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CME

Heparin-Induced Thrombocytopenia (HIT)

General Information

Description

  • HIT is an antibody-mediated disorder of coagulation caused by exposure to heparin and associated with significant risk of thromboembolic complications and death1,2,3
  • HIT is caused by formation of immunoglobulin G antibodies that recognize complexes of platelet factor 4 (PF4) and heparin and activate platelets resulting in mild to moderate thrombocytopenia (platelet count < 150 × 109/L) or a 30%-50% reduction in platelet count from baseline (even if the platelet count is > 150 × 109/L) and a highly prothrombic state with 20%-50% risk of venous or arterial thrombosis1,2,3,4
  • diagnosis requires appropriate clinical presentation (as assessed by clinical scoring system) and detection of platelet-activating anti-PF4/heparin antibodies (27380556Curr Opin Hematol 2016 Sep;23(5):462)
  • management should begin as soon as disease is suspected, including discontinuation of all heparin products and administration of a rapidly-acting thrombin inhibitor5

Definitions

  • isolated HIT - HIT without thrombosis1
  • HITT - HIT with thrombosis1
  • acute HIT - thrombocytopenic, HIT antibody positive1
  • subacute HIT - platelets recovered, but still HIT antibody positive1

Types

  • according to presence or absence of thrombosis5
    • isolated HIT
      • thrombocytopenia is the only manifestation
      • a prothrombotic condition, due to high rates of subsequent thrombosis (20% to 50%)
    • HIT complicated by thrombosis (HITT)
  • according to timing of thrombocytopenia1,2,3,5
    • typical-onset HIT
      • mild to moderate absolute (typically 50-70 × 109/L) or relative thrombocytopenia (platelet count fall of 30%-50%)
      • develops 5-14 days after initiation of heparin (day 0), and a median of 2 days after development of anti-PF4/heparin antibodies
      • about 20%-50% of patients with HIT develop thrombosis
    • rapid-onset HIT
    • delayed-onset HIT
      • develops or worsens after heparin has been discontinued
      • thrombocytopenia typically develops several days after the last heparin exposure, but still within the usual 5–10 day window
      • thrombotic manifestations are delayed for days to weeks after heparin discontinuation and discharge
      • can occur after a single injection of heparin
      • functional assays show strong serum-induced platelet activation even in the absence of heparin
      • often accompanied by
  • according to heparin-dependence of platelet activating antibodies
    • heparin-dependent antibodies mediate typical and rapid-onset HIT
    • heparin-independent antibodies occur in patients with autoimmune HIT including
      • spontaneous HIT2,5,6
        • a rare (about 20 cases reported) variant that develops without prior heparin exposure
        • patients have clinical findings of thrombocytopenia and thrombosis plus positive results for HIT using immunoassays and functional assays in the absence of recent heparin exposure
        • sera from these patients contain high-titer antibodies which
          • bind PF4 and heparin-like glycosaminoglycans (GAGs) on platelets
          • strongly activate platelets even in the absence of heparin (heparin-independent platelet activation)
        • considered a true autoimmune disease caused by autoantibodies to PF4/GAG complexes
        • most reported cases have occurred in either of
          • patients undergoing orthopedic surgery (usually, knee replacement surgery)
          • patients with antecedent infection
        • unlike typical HIT (with increase in platelet count occurring within 2-5 days of anticoagulant initiation), autoimmune HIT may persist for weeks
        • Reference - mnh28846826paph126054283t pa9h126054283t pcxh126054283t pmdc28846826pJ Thromb Haemost 2017 Nov;15(11):2099
      • other types
        • a minority of patients have otherwise typical (heparin-dependent) HIT, especially those with
          • delayed-onset HIT
          • persisting HIT
          • fondaparinux- associated HIT
          • HIT induced by exposure to heparin IV flushes
        • often have atypical clinical features including

References

General references used

  1. Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e495S-530Sfull-text, correction can be found in Chest 2015 Dec;148(6):1529
  2. Greinacher A. CLINICAL PRACTICE. Heparin-Induced Thrombocytopenia. N Engl J Med. 2015 Jul 16;373(3):252-61, commentary can be found in N Engl J Med 2015 Nov 5;373(19):1883
  3. Warkentin TE. Heparin-induced thrombocytopenia in critically ill patients. Semin Thromb Hemost. 2015 Feb;41(1):49-60
  4. Watson H, Davidson S, Keeling D; Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition. Br J Haematol. 2012 Dec;159(5):528-40
  5. Onwuemene O, Arepally GM. Heparin-induced thrombocytopenia: research and clinical updates. Hematology Am Soc Hematol Educ Program. 2016 Dec 2;2016(1):262-268
  6. Arepally GM. Heparin-induced thrombocytopenia. Blood. 2017 May 25;129(21):2864-2872full-text

