hypercoagulability
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Introduction
A physiologic state in which individuals are predisposed to thromboses.
Etiology
- primary (inherited) hypercoagulable states
- aberrant mutations
- coagulation factor V Leiden mutation (most common)
- activated protein C resistance
- predictive of recurrent venous thromboembolism[6]
- mutation in prothrombin gene: prothrombin G20210A[6]
- heterozygosity not predictive of recurrent DVT
- not known if homozygosity increases risk of DVT
- coagulation factor V Leiden mutation (most common)
- protein deficiency
- antithrombin III deficiency
- protein C deficiency
- protein S deficiency
- heparin cofactor II defects
- plasminogen defects
- tissue plasminogen activator or inhibitor defects
- dysfibrinogenemia
- hyperhomocysteinemia/homocystinuria
- increased cysteine-rich glycoprotein
- increased levels of factor VIII[4]
- aberrant mutations
- secondary (acquired) hypercoagulable states
- autoimmune
- malignancy (Trousseau's syndrome)
- myeloproliferative disorders
- thrombotic thrombocytopenic purpura (TTP)
- increased factor VII
- increased fibrinogen
- disseminated intravascular coagulation (DIC)
- acute stroke
- hyperlipidemia
- nephrotic syndrome
- diabetes mellitus
- congestive heart failure
- hyperviscosity syndromes
- paroxysmal nocturnal hemoglobinuria
- Behcet's disease
- cancer chemotherapy
- heparin-induced thrombocytopenia
- estrogen treatment or oral contraceptives
- post-operative states (stasis)
- central venous catheter
- pregnancy (especially postpartum)
- obesity
- immobilization
- warfarin skin necrosis associated with depletion of protein C[3]
- old age
Clinical manifestations
- unprovoked venous thromboembolism
- thromboembolism while on oral contraceptives or while pregnant
- arterial thrombi
- cutaneous manifestations:
Laboratory
- indications
- recurrent idiopathic thrombosis
- patients < 45 years with unprovoked thrombosis[3]
- hypercoagulability in 1st degree relative
- screening of asymptomatic persons not indicated even if family history of thrombophila (hypercoagulability)[3]
- warfarin-induced skin necrosis
- thromboses at unusual sites[3]
- women with a history of recurrent fetal loss
- testing for hypercoagulability is not indicated in the setting of surgery, trauma, or prolonged immobility[10]
- generally does not change acute management except in patients with high risk antiphospholipid antibody syndrome[3]
- complete blood count (CBC)
- JAK2 mutation & PNH testing if CBC abnormal
- PTT, if prolonged mixing study
- anti-phospholipid antibody will not correct
- confirm a positive test later to rule out transient effects due to viral infection
- activated protein C resistance ratio (2nd generation)* identifies factor V mutation
- factor V mutations
- prothrombin G20210A mutation*
- antithrombin III activity%
- protein C activity#
- protein S activity#
- only very low levels of protein S & & homozygous gene deletions are thrombophilic
- ref[9] recommends against routine plasma protein S
- free protein S in plasma[3]
- dilute thrombin time (no longer performed)
- fibrinogen in plasma not recommended[3]
- serum homocysteine*; does not affect management[3]
- antiphospholipid Ab in serum (antiphospholipid Ab testing)
- beta-2 glycoprotein 1 IgG & beta-2 glycoprotein 1 IgM
- tests for functional activity may be altered by acute thrombosis or anticoagulation therapy
- perform testing several weeks after discontinuation of anticoagulation[3][8]
- erythroid colony assay for occult myeloproliferative disorder
- factor VIII activity[4]; does not affect management[3]
- plasminogen activator inhibitor Ag in plasma; does not affect management[3]
- see ARUP consult[7]
* tests without interference from anticoagulation
% test not influenced by warfarin therapy[3]
% heparin may reduce antithrombin III activity
# warfarin may lower activity of protein C & protein S %# acute thrombosis may lower activity of protein C, protein S, & antithrombin III %# apixaban may increase activity of protein C, protein S, & antithrombin III
