Hypercoagulability

Clinical features suggestive of underlying thrombophilia

• VTE characteristics
  • Onset at age < 50 years of either of the following:
    • Unprovoked VTE
    • VTE associated with only weak risk factors
  • Unusual thrombus localization:
    • portal vein thrombosis
    • mesenteric vein thrombosis
    • cerebral venous thrombosis
    • central retinal vein occlusion.
  • Strong family history of VTE
  • Recurrent VTE or multiple VTE
  • History of warfarin-induced skin necrosis
• Frequent obstetrical complications: e.g., recurrent pregnancy loss, IUFD, IUGR, preeclampsia
• Arterial thromboembolism (e.g., stroke) in a young patient with no cardiovascular risk factors

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Acquired causes of hypercoagulability

• Predisposing to venous thrombosis
  • HIV
  • Malignancy
  • Nephrotic syndrome (Loss of plasma antithrombin in urine and an increase in blood viscosity due to extravasation of fluid from albumin loss in urine)
  • Inflammatory bowel disease
  • Cirrhosis
  • Paroxysmal nocturnal hemoglobinuria
  • Preganancy (Clotting factors increase (hypercoagulability), Protein C & S decrease, Venous stasis,  as the uterus enlarges)

• Predisposing to both venous and arterial thrombosis
  • Antiphospholipid syndrome (APLAS)
    • Acquired antibodies directed against plasma proteins bound to phospholipids (e.g., lupus anticoagulant, anti-cardiolipin, beta2-glycoprotein I antibodies) → aggregation of plasma proteins  (e.g., clotting factors) → induces venous and arterial clotting → miscarriages, DVTs, portal vein thrombosis , and strokes
    • Associated with SLE  and rheumatoid arthritis
      • Blood Test: Anti-cardiolipin antibody (ACL)
      • Blood Test: Beta 2 glycoprotein-1 antibody (only if high suspicion for antiphospholipid antibodies)
  • Heparin-induced thrombocytopenia
    • Antibodies against platelet factor 4 (PF-4) → increased activation of platelets (hypercoagulability) and a depletion of platelets
  • Myeloproliferative disorders
  • Systemic lupus erythematosus (SLE)
    • Blood Test: Lupus anticoagulant (LAC)

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Hereditary causes of hypercoagulability:

Antithrombin III deficiency

• Autosomal dominant inheritance
• Occasionally acquired
  • Renal failure
  • Liver failure
  • Nephrotic syndrome (urinary loss of antithrombin)
• Cause severe thrombophilia
• Predisposing to venous thrombosis
• 60% of heterozygotes develop VTE by age 60 years
• Homozygosity generally incompatible with life
• Normally, antithrombin III binds to and inactivates thrombin and factor X → inhibits coagulation.
• Deficiency leads to decreased inhibition and elevated thrombin and factor X.
• Heparin normally increases PTT; however, in patients with antithrombin III deficiency, this increase is diminished.
• No other direct effects on PT, PTT, or thrombin time
• Blood Test: Antithrombin (AT)

Protein C deficiency

• Moderate to severe thrombophilia 
• Predisposing to venous thrombosis
• Up to 50% of heterozygotes develop VTE by age 60 years
• Homozygotes develop severe thrombophilia: neonatal purpura fulminans; disseminated intravascular coagulation
• Blood Test: Protein C (PC)
• Blood Test: Activated Protein C Resistance (APCR)

Protein S deficiency

• Moderate thrombophilia 
• Predisposing to both venous and arterial thrombosis 
• 30% of heterozygotes develop VTE by age 60 years 
• Homozygotes develop severe thrombophilia: neonatal purpura fulminans
• Blood Test: Protein S (PS)

Activated protein C (APC) resistance/factor V Leiden

• autosomal dominant inheritance 
• most common genetic cause of hypercoagulability in white populations
• cause Mild thrombophilia
• Predisposing to venous thrombosis 
• 6% of heterozygotes develop VTE by age 65 years
• homozygotes develop moderate thrombophilia
• Normally, activated protein C (APC) inactivates factor V in the clotting cascade → decreases the activation of thrombin.
• Factor V mutation makes it resistant to cleavage by APC → factor V remains active → activates prothrombin → increases thrombotic events 
• Risk of thromboembolism is several times higher in patients with homozygous mutations than in those with heterozygous mutations.
• Blood Test: Factor V Leiden (FVL)

Prothrombin gene variant

• Prothrombin G20210A mutation
• Mild thrombophilia
• <5% of heterozygotes develop VTE by age 60 years
• Homozygotes develop moderate thrombophilia
• Blood Test: Prothrombin gene mutation (PGM)

Hyperhomocysteinemia

• Changes in thrombomodulin function are due to increased activation of factor VIIa and V, inhibition of protein C, increased blood viscosity, and decreased endothelial antithrombotic activity.
• Homocysteine levels are elevated in patients with vitamin B6  deficiency and mutations in enzymes that metabolize homocysteine (autosomal recessive). Blood Test: Homocysteine (fasting)

Sickle cell anemia

Lipoprotein A

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Thrombophilia SCREENING

• Patients should be considered for tests if they are
  • less than 50 years old with recurrent thrombosis, or 
  • have had a single thrombotic event and have a positive family history. 
  • Other clinical features that may suggest an inherited thrombotic disorder include
    • Thrombosis at unusual sites
    • heparin resistance
    • warfarin induced skin necrosis.

