Thrombophilia
Encyclopedia
Thrombophilia 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.
(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. 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
.
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
. Whether thrombophilia also increases the risk of arterial thrombosis (which is the underlying cause of heart attacks
and stroke
s) is less well established.
Thrombophilia has been linked to recurrent miscarriage, and possibly various complications of pregnancy such as intrauterine growth restriction
, stillbirth
, severe pre-eclampsia
and abruptio placentae.
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.
(a mutation in the F5
gene at position 1691) and a mutation in prothrombin (at position 20210 in the promoter region
of the gene).
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. The main ones are antithrombin III
deficiency, protein C deficiency
and protein S deficiency
. Milder rare congenital thrombophilias are factor XIII
mutation and familial dysfibrinogenemia
(an abnormal fibrinogen
). It is unclear whether congenital disorders of fibrinolysis
(the system that destroys clots) are major contributors to thrombosis risk. 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.
Blood group
determines thrombosis risk to a significant extent. Those with blood groups other than type O are at a two- to fourfold relative risk. Those with type O have lower levels of the blood protein von Willebrand factor
as well as factor VIII
, which confers protection from thrombosis.
, 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-gycoprotein 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
).
Heparin-induced thrombocytopenia
(HIT) is due to an immune system reaction against the anticoagulant drug heparin
(or its derivatives). Though it is named for associated low platelet counts, HIT is strongly associated with risk of venous and arterial thrombosis. 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). Both HIT and PNH require particular treatment.
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. 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.
Cancer
, particularly when metastatic
(spread to other places in the body), is a recognised risk factor for thrombosis. 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 catheter
s for chemotherapy
) may increase the risk of thrombosis further.
Nephrotic syndrome
, in which protein from the bloodstream is released into the urine due to kidney diseases, can predispose to thrombosis; 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
. Inflammatory bowel disease
(ulcerative colitis
and Crohn's disease
) predispose to thrombosis, particularly when the disease is active. Various mechanisms have been proposed.
Pregnancy
is associated with an increased risk of thrombosis. This probably results from a physiological hypercoagulability in pregnancy that protects against postpartum hemorrhage
.
The female hormone estrogen
, when used in the combined oral contraceptive pill and in perimenopausal hormone replacement therapy
, has been associated with a two- to sixfold increased risk of venous thrombosis. The risk depends on the type of hormones used, the dose of estrogen, and the presence of other thrombophilic risk factors. Various mechanisms, such as deficiency of protein S
and tissue factor pathway inhibitor
, are said to be responsible.
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 microvesicle
s (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.
, 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.
There is an association between the blood levels of homocysteine
and thrombosis, although this has not been reported consistently in all studies. 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.
Thrombosis is a multifactorial problem because there are often multiple reasons why a person might develop thrombosis. These risk factor
s 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".
Normal coagulation is initiated by the release of tissue factor
from damaged tissue. Tissue factor binds to circulating factor VII
a. 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. 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).
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.
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.
(with examination of the blood smear
), prothrombin time
, partial thromboplastin time
, 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. Testing may be more or less extensive depending on clinical judgement and abnormalities detected on initial evaluation.
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. 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. In contrast, the combination of thrombophilia with other risk factors may provide an indication for preventative treatment, which is why thrombophilia testing may be performed even in those who would not meet the strict criteria for these tests. 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.
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. 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
. 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, unless the testing is restricted to selected situations.
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
.
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 suffered from thrombosis, the risk of developing thrombosis is increased. Screening this selected group may be beneficial, but even when negative may still indicate residual risk. Professional guidelines therefore suggest that alternative forms of contraception be used rather than relying on screening.
Thrombophilia screening in people with arterial thrombosis is generally regarded unrewarding and is generally discouraged, 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.
There is no specific treatment for thrombophilia, unless it is caused by an underlying medical illness (such as nephrotic syndrome), in which case the treatment of the underlying disease is needed. In those with unprovoked and/or recurrent thrombosis, or those with a high-risk 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. 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.
