Hypercoagulable

Aka: Hypercoagulable, Hypercoagulability, Thrombophilia

1. See Also
   1. Recurrent Venous Thromboembolism Risk
   2. Pulmonary Embolism
   3. Deep Vein Thrombosis
2. History: Findings suggestive of Hypercoagulable State
   1. Thrombosis at a young age (age under 50 years)
   2. Family History of thrombosis before age 50 years old
   3. Recurrent Thrombosis
   4. Thrombosis in an unusual site (hepatic, mesenteric, splenic or cerebral vein)
   5. Recurrent Pregnancy Loss (frequent Miscarriage)
   6. Arterial AND Venous thrombosis
   7. Idiopathic venous thrombembolism or unprovoked VTE (No known predisposing factors)
3. Etiologies: Primary Hypercoagulable States (Hereditary)
   1. Common Causes
      1. Factor V Leiden Defect
      2. Prothrombin 20210
      3. Homocystinuria or Hyperhomocysteinemia
   2. Uncommon Causes
      1. Antithrombin III deficiency
      2. Protein C Deficiency
      3. Protein S Deficiency
      4. Factor VIII Increased
      5. Fibrinolysis
      6. Dysfibrinogenemia
4. Etiologies: Secondary or Acquired Hypercoagulable States
   1. Antiphospholipid Antibody Syndrome (most common)
   2. Pregnancy
   3. Surgery
   4. Trauma
   5. Infection or Sepsis
   6. Malignancy
      1. Cancer in idiopathic Hypercoagulability with unprovoked VTE: 3.9% (as high as 20% in some studies)
         1. Carrier (2015) N Engl J Med 373(8): 697-704 [PubMed]
      2. Basic evaluation for occult malignancy
         1. Standard interval HME screening is appropriate (e.g. Pap Smear, Mammogram, Colonoscopy)
         2. However CT Chest, Abdomen and Pelvis is not recommended for unprovoked VTE alone
            1. Carrier (2015) N Engl J Med 373(8): 697-704 [PubMed]
   7. Medications
      1. Estrogen sources
         1. Oral Contraceptives
         2. Estrogen Replacement Therapy
         3. Tamoxifen
      2. Hydralazine
      3. Phenothiazines
      4. Procainamide
   8. Myeloproliferative disorder
   9. Hyperlipidemia
   10. Homocystinuria
   11. Lupus Inhibitor
   12. Nephrotic Syndrome
5. Labs: Indications for testing based on level of suspicion
   1. General
      1. Hold blood for tests below before Anticoagulation
      2. Avoid testing during acute event (inflammation and Anticoagulation may alter results)
      3. Delay test timing until
         1. Two weeks after stopping Warfarin
         2. Three days after stopping DOACs
         3. Continuous therapy for at least 2 to 3 months (consult hematology for testing on Anticoagulation)
   2. Risk of Thrombophilia determines level of testing
      1. Unlikely to be thrombophilic
         1. Criteria
            1. First episode of Venous Thromboembolism and
            2. Known Thromboembolism Risk Factors and
            3. No Family History of Thromboembolism
               1. No first degree relative under age 50 years
         2. Testing
            1. No testing indicated
      2. Weakly thrombophilic
         1. Criteria
            1. Age over 50 years and
            2. First thromboembolic episode and
               1. No known Thromboembolism Risk Factors
            3. No Family History of Thromboembolism
               1. No first degree relative under age 50 years
         2. Testing
            1. Evaluation of common causes (see below)
      3. Strongly thrombophilic
         1. Criteria
            1. Age <50, no known Thromboembolism Risk Factors or
            2. Recurrent thromboembolic episode or
            3. Family History of Thromboembolism
               1. First degree relative under age 50 years
         2. Testing
            1. Evaluation of common causes and
            2. Evaluation of less common causes (see below)
6. Labs: Evaluation of common causes ($250)
   1. Complete Blood Count with Platelets and morphology
   2. Prothrombin Time
   3. Partial Thromboplastin Time
      1. Lupus Anticoagulant Syndrome suspected if increased PTT that does not correct with 1:1 dilution with normal plasma
   4. Connective Tissue Disorder tests
      1. Test 3-4 weeks after Anticoagulation and acute event resolved and then repeat for confirmation in 12 weeks
      2. Antiphospholipid Antibody Tests
         1. Anticardiolipin Antibody (ELISA)
         2. B2 GlycoproteinAntibody (high Specificity)
      3. Older tests replaced by Antiphospholipid Antibody Tests above
         1. Antinuclear Antibody Test (ANA)
         2. Clotting Assay for Lupus Anticoagulant (affected by Anticoagulants)
   5. Factor V Leiden or APC Resistance (G1681A)
      1. Initial: Clotting based assay
      2. Confirmatory: Factor V Leiden
   6. Factor II Prothrombin Mutation Analysis (G20210A)
7. Labs: Evaluation of less common causes ($900)
   1. General
      1. Indicated for strongly thrombophilic patients
      2. Testing includes all labs above
      3. Obtain lab testing 2 weeks after off Anticoagulants
      4. These conditions are highly thrombophilic
   2. Protein C Levels and Protein S Levels
      1. Antigenic (total Protein) and functional levels
   3. Antithrombin III Level (HeparinCofactor assay)
   4. Other testing to consider
      1. Plasma Factor VIII Level (increased)
      2. Fasting Total Plasma Homocysteine Level
         1. Hyperhomocysteinemia significance in Thrombophilia is in question
         2. If high Homocysteine then check Methylenetetrahydrofolate reductase (C677T)
8. Management
   1. High Risk Indications for life-long Anticoagulation
      1. Two or more spontaneous thrombotic events
      2. One spontaneous life-threatening event
      3. One spontaneous event with high risk cause
         1. Antiphospholipid Syndrome
         2. Antithrombin III deficiency
         3. More than one inherited abnormality
   2. Moderate Risk Indications for event-based prophylaxis
      1. One event with known provocative stimulus
9. Resources
   1. University of Illinois Carle Cancer Center Resources
      1. http://www.med.uiuc.edu/hematology/index.htm
10. References
    1. Bauer (2001) Ann Intern Med 135:367-73 [PubMed]
    2. Harris (1997) Am Fam Physician 56(6):1591-6 [PubMed]
    3. Kyrle (2000) N Engl J Med 343:457-62 [PubMed]
    4. Mount (2022) Am Fam Physician 105(4): 377-85 [PubMed]
    5. Nachman (1996) Ann Intern Med 119:819-27 [PubMed]
    6. Thomas (1997) Ann Intern Med 126:638-44 [PubMed]