Recommendation grading systems used

  • American College of Cardiology Foundation/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACCF/AHA/SCAI) recommendations and level of evidence classifications
    • classifications of recommendations
      • Class I - procedure or treatment should be performed or administered
      • Class IIa - reasonable to perform procedure or administer treatment, but additional studies with focused objectives needed
      • Class IIb - procedure or treatment may be considered; additional studies with broad objectives needed, additional registry data would be useful
      • Class III - procedure or treatment should not be performed or administered because it is not helpful or may be harmful
        • Class III ratings may be subclassified as Class III No Benefit or Class III Harm
    • levels of evidence
      • Level A - data derived from multiple randomized clinical trials or meta-analyses
      • Level B - data derived from single randomized trial or nonrandomized studies
      • Level C - only expert opinion, case studies, or standard of care
  • British Society for Haematology (BSH) GRADE system
    • strength of recommendation
      • Grade 1
        • strong recommendations made when there is confidence that benefits do or do not outweigh harm and burden
        • can be applied uniformly to most patients
        • regard as "recommend"
      • Grade 2
        • weak recommendations made where magnitude of benefit or not is less certain
        • require judicious application to individual patients
        • regard as "suggest"
    • quality of evidence
      • A - high
        • further research very unlikely to change confidence in estimate of effect
        • current evidence derived from randomized clinical trials without important limitations
      • B - moderate
        • further research may well have important impact on confidence in estimate of effect and may change estimate
        • current evidence derived from randomized clinical trials with important limitations or very strong evidence from observational studies or case series
      • C - low
        • further research likely to have important impact on confidence in estimate of effect and likely to change estimate
        • current evidence from observational studies, case series, or just opinion
    • Reference - BSH Grading of Recommendations Assessment, Development and Evaluation (GRADE) system PDF
  • American College of Chest Physicians (ACCP) grades
    • Grade 1 - strong recommendation based on clear risk/benefit balance
    • Grade 2 - weak recommendation based on unclear or close risk/benefit balance
    • Grade A - high-quality evidence based on consistent evidence from randomized trials without important limitations or exceptionally strong evidence from observational studies
    • Grade B - moderate-quality evidence based on randomized trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise results) or very strong evidence from observational studies
    • Grade C - low- or very low-quality evidence based on evidence for ≥ 1 critical outcome from observational studies, case series, or randomized trials with serious flaws or indirect evidence
    • Reference - ACCP evidence-based clinical practice guideline on methodology for development of antithrombotic therapy and prevention of thrombosis (22315256Chest 2012 Feb;141(2 Suppl):53Sfull-text), commentary can be found in 23546508Chest 2013 Apr;143(4):1190
  • American Society for Apheresis (ASFA) recommendation grading system
    • categories of indications for therapeutic apheresis
      • Category I - disorders for which apheresis is accepted as first-line therapy, either as primary stand-alone treatment or in conjunction with other modes of treatment
      • Category II - disorders for which apheresis is accepted as second-line therapy, either as stand-alone treatment or in conjunction with other modes of treatment
      • Category III - optimum role of apheresis therapy is not established and decision-making should be individualized
      • Category IV - disorders in which published evidence demonstrates or suggests apheresis to be ineffective or harmful; Institutional Review Board (IRB) approval is desirable if apheresis treatment is undertaken in these circumstances
    • grades of recommendations
      • Grade 1A - strong recommendation, high-quality evidence
        • can apply to most patients in most circumstances without reservation
        • supported by randomized controlled trials (RCTs) without important limitations or overwhelming evidence from observational studies
      • Grade 1B - strong recommendation, moderate-quality evidence
        • can apply to most patients in most circumstances without reservation
        • supported by RCTs with important limitations (inconsistent results, methodological flaws, indirect, or imprecise) or exceptionally strong evidence from observational studies
      • Grade 1C - strong recommendation, low- or very low-quality evidence
        • recommendation may change when higher quality evidence becomes available
        • supported by observational studies or case series
      • Grade 2A - weak recommendation, high-quality evidence
        • best action may differ depending on circumstances of patients' or societal values
        • supported by RCTs without important limitations or overwhelming evidence from observational studies
      • Grade 2B - weak recommendation, moderate-quality evidence
        • best action may differ depending on circumstances of patients' or societal values
        • supported by RCTs with important limitations (inconsistent results, methodological flaws, indirect, or imprecise) or exceptionally strong evidence from observational studies
      • Grade 2C - weak recommendation, low- or very low-quality evidence
        • very weak recommendation; other alternatives may be equally reasonable
        • supported by observational studies or case series
    • PubMed31180581Journal of clinical apheresisJ Clin Apher20190601343171-354171Reference - ASFA guideline on use of therapeutic apheresis in clinical practice (J Clin Apher 2019 Jun;34(3):171)

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Special acknowledgements

On behalf of the American College of Physicians
  • Barbara Turner, MD, MSEd, MACP, ACP Deputy Editor, Clinical Decision Resource, as part of the ACP-EBSCO Health collaboration, managed the ACP peer review of the Overview and Recommendations section and related clinical content in this topic.
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How to cite

National Library of Medicine, or "Vancouver style" (International Committee of Medical Journal Editors):

  • DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. T115034, Heparin-Induced Thrombocytopenia (HIT); [updated 2018 Nov 30, cited place cited date here]. Available from https://www.dynamed.com/topics/dmp~AN~T115034. Registration and login required.

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