Also Known As
Thrombophilia
This article was last reviewed on
This article waslast modified on
7 March 2018.
What is it?

A hypercoagulable disorder, also known as thrombophilia, is an inherited or acquired condition that increases the risk of inappropriate or excessive thrombus (blood clot) formation.

Clotting is a normal response to blood vessel or tissue injury. When a blood vessel is injured, it begins to leak blood, either externally or into body tissues. The body stops this blood loss through a complex clotting process called haemostasis. During haemostasis, the injured blood vessel constricts to reduce blood flow, platelets adhere to the injury site and clump together to form a loose platelet plug and the coagulation cascade is initiated. During the cascade process, the body sequentially activates coagulation factors, proteins that create a net of fibrin threads, weave them through the platelet plug and stabilise the resulting blood clot. This clot functions as a barrier to further blood loss, one that stays in place until the injury has healed.

Usually, the body activates the clotting process, regulates its speed and volume with feedback mechanisms, and after the site has healed, breaks down the clot and removes it. Hypercoagulable disorders occur when something goes wrong with the clotting process. If the process activates inappropriately, does not self regulate properly, or resists being broken down, then there can be inappropriate and/or excessive blood clot formation.

Blood clots are referred to as thrombi (one – thrombus) when they form in a blood vessel; thrombi may break off and block another blood vessel in another part of the body, where they are referred to as emboli (one – embolus).

  • Venous thromboembolism (VTE) is the most common condition associated with hypercoagulable disorders. It includes conditions like superficial or Deep Vein Thrombosis (DVT) and Pulmonary embolism (PE). DVT is caused by blood clot (thrombosis, plural thrombi) formation in large veins of legs causing redness, pain and swelling particularly at the back of legs below knee. The thrombi may sometimes break (emboli) and travel to other parts of the body through the bloodstream, which is known as embolism. Embolism can be life threatening if the clot travels to the lungs causing PE or to the brain causing strokes 
  • Thrombosis of unusual venous circulations causes cerebral vein thrombosis (brain), hepatic and portal vein thrombosis (liver), mesenteric vein thrombosis (small intestines), renal vein thrombosis (kidney), venous thrombosis in arms and ovarian vein thrombosis 
  • Recurrent foetal loss (miscarriages) and other complications in pregnancy may be associated with thrombophilia. 
  • Pupura fulminas is caused by Protein C deficiency in newborns and even in adults causing tissue death and bleeding under the skin and other organs. 
  • Warfarin induced skin necrosis is caused by Protein C and Protein S deficiency on commencement of anticoagulant treatment with warfarin. 
  • Disseminated intravascular coagulation (DIC) is a life-threatening, acute, acquired condition that causes tiny clots throughout the body. It uses up coagulation factors at an accelerated rate, leading to both bleeding and inappropriate clotting.

Certain inherited gene mutations that may predispose someone to hypercoagulable states, such as factor V Leiden or the prothrombin G20210A mutation, are relatively common in the population, but it is thought that they add only a slight increase in the risk of actually developing a problem with clotting. Other inherited hypercoagulable disorders, such as protein C deficiency, protein S deficiency, and antithrombin deficiency have a higher risk of thrombosis but are relatively rare. These are generally due to genetic mutations that lead to a deficiency or dysfunction in the coagulation protein that the gene produces. All of the inherited disorders (except for antithrombin deficiency) may be seen in heterozygous (one gene copy) or homozygous (two gene copies) form. If someone has two mutated gene copies, they tend to have a more severe form of the condition, and if they are heterozygous in more than one condition, the risk of clotting tends to be additive (and sometimes they multiply the risk). With inherited hypercoagulable disorders, the first thrombotic episode may be seen at a relatively young age (less than 40 years of age). The patient may have recurrent thrombosis, a family history of thrombosis, and blood clots in unusual sites (such as cerebral veins, hepatic veins, and renal veins).

Acquired disorders are more commonly known to be the cause of hypercoagulable states than inherited ones. They may be related to antiphospholipid antibodies liver disease, cancer, surgery or immobilizations. The next few pages describe several hypercoagulable disorders.

 

Accordion Title
About Hypercoagulable Disorders
  • Activation Problems

    Problems with coagulation activation

    Anything that interrupts the smooth blood vessel walls, essential for constant blood flow, may increase the risk of activating the coagulation cascade. They are not considered true “hypercoagulable disorders” but may exacerbate those that do exist.

