: the role of genes, environment, and behavior". Hematology Am. Soc. Hematol. Educ. Program. 2005 (1): 1–12. doi: 10.1182/asheducation-2005.1.1 . PMID   16304352.
  16. Mehta R, Shapiro AD (November 2008). "Plasminogen deficiency". Haemophilia. 14 (6): 1261–8. doi: 10.1111/j.1365-2516.2008.01825.x . PMID   19141167.
  17. 1 2 3 4 Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA (October 2010). "Antiphospholipid syndrome". Lancet. 376 (9751): 1498–509. doi:10.1016/S0140-6736(10)60709-X. hdl: 2318/1609788 . PMID   20822807. S2CID   25554663.
  18. 1 2 Keeling D, Davidson S, Watson H (May 2006). "The management of heparin-induced thrombocytopenia". Br. J. Haematol. 133 (3): 259–69. doi: 10.1111/j.1365-2141.2006.06018.x . PMID   16643427.
  19. 1 2 Brodsky RA (April 2008). "Narrative review: paroxysmal nocturnal hemoglobinuria: the physiology of complement-related hemolytic anemia". Ann. Intern. Med. 148 (8): 587–95. CiteSeerX . doi:10.7326/0003-4819-148-8-200804150-00003. PMID   18413620. S2CID   19715590.
  20. Papadakis E, Hoffman R, Brenner B (November 2010). "Thrombohemorrhagic complications of myeloproliferative disorders". Blood Rev. 24 (6): 227–32. doi:10.1016/j.blre.2010.08.002. PMID   20817333.
  21. Prandoni P, Falanga A, Piccioli A (June 2005). "Cancer and venous thromboembolism". Lancet Oncol. 6 (6): 401–10. doi:10.1016/S1470-2045(05)70207-2. PMID   15925818.
  22. Hull RP, Goldsmith DJ (May 2008). "Nephrotic syndrome in adults". BMJ. 336 (7654): 1185–9. doi:10.1136/bmj.39576.709711.80. PMC   2394708 . PMID   18497417.
  23. Quera R, Shanahan F (October 2004). "Thromboembolism--an important manifestation of inflammatory bowel disease". Am. J. Gastroenterol. 99 (10): 1971–3. doi:10.1111/j.1572-0241.2004.40923.x. PMID   15447758. S2CID   11391129.
  24. Abdul Sultan A, West J, Stephansson O, Grainge MJ, Tata LJ, Fleming KM, Humes D, Ludvigsson JF (November 2015). "Defining venous thromboembolism and measuring its incidence using Swedish health registries: a nationwide pregnancy cohort study". BMJ Open. 5 (11): e008864. doi:10.1136/bmjopen-2015-008864. PMC   4654387 . PMID   26560059.
  25. Bourjeily G, Paidas M, Khalil H, Rosene-Montella K, Rodger M (February 2010). "Pulmonary embolism in pregnancy". Lancet. 375 (9713): 500–12. doi:10.1016/S0140-6736(09)60996-X. PMID   19889451. S2CID   8633455.
  26. Daughety MM, Samuelson Bannow BT (2019). "Hemostasis and Thrombosis in Pregnancy". Hemostasis and Thrombosis. pp. 197–206. doi:10.1007/978-3-030-19330-0_30. ISBN   978-3-030-19329-4. S2CID   201995636.
  27. Gomes MP, Deitcher SR (October 2004). "Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy: a clinical review". Arch. Intern. Med. 164 (18): 1965–76. doi:10.1001/archinte.164.18.1965. PMID   15477430.
  28. 1 2 Tchaikovski SN, Rosing J (July 2010). "Mechanisms of estrogen-induced venous thromboembolism". Thromb. Res. 126 (1): 5–11. doi:10.1016/j.thromres.2010.01.045. PMID   20163835.
  29. Stein PD, Goldman J (September 2009). "Obesity and thromboembolic disease". Clin. Chest Med. 30 (3): 489–93, viii. doi:10.1016/j.ccm.2009.05.006. PMID   19700047.
  30. Borissoff JI, Spronk HM, Heeneman S, ten Cate H (2009). "Is thrombin a key player in the 'coagulation-atherogenesis' maze?". Cardiovasc. Res. 82 (3): 392–403. doi: 10.1093/cvr/cvp066 . PMID   19228706.