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
. These factors tend to be more important in the decision than the presence or absence of a detectable thrombophilia.
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.
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. Warfarin and LMWH may safely be used in breastfeeding.
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.
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.
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.
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. Protein C deficiency followed in 1981, when described by researchers from the Scripps Research Institute and the U.S. Centers of Disease Control
. Protein S deficiency
followed in 1984, described by researchers at the University of Oklahoma
.
Antiphospholipid syndrome was described in full in the 1980s, after various previous reports of specific antibodies in people with systemic lupus erythematosus and thrombosis. The syndrome is often attributed to the British rheumatologist Graham R.V. Hughes, and is often referred to as Hughes syndrome for that reason.
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. 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.
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.
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
(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
Deep vein thrombosis
Deep vein thrombosis is the formation of a blood clot in a deep vein. Deep vein thrombosis commonly affects the leg veins or the deep veins of the pelvis. Occasionally the veins of the arm are affected...
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
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. 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...
. The first major form of thrombophilia, antithrombin deficiency, was identified in 1965, while the most common abnormalities (including factor V Leiden
Factor V Leiden
Factor V Leiden 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...
) were described in the 1990s.
Signs and symptoms
The most common conditions associated with thrombophilia are deep vein thrombosis (DVT) and pulmonary embolismPulmonary embolism
Pulmonary embolism 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 . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
(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
Post-thrombotic syndrome
Post-Thrombotic Syndrome is the term used to describe signs and symptoms that may occur as long-term complications of deep vein thrombosis . It may also be referred to as post-phlebitic syndrome or venous stress disorder.-Incidence of PTS:...
due to damage to valves in the veins. The clot may also break off and migrate (embolize
Embolism
In medicine, an embolism is the event of lodging of an embolus into a narrow capillary vessel of an arterial bed which causes a blockage in a distant part of the body.Embolization is...
) to arteries in the lungs. Depending on the size and the location of the clot, this may lead to sudden-onset shortness of breath
Dyspnea
Dyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...
, chest pain
Chest pain
Chest pain may be a symptom of a number of serious conditions and is generally considered a medical emergency. Even though it may be determined that the pain is non-cardiac in origin, this is often a diagnosis of exclusion made after ruling out more serious causes of the pain.-Differential...
, palpitations and may be complicated by collapse
Syncope (medicine)
Syncope , the medical term for fainting, is precisely defined as a transient loss of consciousness and postural tone characterized by rapid onset, short duration, and spontaneous recovery due to global cerebral hypoperfusion that most often results from hypotension.Many forms of syncope are...
, shock and cardiac arrest
Cardiac arrest
Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...
.
Venous thrombosis may also occur in more unusual places: in the veins of the brain
Cerebral venous sinus thrombosis
Cerebral venous sinus thrombosis is a rare form of stroke that results from thrombosis of the dural venous sinuses, which drain blood from the brain. Symptoms may include headache, abnormal vision, any of the symptoms of stroke such as weakness of the face and limbs on one side of the body, and...
, liver (portal vein thrombosis
Portal vein thrombosis
Portal vein thrombosis is a form of venous thrombosis affecting the hepatic portal vein, which can lead to portal hypertension and reduction in the blood supply to the liver.-Causes:...
and hepatic vein thrombosis
Budd-Chiari syndrome
In medicine , Budd–Chiari syndrome is the clinical picture caused by occlusion of the hepatic veins. It presents with the classical triad of abdominal pain, ascites and hepatomegaly. Examples of occlusion include thrombosis of hepatic veins. The syndrome can be fulminant, acute, chronic, or...
), mesenteric vein
Mesenteric vein
Mesenteric vein can refer to:*Superior mesenteric vein*Inferior mesenteric vein...
, kidney (renal vein thrombosis
Renal vein thrombosis
Renal vein thrombosis is the formation of a clot or thrombus obstructing the renal vein, leading to a reduction in drainage of the kidney.-Presentation:This thrombosis can lead to imbalances in blood clotting factor...