    • Blood vessel wall abnormalities (usually combined with a clotting abnormality)
    • Atherosclerosis -- the build-up of cholesterol, lipid and calcium deposits in the walls of arteries. They make the blood vessel walls less smooth, weaken them, and eventually form plaques that may rupture and lead to abnormal clotting and to strokes and heart attacks.
    • Vasculitis -- inflammation of blood vessel walls may increase the risk of platelet adhesion and coagulation factor activation. Healed vasculitis may provide sites within the vessels for accelerated atherosclerosis.

     

  • Regulation problems

    Problems with coagulation cascade regulation

    Inherited:

    • Factor V Leiden is a condition caused by mutation in Factor 5(FV) gene at position 1691, increasing the risk of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE). It is also known as Activated Protein C resistance because the abnormal Factor is resistant to degradation by activated Protein C, which regulates the clotting process. Studies show that around 3-8% of Caucasians have one copy of mutated FV gene (heterozygous) and 1 in 5000 Europeans have 2 copies of this gene mutation (homozygous). Factor V Leiden mutation is rarer in black Africans, Asians, Australian and American natives.
    • Prothrombin 20210 mutation is caused by mutation in prothrombin gene (factor II) at position 20210 in 3’ untranslated gene region. This increases the blood tendency to thicken and hence clot formation. This mutation is prevalent in Caucasians
    • Antithrombin (formerly called antithrombin III) deficiency or dysfunction - this is a factor that helps decrease the activity of the clotting process by inhibiting factors Xa, IXa, XIa, and thrombin. Inherited or acquired deficiency of antithrombin can lead to a clot formation.
    • Protein C, Protein S and Antithrombin deficiencies are inherited but are very rare. Protein C, protein S and Antithrombin are bodies’ natural anticoagulants, keeping the blood in fluid state but if they are low or not function properly it increases the risks of DVT and PE.
    • Congenital plasminogen deficiency is a rare congenital disorder. Plasminogen is activated to form plasmin. Plasmin helps break apart the clot's cross-linked fibrin net. Most of these patients have eye problems, but it can affect other organs too.

    Acquired:

    • Antiphospholipid syndrome (lupus anticoagulant and anticardiolipin antibody)is caused by antibodies developed against phospholipids which are molecules that participate in the coagulation cascade. These antibodies include lupus anticoagulants (LA), anticardiolipin antibodies and antibodies to beta 2 gycoprotein-1. This is considered as an autoimmune condition causing arterial or venous thrombosis, miscarriages in first trimester of pregnancies and may be associated with systemic lupus erythematosus.
    • Heparin Induced Thrombocytopenia is a condition where a patient receiving an anticoagulant called heparin produces antibodies against the heparin. These antibodies activate platelets, reducing their number and causing venous or arterial thrombosis.
    • Paroxysomal Nocturnal Haemoglobinuria (PNH) results from a mutation in a gene called PIGA. PIGA gene products normally protect red blood cells from complement system. The mutation causes increased thrombosis and haemolytic anaemia due to overactivation of the complement system on the surface of red blood cells.
    • Myeloproliferative neoplasms (formerly known as myeloproliferative disorders) result in excess blood cell production, resulting in polycythaemia vera (increased red blood cell production) and essential thrombocythaemia (increased platelet production). This results in an increased risk of thrombosis.
    • Disseminated intravascular coagulation (DIC)

     

  • Breakdown problems

    Problems with clot breakdown (fibrinolysis)

    Inherited:

    • Congenital plasminogen deficiency - rare factor deficiency; plasminogen is activated to form plasmin. Plasmin helps break apart the clot's cross-linked fibrin net. Most of these patients have eye problems, not thrombotic complications.
    • Dysfibrinogenaemia - abnormal fibrinogen; it leads to fibrin that does not break down normally. Most patients with dysfibrinogenaemia have laboratory results within normal limits, but some have bleeding symptoms, and a small number have been reported to have thrombotic complications.

    Acquired:

    • Plasminogen deficiency -- plasminogen is the precursor to plasmin, which helps to break down clots; may also be an acquired deficiency (see above)
    • Decreased plasminogen activator

     

  • Other factors

    Other factors associated with an increased risk of inappropriate blood clot formation:

    • Cancer – Cancers may cause hypercoagulable states for a variety of reasons.: 1 Tumour growth may cause external compression on a blood vessel, or in some cases, actually extend into the vasculature (for example, renal cell cancers extending into the renal veins). 2 Cancers are often associated with inflammation and immobility. 3 Some cancers release substances which initiate clotting. 4). Treatments for cancer (radiation, chemotherapy) may leave patients more susceptible to hypercoagulation.
    • Venous stasis describes any situation that immobilizes someone for long periods of time, such as prolonged bed rest with an illness or after surgery. Immobility may lead to slow or restricted blood flow (venous stasis) and an increased risk of developing a blood clot especially in the deep veins of the legs (DVT). This can also occur in people travelling on long journeys while immobilised in aeroplanes and coaches 
    • Recent surgery
    • Atrial fibrillation (rapid, uneven heartbeat) – associated with an increased risk of stroke
    • Heart Failure - may cause slowing of blood flow (stasis)
    • Obesity
    • Pregnancy, combined oral contraceptives (“the pill”) and hormone replacement therapy
    • Elevated levels of homocysteine (often associated with with deficiency of ( folic acid, vitamin B6 and B12) slightly increase the risk of a heart attack
    • Possible associations with thrombophilia: Elevated levels of FVII, FVIII, FIX and FXI, fibrinogen and thrombin activable fibrinolysis inhibitors. Deficiency of FXII, tissue factor pathway inhibitor

     

  • Laboratory Tests

    Guidelines recommend that laboratory tests for thrombophilia are used cautiously and are probably done inappropriately in many patients. Testing for heritable or acquired thrombophilia is not indicated in unselected patients presenting with venous thrombosis. Testing selected patients may give an indication of risk of recurrence following completion of anticoagulant therapy, for example those presenting with venous thrombosis at an early age ( <40 years) and who are from apparent thrombosis-prone familes (more than two other symptomatic family members). The British Society for Haematology Guidelines summarise the indications for testing.

    Other selected patient groups in whom the results of testing may influence treatment are children with purpura fulminans and pregnant women at risk of venous thrombosis. The decision to test these selected patients should be based on whether or not test results are likely to influence treatment decisions.

    Although it may be fairly simple to identify that a patient has a clot, identification of the cause may take more time and effort and no underlying cause may be found. This is because several of the diagnostic tests that need to be done are affected by an existing or recent blood clot and by any anticoagulant therapy that is given. Follow-up testing is sometimes helpful in assessing a patient’s risk of developing recurrent blood clots.

    Initial testing may include: a PTPTT, FBC, Activated Protein C Resistance (APCR), Factor V Leiden mutation assay (when APCR is abnormal), Protein C, Protein S, and antithrombin,  and a prothrombin 20210 mutation test, anticardiolipin antibodies and lupus anticoagulant  

    ‘Thrombophilia screen’ describes several different tests that may be requested at the same time. Different labs will have different combinations of these tests. In general, testing may include: 

    Tests for Hypercoagulable Disorders

     

