Heparin-induced thrombocytopenia

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 Benjamin Tillman, MD
Vanderbilt University
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Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASH

Anticoagulation, all lines of therapy

Argatroban monotherapy

Regimen

Study Evidence Comparator Efficacy
Lewis et al. 2001 (ARG-911) Prospective, historical control Multiple Reduced all-cause death, all-cause amputation, and new thrombosis
Lewis et al. 2003 (ARG-915) Prospective, historical control Multiple Reduced all-cause death, all-cause amputation, or new thrombosis
Treschan et al. 2014 (ALicia) Randomized, double-blind Lepirudin Suggests less bleeding in surgical patients with argatroban.
Kang et al. 2014 Retrospective, propensity score-matched Fondaparinux Similar efficacy and safety to fondaparinux
Tardy-Poncet et al. 2015 Prospective None New or extended thrombosis in 25% of patients and major bleeding in 15%.

Note: In ALicia, only 15 patients (23%) in the study had confirmed HIT. Note: In the study by Tardy-Poncet et al. only 20 patients were enrolled, 16 with confirmed by as judged by an independent scientific committee. The majority (14, 70%) were in an intensive care unit, and six patients died due to their underlying medical condition.

Anticoagulation

  • Argatroban (Acova) by the following study-specific criteria:
    • ARG-911 & ARG-915: 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3 times baseline value.
    • ALicia, without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2 times baseline value.
    • ALicia, with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2 times baseline value.
    • Tardy-Poncet: Starting dose of 1 mcg/kg/min IV but those with hepatic impairment or at risk of decreased hepatic perfusion were recommended to start at 0.5 mcg/kg/min. Child-Pugh Class C patients were excluded.

References

  1. ARG-911: Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001 Apr 10;103(14):1838-43. link to original article PubMed
  2. ARG-915: Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; ARG-915 Study Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;164:1849-1856. link to original article PubMed
  3. ALicia: Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. link to original article link to PMC article PubMed NCT00798525
  4. Retrospective: Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. Epub 2014 Dec 16. link to original article PubMed
  5. Tardy-Poncet B, Nguyen P, Thiranos JC, Morange PE, Biron-Andreani C, Gruel Y, Morel J, Wynckel A, Grunebaum L, Villacorta-Torres J, Grosjean S, de Maistre E. Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial. Crit Care. 2015 Nov 11;19:396. link to original article link to PMC article PubMed

Danaparoid monotherapy

Regimen

Study Evidence Comparator Efficacy
Chong et al. 2001 Phase 3 Dextran 70 Improved complete clinical recovery with danaparoid
Kang et al. 2014 Retrospective, propensity score-matched Fondaparinux Similar efficacy and safety to fondaparinux

Anticoagulation

  • Danaparoid (Orgaran) 2400 anti-Xa units IV bolus once on day 1, then 400 units/hr IV for 2 hours, then 300 units/hr IV for 2 hours, then 200 units/hr IV continuous infusion for 120 hours (total dose: 6200 units)

5-day course

References

  1. Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost. 2001 Nov;86(5):1170-5. link to original article PubMed
  2. Retrospective: Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. Epub 2014 Dec 16. link to original article PubMed

Fondaparinux monotherapy

Regimen

Study Evidence Comparator Efficacy
Kang et al. 2014 Retrospective, propensity score-matched 1. Argatroban
2. Danaparoid 		Similar efficacy and safety to argatroban, danaparoid

Anticoagulation

References

  1. Retrospective: Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015 Feb 5;125(6):924-9. Epub 2014 Dec 16. link to original article PubMed

Lepirudin monotherapy

Regimen

Study Evidence Comparator Efficacy
Treschan et al. 2014 (ALicia) Randomized, double-blind Argatroban Suggests less bleeding in surgical patients with argatroban.

Note: Only 15 patients (23%) in the study had confirmed HIT.

