Hereditary and Acquired Hypercoagulability Workup
- Author: Paul Schick, MD; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP more...
The decision to initiate a laboratory workup for thrombophilia is complex.[17, 18] A workup for thrombophilia is usually indicated only in patients with one or more of the following risk factors:
Recurrent thromboembolic episodes
Thromboembolism at a young age (ie, <40 y)
A family history for thromboembolism
Thrombosis in an unusual site
Of patients with idiopathic venous thrombosis, which is defined as venous thromboembolism without any obvious risk factor, about 50% have an underlying thrombophilia. Therefore, some authors have recommended performing a thrombophilia workup in patients with idiopathic venous thrombosis.
The decision to order a thrombophilia workup can be difficult, because the identification of an underlying thrombophilia might not affect therapeutic strategy. If thrombophilia is detected in a patient with no history of thromboembolism, anticoagulation is usually not necessary. Conversely, patients with recurrent thromboembolic events should be anticoagulated even if their workup uncovers no evidence of an underlying thrombophilia or a lupus anticoagulant.
Some benefits may exist with testing patients for thrombophilia and antiphospholipid syndrome (lupus anticoagulants).The presence of more than one risk factor results in an incidence rate of venous thrombosis that is greater than the sum of the individual risks. For example, women with a prothrombotic mutation who are taking estrogen have a 25-fold greater risk of venous thrombosis than women without the mutation who are on estrogen.
Patients who have an identifiable thrombophilic risk factor should be advised to have blood relatives tested, as this information would be important for their physicians, in deciding whether to recommend oral contraception or hormone replacement therapy. Also, this will help determine whether these relatives should receive anticoagulation during surgery or immobilization.
In addition to the challenge of deciding who should be tested, clinicians need to be aware of when to test—or more precisely, when not to. Many of the tests (coagulation-based studies) should not be done while patients are on anticoagulants or during active thrombosis.
Numerous tests are available for each of the hypercoagulable disorders or thrombophilia. A D-dimer assay is useful as a general test for verifying the presence of thrombosis. Testing for specific disorders is described below.
Antiphospholipid syndrome (lupus anticoagulant)[6, 7] screening tests are as follows:
Activated partial thromboplastin time (aPTT)
Prothrombin time (PT)
Confirmation of the diagnosis is based on the following study results:
Prolonged phospholipid-dependent dilute Russell viper venom time (dRVVT), Increased titers of anticardiolipin antibodies (IgG and IgM)
Increased titers of anti-β(2)glycoprotein 1 antibodies (IgG and IgM)
Confirmatory test results should be positive on two occasions 12 weeks apart. Efforts to standardize these tests have been made, to enable reliable diagnosis of lupus anticoagulants and prediction of the risk for thrombosis. It has been suggested that the risk of thrombosis is greater when results from several of these tests are positive.
Factor V Leiden
In patients with suspected factor V Leiden, coagulation testing with an activated protein C (APC) resistance assay should be done first, because a small fraction of APC resistance disorders are due to mutations other that factor V Leiden. In this assay, the ratio of aPTT testing performed with and without added APC is reported as the APC resistance (or sensitivity) ratio.
A ratio of <2.3 suggests abnormal resistance to APC of hereditary origin. In patients who carry the factor V Leiden mutation, those who are homozygous have a very low APC resistance ratio, typically 1.1 to 1.4, while in heterozygous carriers the ratio is usually 1.5 to 1.8.
Patients with an abnormally low APC resistance assay result should undergo genetic testing for factor V Leiden. This test, which is a polymerase chain reaction (PCR) assay, can identify carriers and determine whether they are heterozygous or homozygous.
Antithrombin and prothrombin abnormalities
Available studies for antithrombin deficiency include both functional and antigenic assays. Functional studies should always be performed, because some cases of antithrombin deficiency may be associated with normal antigen levels. The functional study is a chromogenic heparin cofactor assay, which measures the ability of antithrombin to bind heparin and neutralize thrombin or factor Xa. Antithrombin deficiency can be acquired or represent either of two major hereditary types, and further immunologic assessment or DNA sequencing can be done to characterize the specific defect present.
