Management of the multiple phases of heparin-induced thrombocytopenia

 

 Buy Article Permissions and Reprints

Summary

The clinical course of heparin-induced thrombocytopenia (HIT) may be separated into five sequential phases: 1. suspected HIT, 2. acute HIT, 3. subacute HIT A, 4. subacute HIT B, and 5. remote HIT. Each phase confronts the clinician with a unique set of management questions. In this review, the phases of HIT are defined and key management questions associated with each phase are discussed. Among patients with Suspected HIT, I use the 4Ts score to determine which patients have a sufficiently high probability of HIT to justify discontinuation of heparin and initiation of a non-heparin parenteral anticoagulant. An algorithm for selecting an appropriate non-heparin anticoagulant based on the patient’s clinical stability, renal and hepatic function, drug availability, and physician comfort is provided. In patients with Acute HIT, I generally avoid prophylactic platelet transfusion and inferior vena cava filter insertion because of a potential increased risk of thrombosis. I perform 4-limb screening compression ultrasonography. In patients with symptomatic thromboembolism or asymptomatic proximal deep-vein thrombosis, I treat with anticoagulation for three months. In patients without thrombosis, I discontinue anticoagulation upon platelet count recovery. I do not transition patients to an oral anticoagulant until platelet count recovery (i. e. Subacute HIT A). I increasingly choose direct oral anticoagulants over vitamin K antagonists in this setting because of their greater convenience and safety. In Subacute HIT B and Remote HIT, I use heparin for cardiovascular surgery, whereas I use bivalirudin in patients with Acute HIT and Subacute HIT A in whom surgery cannot be delayed.

• References

• 1 Amiral J, Bridey F, Dreyfus M. et al. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost 1992; 68: 95-96.
  Article in Thieme ConnectPubMedGoogle Scholar
• 2 Warkentin TE. Think of HIT. Hematology Am Soc Hematol Educ Program 2006; 408-414.
  PubMedGoogle Scholar
• 3 Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocy-topenia. N Engl J Med 2001; 344: 1286-1292.
  CrossrefPubMedGoogle Scholar
• 4 Cuker A, Cines DB. How I treat heparin-induced thrombocytopenia. Blood 2012; 119: 2209-2218.
  CrossrefPubMedGoogle Scholar
• 5 Lo GK, Juhl D, Warkentin TE. et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006; 04: 759-765.
  CrossrefPubMedGoogle Scholar
• 6 Cuker A, Gimotty PA, Crowther MA. et al. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood 2012; 120: 4160-4167.
  CrossrefPubMedGoogle Scholar
• 7 Linkins LA, Bates SM, Lee AY. et al. Combination of 4Ts score and PF4/H-PaGIA for diagnosis and management of heparin-induced thrombocy-topenia: prospective cohort study. Blood 2015; 126: 597-603.
  CrossrefPubMedGoogle Scholar
• 8 McMahon CM, Cuker A. The 4Ts test in the critically ill: timing is everything. J Crit Care 2014; 29: 468-469.
  CrossrefPubMedGoogle Scholar
• 9 Crowther M, Cook D, Guyatt G. et al. Heparin-induced thrombocytopenia in the critically ill: interpreting the 4Ts test in a randomized trial. J Crit Care 2014; 29: 470 e7-e15.
  PubMedGoogle Scholar
• 10 Cuker A, Arepally G, Crowther MA. et al. The HIT Expert Probability (HEP) Score: a novel pre-test probability model for heparin-induced thrombocytope-nia based on broad expert opinion. J Thromb Haemost 2010; 08: 2642-2650.
  CrossrefPubMedGoogle Scholar
• 11 Lillo-Le Louët A, Boutouyrie P, Alhenc-Gelas M. et al. Diagnostic score for he-parin-induced thrombocytopenia after cardiopulmonary bypass. J Thromb Haemost 2004; 02: 1882-1888.
  CrossrefPubMedGoogle Scholar
• 12 Messmore HL, Fabbrini N, Bird ML. et al. Simple scoring system for early management of heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 2011; 17: 192-201.