) and the veins of the arms
Paget-Schroetter disease
Paget-Schroetter disease, also known as Paget-von Schrötter disease or upper extremity deep vein thrombosis is a medical condition in which blood clots form in the deep veins of the arms. These deep vein thromboses typically occur in the axillary vein or subclavian vein.-Signs and symptoms:The...
. Whether thrombophilia also increases the risk of arterial thrombosis (which is the underlying cause of heart attacks
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
s) is less well established.
Thrombophilia has been linked to recurrent miscarriage, and possibly various complications of pregnancy such as intrauterine growth restriction
Intrauterine growth restriction
Intrauterine growth restriction refers to poor growth of a baby while in the mother's womb during pregnancy. The causes can be many, but most often involve poor maternal nutrition or lack of adequate oxygen supply to the fetus....
, stillbirth
Stillbirth
A stillbirth occurs when a fetus has died in the uterus. The Australian definition specifies that fetal death is termed a stillbirth after 20 weeks gestation or the fetus weighs more than . Once the fetus has died the mother still has contractions and remains undelivered. The term is often used in...
, severe pre-eclampsia
Pre-eclampsia
Pre-eclampsia or preeclampsia is a medical condition in which hypertension arises in pregnancy in association with significant amounts of protein in the urine....
and abruptio placentae.
Protein C deficiency
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. The prevalence of protein C deficiency has been estimated to about 0.2% to 0.5% of the general population...
may cause purpura fulminans
Purpura fulminans
Purpura fulminans is a haemorrhagic condition usually associated with sepsis or previous infection. It occurs mainly in babies and small children.It was first described by Guelliot in 1884.- Presentation :...
, 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
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...
have also been associated with an increased risk of skin necrosis
Warfarin necrosis
Warfarin-induced skin necrosis is a condition in which skin and subcutaneous tissue necrosis occurs due to acquired protein C deficiency following treatment with anti-vitamin K anticoagulants .Warfarin necrosis is a rare but severe complication of treatment with warfarin or related...
on commencing anticoagulant treatment with warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
or related drugs.
Causes
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.Congenital
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. The most common ones are factor V LeidenFactor V Leiden
Factor V Leiden 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...
(a mutation in the F5
Factor V
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...
gene at position 1691) and a mutation in prothrombin (at position 20210 in the promoter region
Five prime untranslated region
A messenger ribonucleic acid molecule codes for a protein through translation. The mRNA also contains regions that are not translated: in eukaryotes these include the 5' untranslated region, 3' untranslated region, 5' cap and poly-A tail....
of the gene).
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. The main ones are antithrombin III
Antithrombin
Antithrombin 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...
deficiency, protein C deficiency
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. The prevalence of protein C deficiency has been estimated to about 0.2% to 0.5% of the general population...
and protein S deficiency
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...
. Milder rare congenital thrombophilias are factor XIII
Factor XIII
Factor XIII or fibrin stabilizing factor is an enzyme of the blood coagulation system that crosslinks fibrin.- Function :Factor XIII is a transglutaminase that circulates in the plasma as a heterotetramer of two catalytic A subunits and two carrier B subunits...
mutation and familial dysfibrinogenemia
Familial dysfibrinogenemia
The dysfibrinogenemias are a group of autosomal dominant disorders of qualitatively abnormal fibrinogens. There are more than 350 different fibrinogen abnormalities, each named after the place where it was discovered. Each dysfibrinogenemia is associated with slightly different effects on the...
(an abnormal fibrinogen
Fibrinogen
Fibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...
). It is unclear whether congenital disorders of fibrinolysis
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 system that destroys clots) are major contributors to thrombosis risk. 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.
Blood group
ABO blood group system
The ABO blood group system is the most important blood type system in human blood transfusion. The associated anti-A antibodies and anti-B antibodies are usually IgM antibodies, which are usually produced in the first years of life by sensitization to environmental substances such as food,...
determines thrombosis risk to a significant extent. Those with blood groups other than type O are at a two- to fourfold relative risk. Those with type O have lower levels of the blood protein von Willebrand factor
Von Willebrand factor
von Willebrand factor 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...
as well as factor VIII
Factor VIII
Factor VIII is an essential blood clotting factor also known as anti-hemophilic factor . In humans, Factor VIII is encoded by the F8 gene...