• The most common findings associated with venous thrombosis are
  • Factor V Leiden and Prothrombin gene mutation. 
  • Protein C, Protein S and Antithrombin deficiency are far less common and are unlikely to be of relevance in “weakly” thrombophilic patients in whom the initial thrombotic event has occurred after the age of 50 years, particularly in the absence of a family history of thrombosis. Therefore, in these patients, factor V leiden, prothrombin gene mutation and tests for APA are appropriate.
• The relevance of the results of thrombophilia screening may be of uncertain significance in some cases, particularly with regard to the Factor V Leiden and Prothrombin mutations, which tend to occur in 5% and 1-4% of the general Caucasian population respectively. 
• Recent studies suggest that the most important predictive factors in terms of recurrence of thrombosis are clinical features and persistent ultrasound abnormalities, rather than the tests for thrombophilia.
• Also, in most cases, detection of a thrombophilic condition does not alter management, particularly where a clear precipitant for thrombosis is responsible for the thrombotic event.
• It is preferable that thrombophilia testing is not performed while a patient is on anticoagulant therapy.

Blood tests for Hereditary Thrombophilia (*= medicare rebatable)

• Protein C (PC) *
• Protein S (PS) *
• Antithrombin (AT) *
• Activated Protein C Resistance (APCR) *
• Factor V Leiden (FVL) *
• Prothrombin gene mutation (PGM) *
• Factor 8 level
• Homocysteine (fasting)
• Coagulation profile/screen
• (Provides an APTT, PT & fibrinogen)

Blood tests for Acquired Thrombophilia

• Lupus anticoagulant (LAC)
• Anti-cardiolipin antibody (ACL)
• Beta 2 glycoprotein-1 antibody (only if high suspicion for antiphospholipid antibodies)
• FBE – to exclude a myeloproliferative disorder.

Medicare Rebates

• A Medicare rebate applies only to the following tests for inherited thrombophilia 
  • PC
  • PS
  • AT
  • APCR
  • FVL
  • PGM
• if the request states that the patient has a personal or family history (in a 1st degree relative) of a venous thromboembolic event (VTE). 
• Where the VTE occurred in a 1st degree relative, the rebate is limited to testing for the identified marker (either by gene testing or coagulation assays). 
• A rebate also applies to confirmatory testing of PC, PS or AT.

Which tests are appropriate?

• If a patient has had NO venous thrombotic episodes (e.g. DVT/PE) but there is a family history, testing for hereditary thrombophilia may be appropriate.
• Random testing in the absence of an established familial abnormality may be misleading as some of these abnormalities are very common in the general community. 
• Appropriate counselling must be given to patients with a positive result.
• If a patient has a personal history of a venous thrombotic episode (e.g. DVT/PE), testing for both hereditary and acquired thrombophilia may be appropriate. 
• The circumstances of the episode and patient age should also be considered before testing is undertaken.

When to test

• Testing during the period of anticoagulant therapy is generally not indicated as the duration of therapy is dictated by the type of event, not by the presence of the abnormality.

• Exceptions to this include:
  • The patient with an elevated APTT prior to commencement of anticoagulants, which may indicate a lupus anticoagulant.
  • When the VTE dictates indefinite anticoagulation (some life threatening or recurrent clots) and the opportunity to test for some abnormalities will not present itself again.
• Timing of Screening:
  • if related to thrombosis should be 4 weeks after completion of anticoagulation
  • should not be on Heparain or Warfarin. Avoid testing in the acute phase of thrombosis as acute phase changes may be present
  • pregnancy, oral contraceptives, HRT and cancer chemotherapy may also affect some tests
  • avoid intercurrent severe illness
  • factor V Leiden and Prothrombin mutation are PCR tests so can be carried out in patients on anticoagulants and in acute phase. However, other tests will also be required later to exclude dual pathology 

• Warfarin effect
  • Protein C and S will be low on warfarin.
  • APCR may be falsely lowered by warfarin but the FV Leiden result will be unaffected.

• Heparin effect
  • Antithrombin result will be lowered by heparin 

• Lupus anticoagulant results may be unreliable during initial anticoagulation period. 
• PS, PC and AT may be consumed and falsely reduced in acute thrombosis. 
• PS is commonly reduced by the OCP and in pregnancy. 

• NICE (2012) suggest with respect to thrombophilia screening (4):
  • do not offer thrombophilia testing to patients who are continuing anticoagulation treatment
  • consider testing for antiphospholipid antibodies in patients who have had unprovoked DVT or PE if it is planned to stop anticoagulation treatment
  • consider testing for hereditary thrombophilia in patients who have had unprovoked DVT or PE and who have a first-degree relative who has had DVT or PE if it is planned to stop anticoagulation treatment
  • do not offer thrombophilia testing to patients who have had provoked DVT or PE
  • do not routinely offer thrombophilia testing to first-degree relatives of people with a history of DVT or PE and thrombophilia