For full discussion, see Antithrombin Deficiency.
Prothrombin (factor II) deficiency can be acquired (eg, due to severe liver disease, vitamin K deficiency, or development of an anti-prothrombin antibody) or hereditary. PCR testing can identify the prothrombin G20210A mutation. For more information, see Factor II.
Protein C deficiency
Although both functional (amidolytic) and antigen assays for protein C are available, functional (amidolytic) studies should always be performed to diagnose protein C deficiency, because some cases of protein C deficiency may be associated with normal antigen levels. For full discussion, see Protein C Deficiency
Protein S deficiency
For protein S deficiency, free antigen, total antigen, and functional assays are available. All three should be performed, because variants of protein S deficiency include the following:
Low total protein S, normal free protein S
Low-normal total protein S, low free protein S
Normal total and free protein S, functionally abnormal protein S
For full discussion, see Protein S Deficiency.
Tests for hypercoagulability are affected by a number of conditions. Therefore, precautions are important when ordering laboratory studies to rule out an underlying thrombophilia. Limitations on studies that can be performed while patients are undergoing anticoagulation therapy include the following:
Testing for antithrombin functional activity should not be done while the patient is on unfractionated heparin or low molecular weight heparin (LMWH)
Testing for protein C or S functional activity should not be done while patients are on warfarin, since protein C and protein S are vitamin K–dependent proteins
Testing for APC resistance should be deferred when patients are on anticoagulant therapy, since this test is a coagulation assay; however, genetic tests of factor V Leiden can be ordered
DRRVT and phospholipid dependence for confirming lupus anticoagulants should not be done while the patient is being anticoagulated, since they are coagulation-based tests, but testing for anticardiolipid antibodies or anti-β(2)glycoprotein 1 antibodies can be performed during anticoagulation
Antithrombin, protein S, and protein C levels may be decreased during acute thromboembolism; therefore, both protein assays and functional assays of these proteins could be inaccurate during the acute phase of thromboembolic disease
The tests should be performed in laboratories that specialize in testing for thrombophilia. In addition, the results can be difficult to interpret, so interpretation is best done by a physician with considerable experience with thrombophilias.
Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet. 1999 Apr 3. 353(9159):1167-73. [Medline].
Hillarp A, Dahlback B, Zoller B. Activated protein C resistance: from phenotype to genotype and clinical practice. Blood Rev. 1995 Dec. 9(4):201-12. [Medline].
Wu KK, Thiagarajan P. Role of endothelium in thrombosis and hemostasis. Annu Rev Med. 1996. 47:315-31. [Medline].
Colman-Brochu S. Deep vein thrombosis in pregnancy. MCN Am J Matern Child Nurs. 2004 May-Jun. 29(3):186-92. [Medline].
Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun. 133(6 suppl):844S-886S. [Medline].
Rand JH, Senzel L. Antiphospholipid antibodies and the antiphospholipid syndrome. Colman RW, Marder VJ, Clowes AW, et al, eds. Hemostasis and Thrombosis. 5th ed. Philadelphia, Pa: Lippincott, Williams and Wilkins; 2006. 1621-36.
Triplett DA. Antiphospholipid antibodies. Clin Adv Hematol Oncol. 2003 Dec. 1(12):726-30. [Medline].
Franchini M, Mannucci PM. ABO blood group and thrombotic vascular disease. Thromb Haemost. 2014 Dec. 112 (6):1103-9. [Medline].
Heit JA, Cunningham JM, Petterson TM, et al. Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism. J Thromb Haemost. 2011 Jun. 9(6):1133-42. [Medline]. [Full Text].
Eroglu A, Egin Y, Cam R, Akar N. The 19-bp deletion of dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR) C677T, Factor V Leiden, prothrombin G20210A polymorphisms in cancer patients with and without thrombosis. Ann Hematol. 2009 Jan. 88(1):73-6. [Medline].