*** Best time for hypercoagulability workup is 2 weeks after completing 6 months of anticoagulation[3].
Management
- see specific disorder
- anticoagulation for thrombotic complications
- lifelong anticoagulation for
- persistent lupus anticoagulant or anticardiolipin antibody
- homozygous for factor V Leiden mutation
- antithrombin III deficiency & recurrent venous thromboembolism
- in the absence of venous thromboembolism, anabnormal test for thrombophilia or hypercoagulability does not warrant life-long anticoagulation
- temporary prophylactic anticoagulation for all patients with hypercoagulability during high-risk situations:
- surgery
- prolonged immobilization
- pregnancy
- lifelong anticoagulation for
- suspect malignancy, myleoproliferative disorder or anti-phospholipid antibodies in patients with recurrent thrombosis despite therapeutic INR
- hydroxyurea to lower platelet counts in patients with thrombosis secondary to myleloproliferative disorder
More general terms
More specific terms
- activated protein C (APC) resistance
- antiphospholipid syndrome (APS); Hughes syndrome
- antithrombin deficiency
- congenital absence of inferior vena cava
- cryofibrinogenemia
- disseminated intravascular coagulation (DIC)
- dysfibrinogenemia
- heparin-induced thrombocytopenia; heparin-associated antibody syndrome (HIT)
- hypercoagulability associated with malignancy
- hyperhomocysteinemia
- paroxysmal nocturnal hemoglobinuria (PNH, Marchiafava-Micheli syndrome)
- plasminogen deficiency
- polycythemia
- portal vein thrombosis
- protein C deficiency
- protein S deficiency
- sticky platelet syndrome
- thrombophilia
- thrombophilia due to factor IX defect
- thrombotic thrombocytopenic purpura (TTP)
- venous thromboembolism associated with pregnancy
Additional terms
References
- ↑ Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 283
- ↑ Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 775
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006,2009, 2012, 2015, 2018, 2022
Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - ↑ 4.0 4.1 4.2 Journal Watch 20(18):142, 2000 Kyrle et al N Engl J Med 343:457, 2000
- ↑ Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 345
- ↑ 6.0 6.1 6.2 Segal JB et al Predictive Value of Factor V Leiden and Prothrombin G20210A in Adults With Venous Thromboembolism and in Family Members of Those With a Mutation JAMA. 2009;301(23):2472-2485 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/19531787 <Internet> http://jama.ama-assn.org/cgi/content/short/301/23/2472
- ↑ 7.0 7.1 ARUP Consult: Hypercoagulable States - Thrombophilia The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/hypercoagulable-states
- ↑ 8.0 8.1 Favaloro EJ, McDonald D, Lippi G. Laboratory investigation of thrombophilia: the good, the bad, and the ugly. Semin Thromb Hemost. 2009 Oct;35(7):695-710. PMID: https://www.ncbi.nlm.nih.gov/pubmed/20013536
- ↑ 9.0 9.1 Pintao MC et al. Protein S levels and the risk of venous thrombosis: Results from the MEGA case-control study. Blood 2013 Oct 31; 122:3210 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24014240 <Internet> http://bloodjournal.hematologylibrary.org/content/122/18/3210
- ↑ 10.0 10.1 Hicks LK et al. The ASH Choosing Wisely Campaign: Five hematologic tests and treatments to question. Blood 2013 Dec 5; 122:3879. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24319155 <Internet> http://bloodjournal.hematologylibrary.org/content/122/24/3879
Hicks LK, Bering H, Carson KR et al The ASH Choosing Wisely campaign: five hematologic tests and treatments to question. Blood. 2013 Dec 5;122(24):3879-83 PMID: https://www.ncbi.nlm.nih.gov/pubmed/24307720 - ↑ Middeldorp S Is thrombophilia testing useful? Hematology Am Soc Hematol Educ Program. 2011;2011:150-5 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22160027
- ↑ Baglin T, Gray E, Greaves M et al Clinical guidelines for testing for heritable thrombophilia. Br J Haematol. 2010 Apr;149(2):209-20 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20128794
- ↑ 13.0 13.1 Thornsberry LA, LoSicco KI, English JC 3rd. The skin and hypercoagulable states. J Am Acad Dermatol. 2013 Sep;69(3):450-62 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23582572