  31. Borissoff JI, Spronk HM, ten Cate H (2011). "The hemostatic system as a modulator of atherosclerosis". N. Engl. J. Med. 364 (18): 1746–1760. doi:10.1056/NEJMra1011670. PMID   21542745.
  32. 1 2 3 Dalen JE (June 2008). "Should patients with venous thromboembolism be screened for thrombophilia?". Am. J. Med. 121 (6): 458–63. doi: 10.1016/j.amjmed.2007.10.042 . PMID   18501222.
  33. Wu O, Robertson L, Twaddle S, et al. (October 2005). "Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis". Br. J. Haematol. 131 (1): 80–90. doi: 10.1111/j.1365-2141.2005.05715.x . PMID   16173967.
  34. 1 2 American Society of Hematology (September 2013), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation , American Society of Hematology , retrieved 10 December 2013, which cites
  35. Hicks LK, Bering H, Carson KR, et al. (2013). "The ASH Choosing Wisely(R) campaign: five hematologic tests and treatments to question". Blood. 122 (24): 3879–83. doi: 10.1182/blood-2013-07-518423 . PMID   24307720.
  36. Simpson EL, Stevenson MD, Rawdin A, Papaioannou D (January 2009). "Thrombophilia testing in people with venous thromboembolism: systematic review and cost-effectiveness analysis". Health Technol. Assess. 13 (2): iii, ix–x, 1–91. doi: 10.3310/hta13020 . PMID   19080721.
  37. Wu O, Greer IA (September 2007). "Is screening for thrombophilia cost-effective?". Curr. Opin. Hematol. 14 (5): 500–3. doi:10.1097/MOH.0b013e32825f5318. PMID   17934357. S2CID   22896788.
  38. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ (June 2008). "Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)". Chest. 133 (6 Suppl): 454S–545S. doi:10.1378/chest.08-0658. PMID   18574272. Archived from the original on 2013-01-12.
  39. 1 2 Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J (June 2008). "Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)". Chest. 133 (6 Suppl): 844S–886S. doi:10.1378/chest.08-0761. PMID   18574280. Archived from the original on 2013-01-12.
  40. Skeith L, Carrier M, Kaaja R, Martinelli I, Petroff D, Schleußner E, Laskin CA, Rodger MA (2016). "A meta-analysis of low-molecular-weight heparin to prevent pregnancy loss in women with inherited thrombophilia". Blood. 127 (13): 1650–55. doi: 10.1182/blood-2015-12-626739 . PMID   26837697.
  41. Egeberg O (June 1965). "Inherited antithrombin deficiency causing thrombophilia". Thromb. Diath. Haemorrh. 13 (2): 516–30. doi:10.1055/s-0038-1656297. PMID   14347873. S2CID   42594050.
  42. Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C (November 1981). "Deficiency of protein C in congenital thrombotic disease". J. Clin. Invest. 68 (5): 1370–3. doi:10.1172/JCI110385. PMC   370934 . PMID   6895379.
  43. Comp PC, Esmon CT (December 1984). "Recurrent venous thromboembolism in patients with a partial deficiency of protein S". N. Engl. J. Med. 311 (24): 1525–8. doi:10.1056/NEJM198412133112401. PMID   6239102.
  44. Hughes GR (October 1983). "Thrombosis, abortion, cerebral disease, and the lupus anticoagulant". Br. Med. J. (Clin. Res. Ed.). 287 (6399): 1088–89. doi:10.1136/bmj.287.6399.1088. PMC   1549319 . PMID   6414579.
  45. Sanna G, D'Cruz D, Cuadrado MJ (August 2006). "Cerebral manifestations in the antiphospholipid (Hughes) syndrome". Rheum. Dis. Clin. North Am. 32 (3): 465–90. doi:10.1016/j.rdc.2006.05.010. PMID   16880079.
  46. Bertina RM, Koeleman BP, Koster T, et al. (May 1994). "Mutation in blood coagulation factor V associated with resistance to activated protein C". Nature. 369 (6475): 64–7. Bibcode:1994Natur.369...64B. doi:10.1038/369064a0. PMID   8164741. S2CID   4314040.
  47. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM (November 1996). "A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis" (PDF). Blood. 88 (10): 3698–703. doi: 10.1182/blood.V88.10.3698.bloodjournal88103698 . PMID   8916933.