, which confers protection from thrombosis.
Acquired
A number of acquired conditions augment the risk of thrombosis. A prominent example is antiphospholipid syndromeAntiphospholipid syndrome
Antiphospholipid syndrome or antiphospholipid antibody syndrome , often also Hughes syndrome, is an autoimmune, hypercoagulable state caused by antibodies against cell-membrane phospholipids that provokes blood clots in both arteries and veins as well as pregnancy-related complications such as...
, which is caused by antibodies against constituents of the cell membrane, particularly lupus anticoagulant
Lupus anticoagulant
Lupus anticoagulant is an immunoglobulin that binds to phospholipids and proteins associated with the cell membrane. It is important to note that this disease name is actually a misnomer...
(first found in people with the disease systemic lupus erythematosus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
but often detected in people without the disease), anti-cardiolipin antibodies
Anti-cardiolipin antibodies
Anti-cardiolipin antibodies are antibodies often directed against cardiolipin and found in several diseases including syphilis, antiphospholipid syndrome, livedoid vasculitis, vertebrobasilar insufficiency, Behçet's syndrome, idiopathic spontaneous abortion, and systemic lupus erythematosus. They...
, and anti-β2-gycoprotein 1 antibodies
Anti-apolipoprotein antibodies
In autoimmune disease, anti-apolipoprotein H antibodies, also called anti-β2 glycoprotein I antibodies, comprise a subset of anti-cardiolipin antibodies and lupus anticoagulant. These antibodies are involved in sclerosis and are strongly associated with thrombotic forms of lupus....
; it is therefore regarded as an autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
. 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
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
).
Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia is the development of thrombocytopenia , due to the administration of various forms of heparin, an anticoagulant...
(HIT) is due to an immune system reaction against the anticoagulant drug heparin
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...
(or its derivatives). Though it is named for associated low platelet counts, HIT is strongly associated with risk of venous and arterial thrombosis. Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria , sometimes referred to as Marchiafava-Micheli syndrome, is a rare, acquired, potentially life-threatening disease of the blood characterised by complement-induced intravascular hemolytic anemia , red urine and thrombosis...
(PNH) is a rare condition resulting from acquired alterations in the PIGA
PIGA
Phosphatidylinositol N-acetylglucosaminyltransferase subunit A is an enzyme that in humans is encoded by the PIGA gene.-Further reading:...
gene, which plays a role in the protection of blood cells from the complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
. PNH increases the risk of venous thrombosis but is also associated with hemolytic anemia
Hemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...
(anemia resulting from destruction of red blood cells). Both HIT and PNH require particular treatment.
Hematologic conditions associated with sluggish blood flow can increase risk for thrombosis. For example, sickle-cell disease
Sickle-cell disease
Sickle-cell disease , or sickle-cell anaemia or drepanocytosis, is an autosomal recessive genetic blood disorder with overdominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various...
(caused by mutations of hemoglobin
Hemoglobin
Hemoglobin 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...
) is regarded as a mild prothrombotic state induced by impaired flow. Similarly, myeloproliferative disorders, in which the bone marrow produces too many blood cells, predispose to thrombosis, particularly in polycythemia vera
Polycythemia vera
Polycythemia vera is a blood disorder in which the bone marrow makes too many red blood cells. It may also result in the overproduction of white blood cells and platelets. Most of the health concerns associated with polycythemia vera are caused by the blood being thicker as a result of the...
(excess red blood cells) and essential thrombocytosis
Essential thrombocytosis
Essential thrombocythemia is a rare chronic blood disorder characterized by the overproduction of platelets by megakaryocytes in the bone marrow in the absence of an alternative cause. In some cases this disorder may be progressive, and rarely may evolve into acute myeloid leukemia or myelofibrosis...