Mayo Clinic. Activated Protein C Resistance V (APCRV). Mayo Medical Laboratories. Available at http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/81967. Accessed: February 13, 2016.
Couturaud F, Leroyer C, Julian JA, et al. Factors that predict risk of thrombosis in relatives of patients with unprovoked venous thromboembolism. Chest. 2009 Jul 10. epub ahead of print. [Medline].
Lijfering WM, Veeger NJ, Middeldorp S, et al. A lower risk of recurrent venous thrombosis in women compared with men is explained by sex-specific risk factors at time of first venous thrombosis in thrombophilic families. Blood. 2009 Sep 3. 114(10):2031-6. [Medline]. [Full Text].
Roberts LN, Patel RK, Arya R. Venous thromboembolism and ethnicity. Br J Haematol. 2009 Aug. 146(4):369-83. [Medline].
Aiach M, Emmerrich J. Thrombophilia genetics. Colman RW, Marder VJ, Clowes AW, et al, eds. Hemostasis and Thrombosis. 5th ed. Philadelphia, Pa: Lippincott, Williams and Wilkins; 2006. 779-93.
Straczek C, Oger E, Yon de Jonage-Canonico MB, et al. Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Circulation. 2005 Nov 29. 112(22):3495-500. [Medline]. [Full Text].
Urbanus RT, de Groot PG. Antiphospholipid antibodies--we are not quite there yet. Blood Rev. 2011 Mar. 25(2):97-106. [Medline].
Kearon C, Julian JA, Kovacs MJ, et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood. 2008 Dec 1. 112(12):4432-6. [Medline]. [Full Text].
Warkentin TE. Agents for the treatment of heparin-induced thrombocytopenia. Hematol Oncol Clin North Am. 2010 Aug. 24(4):755-75, ix. [Medline].
Adam SS, McDuffie JR, Lachiewicz PF, Ortel TL, Williams JW. Comparative Effectiveness of Newer Oral Anticoagulants and Standard Anticoagulant Regimens for Thromboprophylaxis in Patients Undergoing Total Hip or Knee Replacement [Internet]. VA Evidence-based Synthesis Program Reports. 2012 Dec. [Medline].
Perez A, Merli GJ. Novel Anticoagulant Use for Venous Thromboembolism: A 2013 Update. Curr Treat Options Cardiovasc Med. 2013 Feb 6. [Medline].
Dobesh PP, Oestreich JH. Novel Direct-Acting Anticoagulants for Risk Reduction in ACS. J Pharm Pract. 2012 Nov 19. [Medline].
Merli GJ. The new oral anticoagulants: a challenge for hospital formularies. Hosp Pract (Minneap). 2012 Aug. 40(3):126-8. [Medline].
Komócsi A, Vorobcsuk A, Kehl D, Aradi D. Use of new-generation oral anticoagulant agents in patients receiving antiplatelet therapy after an acute coronary syndrome: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2012 Nov 12. 172(20):1537-45. [Medline].
Kar S, Bhatt DL. Anticoagulants for the treatment of acute coronary syndrome in the era of new oral agents. Coron Artery Dis. 2012 Sep. 23(6):380-90. [Medline].
Rajasekhar A, Beyth R, Crowther MA. Newer anticoagulants in critically ill patients. Crit Care Clin. 2012 Jul. 28(3):427-51, vii. [Medline].
Lee AY. Treatment of established thrombotic events in patients with cancer. Thromb Res. 2012 Apr. 129 Suppl 1:S146-53. [Medline].
Cohen AT, Gurwith MM, Dobromirski M. Thromboprophylaxis in non-surgical cancer patients. Thromb Res. 2012 Apr. 129 Suppl 1:S137-45. [Medline].
Vande Griend JP, Marcum ZA, Linnebur SA. A year in review: new drugs for older adults in 2011. Am J Geriatr Pharmacother. 2012 Aug. 10(4):258-63. [Medline].
