Heparin-induced thrombocytopenia

Section editor
	Benjamin Tillman, MD Vanderbilt University Nashville, TN

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Guidelines

ASH

• 2018: Cuker et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia

Anticoagulation

Argatroban monotherapy

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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. 2015	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

• ARG-911, ARG-915: Argatroban (Acova) 2 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 3.0 times baseline value.
• ALicia: Argatroban (Acova) without liver dysfunction: 0.5 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.
• ALicia: Argatroban (Acova) with severe liver dysfunction (bilirubin >4 mg/dL): 0.25 mcg/kg/min IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 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
4. 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. 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 PubMed

Danaparoid monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Chong et al. 2001	Phase III	Dextran 70	Improved complete clinical recovery with danaparoid
Kang et al. 2015	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. 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. link to original article PubMed

Fondaparinux monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Kang et al. 2015	Retrospective, propensity score-matched	1. Argatroban 2. Danaparoid	Similar efficacy and safety to argatroban, danaparoid

To be completed

Anticoagulation

• Fondaparinux (Arixtra)

References

1. 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. link to original article PubMed

Lepirudin monotherapy

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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) as follows:
  • Patients with continuous renal replacement therapy: 5 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.
  • Patients with moderate renal impairment (creatinine 1.3 mg/dl or more): 10 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 times baseline value.
  • Patients with without renal impairment (creatinine less than 1.3 mg/dl): 50 mcg/kg/hr IV adjusted to maintain activated partial thromboplastin time 1.5 to 2.0 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

Rivaroxaban monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Linkins et al. 2016	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

References

1. 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. link to original article PubMed
   1. UPDATE: Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017; 130:1104-1113. link to original article PubMed

Other Treatments

Intravenous Immunoglobulin

Regimen

Study	Evidence	Comparator	Efficacy
Padmanabhan et al. 2017	Case Series	None	Resolution of thrombocytopenia

• Intravenous Immunoglobulin

References

1. 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. doi: 10.1016/j.chest.2017.03.050. Epub 2017 Apr 17. link to original article PubMed