(excess platelets). Again, these conditions usually warrant specific treatment when identified.
Cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, particularly when metastatic
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
(spread to other places in the body), is a recognised risk factor for thrombosis. 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 catheter
Central venous catheter
In medicine, a central venous catheter is a catheter placed into a large vein in the neck , chest or groin...
s for chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
) may increase the risk of thrombosis further.
Nephrotic syndrome
Nephrotic syndrome
Nephrotic syndrome is a nonspecific disorder in which the kidneys are damaged, causing them to leak large amounts of protein from the blood into the urine....
, in which protein from the bloodstream is released into the urine due to kidney diseases, can predispose to thrombosis; this is particularly the case in more severe cases (as indicated by blood levels of albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
below 25 g/l) and if the syndrome is caused by the condition membranous nephropathy
Membranous glomerulonephritis
Membranous glomerulonephritis is a slowly progressive disease of the kidney affecting mostly patients between ages of 30 and 50 years, usually Caucasian.It is one of the more common forms of nephrotic syndrome.-Terminology:...
. Inflammatory bowel disease
Inflammatory bowel disease
In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...
(ulcerative colitis
Ulcerative colitis
Ulcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the colon , that includes characteristic ulcers, or open sores. The main symptom of active disease is usually constant diarrhea mixed with blood, of gradual onset...
and Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
) predispose to thrombosis, particularly when the disease is active. Various mechanisms have been proposed.
Pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
is associated with an increased risk of thrombosis. This probably results from a physiological hypercoagulability in pregnancy that protects against postpartum hemorrhage
Postpartum hemorrhage
Hemorrhage after delivery, or postpartum hemorrhage, is the loss of greater than 500 ml of blood following vaginal delivery, or 1000 ml of blood following cesarean section...
.
The female hormone estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
, when used in the combined oral contraceptive pill and in perimenopausal hormone replacement therapy
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
, has been associated with a two- to sixfold increased risk of venous thrombosis. The risk depends on the type of hormones used, the dose of estrogen, and the presence of other thrombophilic risk factors. Various mechanisms, such as deficiency of protein S
Protein S
Protein S 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. In humans, protein S is encoded by the PROS1 gene...
and tissue factor pathway inhibitor
Tissue factor pathway inhibitor
Tissue factor pathway inhibitor is a single-chain polypeptide which can reversibly inhibit Factor Xa and Thrombin...
, are said to be responsible.
Obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
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
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
. Various coagulation abnormalities have been described in the obese. Plasminogen activator inhibitor-1
Plasminogen activator inhibitor-1
Plasminogen activator inhibitor-1 also known as endothelial plasminogen activator inhibitor or serpin E1 is a protein that in humans is encoded by the SERPINE1 gene....
, an inhibitor of fibrinolysis, is present in higher levels in people with obesity. Obese people also have larger numbers of circulating microvesicle
Circulating microvesicle
The identification of small, membrane-bound vesicles has opened a new era in the understanding of cell signaling and the process of molecular communication between cells. Human body fluids contain small, membrane-bound exosomes and larger vesicular bodies, collectively referred to as circulating...
s (fragments of damaged cells) that bear tissue factor. Platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
aggregation may be increased, and there are higher levels of coagulation proteins such as von Willebrand factor, fibrinogen, factor VII
Factor VII
Factor VII is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class. A recombinant form of human factor VIIa has U.S. Food and Drug Administration approval for uncontrolled bleeding in hemophilia patients...
and factor VIII
Factor VIII
Factor VIII is an essential blood clotting factor also known as anti-hemophilic factor . In humans, Factor VIII is encoded by the F8 gene...
. Obesity also increases the risk of recurrence after an initial episode of thrombosis.
Unclear
A number of conditions that have been linked with venous thrombosis are possibly genetic and possibly acquired. These include: elevated levels of factor VIII, factor IXFactor IX
Factor IX 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...