  PubMedGoogle Scholar
• 13 Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytope-nia. Am J Med 1996; 101: 502-507.
  CrossrefPubMedGoogle Scholar
• 14 Farner B, Eichler P, Kroll H. et al. A comparison of danaparoid and lepirudin in heparin-induced thrombocytopenia. Thromb Haemost 2001; 85: 950-957.
  Article in Thieme ConnectPubMedGoogle Scholar
• 15 Lewis BE, Wallis DE, Berkowitz SD. et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; 103: 1838-1843.
  CrossrefPubMedGoogle Scholar
• 16 Lewis BE, Wallis DE, Leya F. et al. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003; 163: 1849-1856.
  CrossrefPubMedGoogle Scholar
• 17 Lewis BE, Wallis DE, Hursting MJ. et al. Effects of argatroban therapy, demographic variables, and platelet count on thrombotic risks in heparin-induced thrombocytopenia. Chest 2006; 129: 1407-1416.
  CrossrefPubMedGoogle Scholar
• 18 Walenga JM, Jeske WP, Wood JJ. et al. Laboratory tests for heparin-induced thrombocytopenia: a multicenter study. Semin Hematol 1999; 36: 22-28.
  PubMedGoogle Scholar
• 19 Linkins LA, Dans AL, Moores LK. et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9^th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e495S-e530S.
  CrossrefPubMedGoogle Scholar
• 20 Lehman SJ, Chew DP. Bivalirudin in percutaneous coronary intervention. Vasc Health Risk Manag 2006; 02: 357-363.
  CrossrefPubMedGoogle Scholar
• 21 Dyke CM, Smedira NG, Koster A. et al. A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopul-monary bypass: the EVOLUTION-ON study. J Thorac Cardiovasc Surg 2006; 131: 533-539.
  CrossrefPubMedGoogle Scholar
• 22 Koster A, Spiess B, Jurmann M. et al. Bivalirudin provides rapid, effective, and reliable anticoagulation during off-pump coronary revascularization: results of the “EVOLUTION OFF” trial. Anesth Analg 2006; 103: 540-544.
  CrossrefPubMedGoogle Scholar
• 23 Kiser TH, Fish DN. Evaluation of bivalirudin treatment for heparin-induced thrombocytopenia in critically ill patients with hepatic and/or renal dysfunction. Pharmacotherapy 2006; 26: 452-460.
  CrossrefPubMedGoogle Scholar
• 24 Joseph L, Casanegra AI, Dhariwal M. et al. Bivalirudin for the treatment of patients with confirmed or suspected heparin-induced thrombocytopenia. J Thromb Haemost 2014; 12: 1044-1053.
  CrossrefPubMedGoogle Scholar
• 25 Boyce SW, Bandyk DF, Bartholomew JR. et al. A randomized, open-label pilot study comparing desirudin and argatroban in patientswith suspected heparin-induced thrombocytopenia with or without thrombosis. Am J Ther 2011; 18: 14-22.
  CrossrefPubMedGoogle Scholar
• 26 Chong BH, Gallus AS, Cade JF. et al. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Hae-most 2001; 86: 1170-1175.
  Article in Thieme ConnectPubMedGoogle Scholar
• 27 Magnani HN, Gallus A. Heparin-induced thrombocytopenia (HIT) A report of 1,478 clinical outcomes of patients treated with danaparoid (Orgaron) from 1982 to mid-2004. Thromb Haemost 2006; 95: 967-981.
  Article in Thieme ConnectPubMedGoogle Scholar
• 28 Warkentin TE, Pai M, Sheppard JI. et al. Fondaparinux treatment of acute hepa-rin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series. J Thromb Haemost 2014; 09: 2389-2396. Schin-dewolf M, Steindl J, Beyer-Westendorf, J et al. Frequent off-label use of fonda-parinux in patients with suspected acute heparin-induced thrombocytopenia (HIT)–findings from the GerHIT multi-centre registry study. Thromb Res 2014;134: 29–35.
