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heparin-induced thrombocytopenia; heparin-associated antibody syndrome (HIT)

Etiology: 1) immune-mediated - reactivation is due to circulating IgG antibodies to heparin-platelet factor IV complex 2) non-immune form - direct weak activation of platelets by heparin 3) may occur with therapeutic dose, prophylaxis or intravenous flushes 5) low molecular weight heparin is significantly less likely to cause HIT than unfractionated heparin Epidemiology: 1) 1 in 5000 hospitalized patients 2) 10-folder higher among patients receiving unfractionated heparin vs LMW heparin [12] 3) 1% at 7 days, 3% at 14 days in patients receiving unfractionated heparin 4) often occurs in patients initially treated with heparin for antithrombotic prophylaxis for atrial fibrillation Pathology: 1) immune-mediated a) life-threatening venous & arterial thrombotic complications b) in-vivo platelet activation c) generation of procoagulant platelet-derived micro-particles d) IgG antiheparin antibody that reacts with: - circulating heparin - platelet factor-4 (PF4) (an alpha-granule protein) e) immune complex binds to circulating platelets & activates Fc receptors which promote intravascular platelet aggregation f) immune complex also bind vascular endothelial cells & induce endothelial cell expression of tissue factor g) venous thrombosis in > 80% of patients h) arterial thrombosis may also occur i) IgG antiheparin antibody declines to undetectable levels at about 2 months [2] 2) non-immune form a) generally NOT associated with adverse clinical outcomes b) spontaneous resolves or resolves with heparin withdrawal Clinical manifestations: 1) immune form (type 2) a) generally occurs from 5-10 days [1] (4-10 days [2]) after initiation of unfractionated heparin therapy b) may occur much earlier (< 10 hours) in patients previously exposed (within 100 days) to unfractionated heparin (re-activation) c) may occur AFTER hospital discharge d) hypercoagulability - arterial thromboembolism or venous thromboemboism (DVT) 2) non-immune form (type 1) - generally occurs within 1st 2 days of heparin administration Laboratory: 1) complete blood count (CBC) - thrombocytopenia (or decrease in platelet count of > 50%) 2) 4T score prior to confirmatory testing [1] - estimate pretest probability of HIT - can be useful in guiding therapy [1] - most patients on heparin who develop thrombocytopenia but have a low 4T score need no further evaluation [1] 3) screening with antigen assays based upon reactivity with platelet factor 4 (PF4) complexed with heparin, Heparin-PF4 ELISA [1] 4) confirmation with functional heparin-induced thrombocytopenia assay - heparin-induced platelet aggregation or serotonin-release assay* 5) platelet-activating IgG prior to subsequent heparin exposure [7] - heparin-associated platelet antibody - high negative predictive value - low positive predictive value [11] - heparin-platelet factor 4 antibody - platelet antibody in serum 6) see ARUP consult [4] * gold standard [1] Complications: - thromboembolic event 5-10 days after starting heparin - may occur much earlier (< 10 hours) in patients previously exposed (within 100 days) to unfractionated heparin (re-activation) Management: 1) discontinue heparin - cessation of all forms of heparin therapy including removal of heparin-coated catheters 2) stabilize patient with direct thrombin inhibitor or danaparoid a) argatroban (avoid in hepatic insufficiency) b) lepirudin (avoid in renal insufficiency) c) danaparoid (anti factor Xa) d) fondaparinux [8,9] - more cost effective than argatroban or bivalirudin ($151 vs. $1250 or $1466, respectively) & less likely associated with adverse events [16] e) direct oral anticoagulants are safe & effective for acute HIT [17] f) avoid warfarin in patients with acute HIT [11] 3) bivalirudin is indicated for patients undergoing cardiac procedures [1] 4) dextran followed by warfarin has also been used; dextran has been used as a substitute for heparin to prevent large artery thrombosis 5) low-molecular weight heparin has about 90% cross-reactivity - substituting LMW heparin for unfractionated heparin reduces cases of HIT from 10.7 to 2.2 per 10,000 admissions (RRR=79%) & HIT with thrombosis from 4.6 to 0.4 per 10,000 admissions (RRR=91%) [15] 6) promising agents a) anacrod (defibrinogenating snake venom) b) heparinoid 7) risk for inducing a second episode of heparin-induced thrombocytopenia by reexposure to heparin is low Notes: - 4Ts predictive scoring system should be used prior to diagnostic testing or treatment [1,6] - clinical syndrome closely resembling heparin-induced thrombocytopenia, but not provoked by heparin is described [8]

Related

4T score

General

thrombocytopenia hypercoagulability

References

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  2. Journal Watch 21(10):77, 2001 Wartentin TE et al Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 344:1286, 2001 PMID: 11320387
  3. Journal Watch 22(7):57, 2002 Rice L et al Delayed-onset heparin-induced thrombocytopenia. Ann Intern Med 136:210, 2002 PMID: 11827497
  4. ARUP Consult: Heparin-Induced Thrombocytopenia - HIT The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/heparin-induced-thrombocytopenia
  5. Cuker A et al. Predictive value of the 4Ts scoring system for heparin- induced thrombocytopenia: A systematic review and meta- analysis. Blood 2012 Nov 15; 120:4160. PMID: 22990018
  6. Hong MS, Amanullah AM. Heparin-induced thrombocytopenia: a practical review. Rev Cardiovasc Med. 2010 Winter;11(1):13-25. PMID: 20495512
  7. Warkentin TE and Sheppard JI. Serological investigation of patients with a previous history of heparin-induced thrombocytopenia who are re-exposed to heparin. Blood 2014 Feb 10; PMID: 24516044 http://bloodjournal.hematologylibrary.org/content/early/2014/02/10/blood-2013-10-533083
  8. Warkentin TE et al. Spontaneous heparin-induced thrombocytopenia syndrome: 2 new cases and a proposal for defining this disorder. Blood 2014 Jun 5; 123:3651 PMID: 24677540
  9. Kang M et al. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: A propensity score-matched study. Blood 2014 Dec 16 PMID: 25515959 http://www.bloodjournal.org/content/early/2014/12/15/blood-2014-09-599498?sso-checked=true
  10. Linkins L-A et al. Combination of 4Ts score and PF4/H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia: Prospective cohort study. Blood 2015 Apr 29; PMID: 25926600 http://www.bloodjournal.org/content/early/2015/04/29/blood-2014-12-618165
  11. Greinacher A Heparin-Induced Thrombocytopenia. N Engl J Med 2015; 373:252-261. July 16, 2015 PMID: 26176382 http://www.nejm.org/doi/full/10.1056/NEJMcp1411910
  12. Rothaus C Heparin-Induced Thrombocytopenia. http://blogs.nejm.org/now/index.php/heparin-induced-thrombocytopenia/2015/07/17/
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  17. Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: Update of Hamilton experience and literature review. Blood 2017 Jun 23; blood-2017-04-778993 PMID: 28646118 http://www.bloodjournal.org/content/early/2017/06/23/blood-2017-04-778993
  18. NEJM Knowledge+ Question of the Week. March 31, 2020 https://knowledgeplus.nejm.org/question-of-week/377/
  19. Larsen EL et al. Accuracy of diagnosing heparin-induced thrombocytopenia. JAMA Netw Open 2024 Mar; 7:e243786. PMID: 38530310 PMCID: PMC10966416 Free PMC article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2816742