, factor XI
Factor XI
Factor XI or plasma thromboplastin antecedent is the zymogen form of factor XIa, one of the enzymes of the coagulation cascade. Like many other coagulation factors, it is a serine protease. In humans, Factor XI is encoded by the F11 gene....
, fibrinogen
Fibrinogen
Fibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...
and
thrombin-activatable fibrinolysis inhibitor
Carboxypeptidase B2
Carboxypeptidase B2 also known as carboxypeptidase U , plasma carboxypeptidase B , or thrombin-activable fibrinolysis inhibitor is an enzyme that in humans is encoded by the CPB2 gene.- Function :...
, and decreased levels of tissue factor pathway inhibitor
Tissue factor pathway inhibitor
Tissue factor pathway inhibitor is a single-chain polypeptide which can reversibly inhibit Factor Xa and Thrombin...
. Activated protein C resistance
Activated protein C resistance
Activated protein C resistance is a hemostatic disorder characterized by a poor anticoagulant response to activated protein C . This results in an increased risk of venous thrombosis, which can cause heart attacks, strokes, and other problems with circulation.The disorder can be acquired or...
that is not attributable to factor V mutations is probably caused by other factors and remains a risk factor for thrombosis.
There is an association between the blood levels of homocysteine
Homocysteine
Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...
and thrombosis, although this has not been reported consistently in all studies. Homocysteine levels are determined by mutations in the MTHFR
Methylenetetrahydrofolate reductase
Methylenetetrahydrofolate reductase is an enzyme that in humans is encoded by the MTHFR gene. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine...
and CBS
Cystathionine beta synthase
Cystathionine-β-synthase, also known as CBS, is an enzyme that in humans is encoded by the CBS gene. It catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine:...
genes, but also by levels of folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
, vitamin B6
Vitamin B6
Vitamin B6 is a water-soluble vitamin and is part of the vitamin B complex group. Several forms of the vitamin are known, but pyridoxal phosphate is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation...
and vitamin B12
Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
, which depend on diet.
Mechanism
Risk factor
In epidemiology, a risk factor is a variable associated with an increased risk of disease or infection. Sometimes, determinant is also used, being a variable associated with either increased or decreased risk.-Correlation vs causation:...
s 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".
Normal coagulation is initiated by the release of tissue factor
Tissue factor
Tissue factor, also called platelet tissue factor, factor III, thrombokinase, or CD142 is a protein present in subendothelial tissue, platelets, and leukocytes necessary for the initiation of thrombin formation from the zymogen prothrombin. An incorrect synonym is thromboplastin...
from damaged tissue. Tissue factor binds to circulating factor VII
Factor VII
Factor VII is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class. A recombinant form of human factor VIIa has U.S. Food and Drug Administration approval for uncontrolled bleeding in hemophilia patients...
a. The combination activates factor X
Factor X
Factor X, also known by the eponym Stuart-Prower factor or as prothrombinase, is an enzyme of the coagulation cascade. It is a serine endopeptidase .-Physiology:...
to factor Xa and factor IX
Factor IX
Factor IX 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...
to factor IXa. Factor Xa (in the presence of factor V
Factor V
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...
) activates prothrombin into thrombin. Thrombin is a central enzyme in the coagulation process: it generates fibrin from fibrinogen
Fibrinogen
Fibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...
, and activates a number of other enzymes and cofactors (factor XIII
Factor XIII
Factor XIII or fibrin stabilizing factor is an enzyme of the blood coagulation system that crosslinks fibrin.- Function :Factor XIII is a transglutaminase that circulates in the plasma as a heterotetramer of two catalytic A subunits and two carrier B subunits...
, factor XI
Factor XI
Factor XI or plasma thromboplastin antecedent is the zymogen form of factor XIa, one of the enzymes of the coagulation cascade. Like many other coagulation factors, it is a serine protease. In humans, Factor XI is encoded by the F11 gene....
, factor V and factor VIII
Factor VIII
Factor VIII is an essential blood clotting factor also known as anti-hemophilic factor . In humans, Factor VIII is encoded by the F8 gene...