    Test Measures Ordered When/To Abnormal Results May Indicate
    Activated Partial Thromboplastin Time (APTT) Time to clot test; Evaluates the intrinsic and common pathways of coagulation cascade Screens for lupus anticoagulant, monitor anticoagulant therapy Prolonged PTT suggests need for further tests. May indicate nonspecific inhibitor (such as lupus anticoagulant)
    Anticardiolipin antibodies, including anti-beta 2 gycoprotein-1 antibodies Presence of antibody Evaluate recurrent blood clots and/or miscarriages Antiphospholipid Syndrome
    Antithrombin (III) Activity Activity of Antithrombin Evaluate recurrent blood clots Low activity may increase thrombotic risk
    Antithrombin (III) Antigen Quantity of antithrombin Activity is consistently low Decreased production or increased use of factor, may increase thrombotic risk
    APCR (Activated Protein C Resistance) Resistance to degradation of activated factor V by APC Evaluate recurrent blood clots Need to confirm by checking for Factor V Leiden mutation
    D-dimer, or fibrin degradation products Level of a specific type of crosslinked fibrin degradation product Evaluate blood clot formation during bleeding and clotting episodes If elevated, indicates recent clotting activity. May be due to acute or chronic condition, such as a thromboembolism or DIC (disseminated intravascular coagulation)
    Dilute Russell Viper Venom Test (dRVVT) Time to clot test, Evaluates the common pathway of coagulation. Dilute refers to lipid concentration. Evaluate recurrent blood clots, when PTT is prolonged, looking for a lupus anticoagulant. When prolonged, suggests lupus anticoagulant may be present, increased risk of thrombosis.
    Factor V Leiden mutation Genetic mutation that results in formation of an activated Factor V that resists degradation by APC Recurrent blood clots Increased risk of thrombosis
    FDP (Fibrin Degradation Products), or D-dimers Reflection of clotting and fibrinolytic (clot breakdown) activity Evaluate bleeding and clotting If increased, indicates recent blood clot formation and breakdown
    Fibrinogen Amount of fibrinogen in the circulation. Evaluate bleeding and clotting If low, may indicate decreased production or increased use, may be elevated with inflammation, it is an acute phase reactant
    Heparin Induced Thrombocytopenia (HIT)ELISA Heparin antibodies against PF4-heparin complex (i.e. antibodies produced by heparin causing platelet aggregation) Low platelet count (less than 150x109/L) Heparin Induced Thrombocytopenia
    Homocysteine Level in blood Recurrent blood clots If elevated, increased cardiac risk and risk of thrombosis
    JAK2/CALR/MPL mutations Mutations present in blood cells Suspected myeloproliferative neoplasm or thrombosis in unusual site Myeloproliferative neoplasm
    Lupus Anticoagulant Panel of tests are used to check for Lupus antibody Reccurent blood clots and/or miscarriages, prolonged PTT When PTT and LA sensitive PTT and dRVVT are prolonged it suggests LA, usually confirmed with additional testing; if present, increased risk of thrombosis
    LA-sensitive PTT (PTT-LA) Time to clot test When Lupus anticoagulant (LA) suspected If prolonged and ‘corrects’ to normal when phospholipids added, may be due to LA
    Methylenetetrahydrofolate Reductase (MTHFR) Genetic mutation Homocysteine level is elevated with no clear acquired cause. Increased risk for developing elevated homocysteine levels.
    Plasminogen activity Levels of plasminogen produced by liver In conjunction with other thrombophilia tests Ligneous conjunctivits/gingivitis and increased risk of thrombosis
    Platelet Neutralization Procedure (PNP) Timed test using either the PTT or the dRVVT, using platelets as a source of phospholipids Evaluate prolonged PTT and recurrent blood clots If test corrects to normal with the addition of platelets, may indicate presence of a lupus anticoagulant
    PNH testing by flow cytometry Imunophenotypic detection of absence of PIG linked antigens such as FLAER, CD14/16/55/59 on blood cell Thrombosis in unusual site, evidence of haemolysis or aplastic anaemia Paroxxysmal Nocturnal Haemoglobinuria (PNH)
    Protein C Activity Function of Protein C Recurrent blood clots Protein C helps slow down the coagulation cascade by degrading activated Factors V and VIII. If activity is low, there is an increased risk of thrombosis
    Protein C Antigen Quantity of Protein C When Protein C activity is low If decreased, may be due to inherited or acquired condition. Increased risk of thrombosis
    Protein S Activity Function of Protein S Recurrent blood clots Protein S is a cofactor, helps Protein C
    Protein S Antigen (free and total) Quantity of total and free Protein S When Protein S activity low Only free Protein S is available to assist Protein C; total protein S includes free protein S and protein S bound to C4b-binding protein.
    Prothrombin 20210 mutation Genetic mutation Recurrent blood clots Increased risk of thrombosis
    Prothrombin Time (PT) Time to clot As part of an initial workup for bleeding or clotting, monitor anticoagulant therapy Prolonged PT suggests need for additional tests
    Thrombin Time (TT) Thrombin activates fibrinogen to fibrin strands; TT detects presence of inhibitors to this process Help evaluate bleeding episode; sometimes when aPTT prolonged; due to heparin contamination If elevated, heparin may be contaminating blood sample; also elevated with Fibrin Degradation Products, very low levels of fibrinogen and abnormal fibrinogen (dysfibrinogenemia)

     

  • Treatments

    Thrombophilia has no specific treatment but it indicates that extra care may need to be taken to reduce the risk of thrombosis. This is a complex area . A finding of an abnormal thrombophila test result does not indicate that treatments should be changed or started in most cases. It is recommended that patients seek consultation with a haematologist with a specialist interest in thrombosis before they consider testing for thrombophilia or need advice about an abnormal result. Regardless of the cause of thrombosis and the presence of absence of thrombophilia, the treatment for an acute thrombosis is often fairly standard. It often consists of short term heparin (or, more commonly, low-molecular weight heparin) anticoagulant therapy, followed by an overlap of heparin and warfarin therapy, followed by several months or longer of warfarin therapy. this treatment regimen, unfractionated (standard) heparin is monitored using the PTT test or heparin assay, and warfarin therapy is monitored with the international normalized ratio (INR).

    Newer drugs called direct acting oral anticoagulants (DOACs) are being used increasingly instead of heparin and warfarin.

    After several months of anticoagulation, your doctor may evaluate your risk of clot recurrence. The doctor must weigh the risk of recurrent clotting against the very real risk of bleeding episodes with continued anticoagulation. If you are at a high risk of recurrent clotting, anticoagulant therapy may be continued indefinitely. If you are at a lower risk, the anticoagulant will most likely be discontinued but you will need to be vigilant, going back to your doctor promptly if thrombotic symptoms return. Thrombophilia tesing may help in this decision-making process, but often other factors are more important than the results of these tests