Burke DA, Warraich HJ, Pinto DS. Which antithrombin for whom? Identifying the patient population that benefits most from novel antithrombin agents. Curr Cardiol Rep. 2012 Aug. 14(4):493-501. [Medline].
Di Nisio M, Middeldorp S, Büller HR. Direct thrombin inhibitors. N Engl J Med. 2005 Sep 8. 353 (10):1028-40. [Medline].
[Guideline] Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb. 141 (2 Suppl):e419S-94S. [Medline]. [Full Text].
[Guideline] Kitchen S, Gray E, Mackie I, Baglin T, Makris M, BCSH committee. Measurement of non-coumarin anticoagulants and their effects on tests of Haemostasis: Guidance from the British Committee for Standards in Haematology. Br J Haematol. 2014 Sep. 166 (6):830-41. [Medline]. [Full Text].
Cho L, Kottke-Marchant K, Lincoff AM, et al. Correlation of point-of-care ecarin clotting time versus activated clotting time with bivalirudin concentrations. Am J Cardiol. 2003 May 1. 91(9):1110-3. [Medline].
Welsby IJ, McDonnell E, El-Moalem H, Stafford-Smith M, Toffaletti JG. Activated clotting time systems vary in precision and bias and are not interchangeable when following heparin management protocols during cardiopulmonary bypass. J Clin Monit Comput. 2002 Jul. 17(5):287-92. [Medline].
Chang LC, Lee HF, Yang Z, Yang VC. Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (I): preparation and characterization. AAPS PharmSci. 2001. 3(3):E17. [Medline].
Schick BP, Maslow D, Moshinski A, San Antonio JD. Novel concatameric heparin-binding peptides reverse heparin and low-molecular-weight heparin anticoagulant activities in patient plasma in vitro and in rats in vivo. Blood. 2004 Feb 15. 103(4):1356-63. [Medline]. [Full Text].
Welsby IJ, Stafford-Smith M. Monitoring direct thrombin inhibitors: time for standardization. Anesthesiology. 2004 Oct. 101(4):1048-9. [Medline].
Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6. 375(9717):807-15. [Medline].
Romualdi E, Ageno W. Oral Xa inhibitors. Hematol Oncol Clin North Am. 2010 Aug. 24(4):727-37, viii-ix. [Medline].
Medi C, Hankey GJ, Freedman SB. Stroke risk and antithrombotic strategies in atrial fibrillation. Stroke. 2010 Nov. 41(11):2705-13. [Medline].
Becattini C, Lignani A, Agnelli G. New anticoagulants for the prevention of venous thromboembolism. Drug Des Devel Ther. 2010. 4:49-60. [Medline].
Desai SS, Massad MG, DiDomenico RJ, et al. Recent developments in antithrombotic therapy: will sodium warfarin be a drug of the past?. Recent Pat Cardiovasc Drug Discov. 2006 Nov. 1(3):307-16. [Medline].
Keeney M, Allan DS, Lohmann RC, Yee IH. Effect of activated recombinant human factor 7 (Niastase) on laboratory testing of inhibitors of factors VIII and IX. Lab Hematol. 2005. 11(2):118-23. [Medline].
Malherbe S, Tsui BC, Stobart K, Koller J. Argatroban as anticoagulant in cardiopulmonary bypass in an infant and attempted reversal with recombinant activated factor VII. Anesthesiology. 2004 Feb. 100(2):443-5. [Medline].
Powner DJ, Hartwell EA, Hoots WK. Counteracting the effects of anticoagulants and antiplatelet agents during neurosurgical emergencies. Neurosurgery. 2005 Nov. 57(5):823-31; discussion 823-31. [Medline].
|Condition||Prevalence in General Population (%)||Relative Risk of VTE (%)||Relative Risk of Recurrent VTE (%)|
|Factor V Leiden
|Protein C deficiency
|Protein S deficiency
|VTE = Venous thromboembolism|