, TAFI) that enhance the fibrin clot. 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
Protein Z
Protein Z also known as 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 vitamin K-dependent, and its functionality is therefore impaired in warfarin therapy...
(which inhibits factor Xa).
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.
In addition to its effects on thrombosis, hypercoagulable states may accelerate the development of atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, the arterial disease that underlies myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
and other forms of cardiovascular disease.
Diagnosis
Tests for thrombophilia include complete blood countComplete blood count
A complete blood count , also known as full blood count or full blood exam or blood panel, is a test panel requested by a doctor or other medical professional that gives information about the cells in a patient's blood...
(with examination of the blood smear
Blood film
A blood film or peripheral blood smear is a thin layer of blood smeared on a microscope slide and then stained in such a way to allow the various blood cells to be examined microscopically...
), prothrombin time
Prothrombin time
The prothrombin time and its derived measures of prothrombin ratio and international normalized ratio are measures of the extrinsic pathway of coagulation. This test is also called "ProTime INR" and "INR PT". They are used to determine the clotting tendency of blood, in the measure of warfarin...
, partial thromboplastin time
Partial thromboplastin time
The partial thromboplastin time or activated partial thromboplastin time is a performance indicator measuring the efficacy of both the "intrinsic" and the common coagulation pathways...
, thrombin time and reptilase time
Reptilase time
Reptilase time is a blood test used to detect deficiency or abnormalities in fibrinogen, especially in cases of heparin contamination.Reptilase, an enzyme found in the venom of Bothrops snakes, has activity similar to thrombin. Unlike thrombin, reptilase is resistant to inhibition by antithrombin...
, lupus anticoagulant
Lupus anticoagulant
Lupus anticoagulant is an immunoglobulin that binds to phospholipids and proteins associated with the cell membrane. It is important to note that this disease name is actually a misnomer...
, anti-cardiolipin antibody, anti-β2 glycoprotein 1 antibody, activated protein C resistance, fibrinogen
Fibrinogen
Fibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...
tests, factor V Leiden
Factor V Leiden
Factor V Leiden 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...
and prothrombin mutation, and basal homocysteine
Homocysteine
Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...
levels. Testing may be more or less extensive depending on clinical judgement and abnormalities detected on initial evaluation.
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. Recurrent thromboembolism, or thrombosis in unusual sites (e.g. the hepatic vein
Hepatic vein
In human anatomy, the hepatic veins are the blood vessels that drain de-oxygenated blood from the liver and blood cleaned by the liver into the inferior vena cava....
in Budd-Chiari syndrome
Budd-Chiari syndrome
In medicine , Budd–Chiari syndrome is the clinical picture caused by occlusion of the hepatic veins. It presents with the classical triad of abdominal pain, ascites and hepatomegaly. Examples of occlusion include thrombosis of hepatic veins. The syndrome can be fulminant, acute, chronic, or...
), 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. In contrast, the combination of thrombophilia with other risk factors may provide an indication for preventative treatment, which is why thrombophilia testing may be performed even in those who would not meet the strict criteria for these tests. 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
Orthopedic surgery
Orthopedic surgery or orthopedics is the branch of surgery concerned with conditions involving the musculoskeletal system...
, it is regarded as "provoked" by the immobilization and the surgery, and it is less likely that investigations will yield clinically important results.
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. 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
Evidence-based medicine
Evidence-based medicine or evidence-based practice aims to apply the best available evidence gained from the scientific method to clinical decision making. It seeks to assess the strength of evidence of the risks and benefits of treatments and diagnostic tests...
. 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, unless the testing is restricted to selected situations.
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
Thromboelastography
Thrombelastography is a method of testing the efficiency of coagulation in the blood. It was first developed by the German Dr. Hellmut Hartert at University of Heidelberg School of Medicine in 1948...
.
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 suffered from thrombosis, the risk of developing thrombosis is increased. Screening this selected group may be beneficial, but even when negative may still indicate residual risk. Professional guidelines therefore suggest that alternative forms of contraception be used rather than relying on screening.