Anticoagulation

  • Lepirudin (Refludan) by the following renal function-based criteria:
    • Continuous renal replacement therapy: 5 mcg/kg/hr IV continuous infusion, adjusted to maintain activated partial thromboplastin time 1.5 to 2 times baseline value
    • Creatinine 1.3 mg/dl or more: 10 mcg/kg/hr IV continuous infusion, adjusted to maintain activated partial thromboplastin time 1.5 to 2 times baseline value
    • Creatinine less than 1.3 mg/dl: 50 mcg/kg/hr IV continuous infusion, adjusted to maintain activated partial thromboplastin time 1.5 to 2 times baseline value

References

  1. ALicia: Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus lepirudin in critically ill patients (ALicia): a randomized controlled trial. Critical Care. 2014 Oct 25;18(5):588. link to original article link to PMC article PubMed NCT00798525

Rivaroxaban monotherapy

Regimen

Study Evidence Comparator Efficacy
Linkins et al. 2016 (McMaster 2012-02-09) Prospective cohort None New thrombosis in one of the HIT patients (8.3%)

Note: In the first prospective study of DOACs in HIT by Linkins, 22 patients were enrolled with suspected HIT. The overall symptomatic recurrent VTE rate was 4.5% (1 patient out of 22), but only 12 of the patients were confirmed to have HIT. The thrombotic event rate among HIT-positive participants was 8.3%. The study was stopped early due to slow accrual but had enrolled the minimum required number of HIT patients.

Anticoagulation

  • Rivaroxaban (Xarelto): 15 mg PO twice per day until platelet recovery (or until day 21 if acute thrombosis present at study entry), then 20 mg once per day until day 30

30-day course

References

  1. McMaster 2012-02-09: Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, Wu C, Nazi I, Crowther MA. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016 Jun;14(6):1206-10. Epub 2016 May 10. link to original article PubMed NCT01598168
    1. Update: Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017 Aug 31; 130:1104-1113. Epub 2017 Jun 23. link to original article PubMed

Other Treatments, all lines of therapy

IVIG monotherapy

Regimen

Study Evidence Efficacy
Frame et al. 1989 First published report First report of IVIg use in HIT
Winder et al. 1998 Case series Three additional cases in the literature
Padmanabhan et al. 2017 Case series Three refractory cases with resolution of thrombocytopenia
Park et al. 2018 Case series Two additional cases

Note: There is a growing interest in the use of intravenous immunoglobulin for difficult cases of heparin-induced thrombocytopenia. There are no prospective, randomized studies, but there is a growing body of scientific literature to support the rationale in certain select cases. Thus, IVIg is included on this page for reference.

Supportive therapy

  • Intravenous immunoglobulin (IVIG) 1 g/kg IV once per day for two days (Winder et al., Padmanabhan et al., and Park et al.)
    • The case reported from 1989 used 0.4 gm/kg/d for three days.

References

  1. Case report: Frame JN, Mulvey KP, Phares JC, Anderson MJ. Correction of severe heparin-associated thrombocytopenia with intravenous immunoglobulin. Ann Intern Med. 1989 Dec 1;111(11):946-7. link to original article PubMed
  2. Case series: Winder A, Shoenfeld Y, Hochman R, Keren G, Levy Y, Eldor A. High-dose intravenous gamma-globulins for heparin-induced thrombocytopenia: a prompt response. J Clin Immunol. 1998 Sep;18(5):330-4. link to original article PubMed
  3. Case series: Padmanabhan A, Jones CG, Pechauer SM, Curtis BR, Bougie DW, Irani MS, Bryant BJ, Alperin JB, Deloughery TG, Mulvey KP, Dhakal B, Wen R, Wang D, Aster RH. IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia. Chest. 2017 Sep;152(3):478-485. Epub 2017 Apr 17. link to original article link to PMC article PubMed
  4. Case series: Park BD, Kumar M, Nagalla S, De Simone N, Aster RH, Padmanabhan A, Sarode R, Rambally S. Intravenous immunoglobulin as an adjunct therapy in persisting heparin-induced thrombocytopenia. Transfus Apher Sci. 2018 Aug;57(4):561-565. Epub 2018 Jun 26. link to original article link to PMC article PubMed
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