  PubMedGoogle Scholar
• 29 Kang M, Alahmadi M, Sawh S. et al. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015; 125: 924-929.
  CrossrefPubMedGoogle Scholar
• 30 Motokawa S, Torigoshi T, Maeda Y. et al. IgG-class anti-PF4/heparin antibodies and symptomatic DVT in orthopedic surgery patients receiving different anti-thromboembolic prophylaxis therapeutics. BMC Musculoskelet Disord 2011; 12: 22.
  CrossrefPubMedGoogle Scholar
• 31 Warkentin TE. HIT paradigms and paradoxes. J Thromb Haemost 2011; 09: 105-117.
  CrossrefPubMedGoogle Scholar
• 32 Hursting MJ, Verme-Gibboney CN. Risk factors for major bleeding in patients with heparin-induced thrombocytopenia treated with argatroban: a retrospective study. J Cardiovasc Pharmacol 2008; 52: 561-566.
  CrossrefPubMedGoogle Scholar
• 33 Warkentin TE. Anticoagulant failure in coagulopathic patients: PTT confounding and other pitfalls. Expert Opin Drug Saf 2014; 13: 25-43.
  CrossrefPubMedGoogle Scholar
• 34 Sheth SB, DiCicco RA, Hursting MJ. et al. Interpreting the International Normalized Ratio (INR) in individuals receiving argatroban and warfarin. Thromb Haemost 2001; 85: 435-440.
  Article in Thieme ConnectPubMedGoogle Scholar
• 35 Krauel K, Hackbarth C, Fürll B. et al. Heparin-induced thrombocytopenia: in vitro studies on the interaction of dabigatran, rivaroxaban, and low-sulfated he-parin, with platelet factor 4 and anti-PF4/heparin antibodies. Blood 2012; 119: 1248-1255.
  CrossrefPubMedGoogle Scholar
• 36 Greinacher A. CLINICAL PRACTICE. Heparin-Induced Thrombocytopenia. N Engl J Med 2015; 373: 252-261.
  CrossrefPubMedGoogle Scholar
• 37 Linkins LA, Warkentin TE, Pai M. et al. Design of the rivaroxaban for hepa-rin-induced thrombocytopenia study. J Thromb Thrombolysis 2014; 38: 485-492.
  CrossrefPubMedGoogle Scholar
• 38 Sachais BS, Rux AH, Cines DB. et al. Rational design and characterization of platelet factor 4 antagonists for the study of heparin-induced thrombocytope-nia. Blood 2012; 119: 5955-5962.
  CrossrefPubMedGoogle Scholar
• 39 Reilly MP, Sinha U, André P. et al. PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model. Blood 2011; 117: 2241-2246.
  CrossrefPubMedGoogle Scholar
• 40 Stolla M, Stefanini L, Andre P. et al. CalDAG-GEFI deficiency protects mice in a novel model of FcγRIIA-mediated thrombosis and thrombocytopenia. Blood 2011; 118: 1113-1120.
  CrossrefPubMedGoogle Scholar
• 41 Cai Z, Yarovoi SV, Zhu Z. et al. Atomic description of the immune complex involved in heparin-induced thrombocytopenia. Nat Comm 2015; 06: 8277.
  CrossrefPubMedGoogle Scholar
• 42 Tardy B, Tardy-Poncet B, Fournel P. et al. Lower limb veins should be systematically explored in patients with isolated heparin-induced thrombocytopenia. Thromb Haemost 1999; 82: 1199-1200.
  Article in Thieme ConnectPubMedGoogle Scholar
• 43 Hopkins CK, Goldfinger D. Platelet transfusions in heparin-induced throm-bocytopenia: a report of four cases and review of the literature. Transfusion 2008; 48: 2128-2132.
  CrossrefPubMedGoogle Scholar
• 44 Refaai MA, Chuang C, Menegus M. et al. Outcomes after platelet transfusion in patients with heparin-induced thrombocytopenia. J Thromb Haemost 2010; 08: 1419-1421.
  CrossrefPubMedGoogle Scholar
• 45 Goel R, Ness PM, Takemoto CM. et al. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Blood 2015; 125: 1470-1476.