Thrombophilia screening in people with arterial thrombosis is generally regarded unrewarding and is generally discouraged, except possibly for unusually young patients (especially when precipitated by smoking
Tobacco smoking
Tobacco smoking is the practice where tobacco is burned and the resulting smoke is inhaled. The practice may have begun as early as 5000–3000 BCE. Tobacco was introduced to Eurasia in the late 16th century where it followed common trade routes...
or use of estrogen-containing hormonal contraceptives) and those in whom revascularization, such as coronary arterial bypass
Coronary artery bypass surgery
Coronary artery bypass surgery, also coronary artery bypass graft surgery, and colloquially heart bypass or bypass surgery is a surgical procedure performed to relieve angina and reduce the risk of death from coronary artery disease...
, fails because of rapid occlusion of the graft.
Treatment
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
, on a long-term basis to reduce the risk of further episodes. 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.
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
Inferior vena cava filter
An inferior vena cava filter, also IVC filter or Greenfield Filter a type of vascular filter, is a medical device that is implanted by interventional radiologists or vascular surgeons into the inferior vena cava to prevent fatal pulmonary emboli .IVC filters are used in case of contraindication to...
, the presence of cancer, symptoms of post-thrombotic syndrome
Post-thrombotic syndrome
Post-Thrombotic Syndrome is the term used to describe signs and symptoms that may occur as long-term complications of deep vein thrombosis . It may also be referred to as post-phlebitic syndrome or venous stress disorder.-Incidence of PTS:...
, and obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
. These factors tend to be more important in the decision than the presence or absence of a detectable thrombophilia.
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
Antibody titer
An antibody titer is a measurement of how much antibody an organism has produced that recognizes a particular epitope, expressed as the greatest dilution that still gives a positive result. ELISA is a common means of determining antibody titers....
(amount of antibodies), whether multiple antibodies are detected, and whether it is detected repeatedly or only on a single occasion.
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
Low molecular weight heparin
In medicine, low-molecular-weight heparin is a class of medication used as an anticoagulant in diseases that feature thrombosis, as well as for prophylaxis in situations that lead to a high risk of thrombosis....
(LMWH, such as enoxaparin
Enoxaparin
Enoxaparin is a low molecular weight heparin marketed under the trade names Lovenox and Clexane, among others. It is an anticoagulant used to prevent and treat deep vein thrombosis or pulmonary embolism, and is given as a subcutaneous injection...
) is generally used as an alternative. Warfarin and LMWH may safely be used in breastfeeding.
Prognosis
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. In general, men are more likely than women to experience repeated episodes of venous thrombosis.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.
Epidemiology
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.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.
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.
History
Rudolf Virchow
Rudolph Carl Virchow was a German doctor, anthropologist, pathologist, prehistorian, biologist and politician, known for his advancement of public health...
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. Protein C deficiency followed in 1981, when described by researchers from the Scripps Research Institute and the U.S. Centers of Disease Control
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...
. Protein S deficiency
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...
followed in 1984, described by researchers at the University of Oklahoma
University of Oklahoma
The University of Oklahoma is a coeducational public research university located in Norman, Oklahoma. Founded in 1890, it existed in Oklahoma Territory near Indian Territory for 17 years before the two became the state of Oklahoma. the university had 29,931 students enrolled, most located at its...
.
Antiphospholipid syndrome was described in full in the 1980s, after various previous reports of specific antibodies in people with systemic lupus erythematosus and thrombosis. The syndrome is often attributed to the British rheumatologist Graham R.V. Hughes, and is often referred to as Hughes syndrome for that reason.
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. 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.
It is suspected that other genetic abnormalities underlying familial thrombosis will in future be discovered through studies of the entire genetic code
Genome-wide association study
In genetic epidemiology, a genome-wide association study , also known as whole genome association study , is an examination of many common genetic variants in different individuals to see if any variant is associated with a trait...
, looking for small alternations in genes.