  CrossrefPubMedGoogle Scholar
• 46 Nagler M, Bachmann LM, Ten Cate H. et al. Diagnostic value of immunoassays for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood 2016; 127: 546-557.
  CrossrefPubMedGoogle Scholar
• 47 Kelton JG, Hursting MJ, Heddle N. et al. Predictors of clinical outcome in patients with heparin-induced thrombocytopenia treated with direct thrombin inhibition. Blood Coagul Fibrinolysis 2008; 19: 471-475.
  CrossrefPubMedGoogle Scholar
• 48 Greinacher A, Farner B, Kroll H. et al. Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis: a retrospective analysis of 408 patients. Thromb Haemost 2005; 94: 132-135.
  Article in Thieme ConnectPubMedGoogle Scholar
• 49 Hong AP, Cook DJ, Sigouin CS. et al. Central venous catheters and upper-extremity deep-vein thrombosis complicating immune heparin-induced throm-bocytopenia. Blood 2003; 101: 3049-3051.
  CrossrefPubMedGoogle Scholar
• 50 Ishibashi H, Takashi O, Hosaka M. et al. Heparin-induced thrombocytopenia complicated with massive thrombosis of the inferior vena cava after filter placement. Int Angiol 2005; 24: 387-390.
  PubMedGoogle Scholar
• 51 Warkentin TE, Elavathil LJ, Hayward CP. et al. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med 1997; 127: 804-812.
  CrossrefPubMedGoogle Scholar
• 52 Srinivasan AF, Rice L, Bartholomew JR. et al. Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia. Arch Intern Med 2004; 164: 66-70.
  CrossrefPubMedGoogle Scholar
• 53 Warkentin TE, Roberts RS, Hirsh J. et al. An improved definition of immune he-parin-induced thrombocytopenia in postoperative orthopedic surgery patients. Arch Intern Med 2003; 163: 2518-2524.
  CrossrefPubMedGoogle Scholar
• 54 Sheth SB, DiCicco RA, Hursting MJ. et al. Interpreting the International Normalized Ratio (INR) in individuals receiving argatroban and warfarin. Thromb Haemost 2001; 85: 435-440.
  Article in Thieme ConnectPubMedGoogle Scholar
• 55 Chai-Adisaksopha C, Crowther M, Isayama T. et al. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood 2014; 124: 2450-2458.
  CrossrefPubMedGoogle Scholar
• 56 Warkentin TE, Sheppard JA, Chu FV. et al. Plasma exchange to remove HIT antibodies: dissociation between enzyme-immunoassay and platelet activation test reactivities. Blood 2015; 125: 195-198.
  CrossrefPubMedGoogle Scholar
• 57 Welsby IJ, Um J, Milano CA. et al. Plasmapheresis and heparin reexposure as a management strategy for cardiac surgical patients with heparin-induced throm-bocytopenia. Anesth Analg 2010; 110: 30-35.
  CrossrefPubMedGoogle Scholar
• 58 Potzsch B, Klovekorn WP, Madlener K. Use of heparin during cardiopulmonary bypass in patients with a history of heparin-induced thrombocytopenia. N Engl J Med 2000; 343: 515.
  CrossrefPubMedGoogle Scholar
• 59 Selleng S, Haneya A, Hirt S. et al. Management of anticoagulation in patients with sub acute heparin-induced thrombocytopenia scheduled for heart transplantation. Blood 2008; 112: 4024-4027.
  CrossrefPubMedGoogle Scholar
• 60 Warkentin TE. Anderson How I Treat. Submitted for publication.
  PubMedGoogle Scholar
• 61 Carrier M, Knoll GA, Kovacs MJ. et al. The prevalence of antibodies to the platelet factor 4-heparin complex and association with access thrombosis in patients on chronic hemodialysis. Thromb Res 2007; 120: 215-220.
  CrossrefPubMedGoogle Scholar
• 62 Asmis LM, Segal JB, Plantinga LC. et al. Heparin-induced antibodies and cardiovascular risk in patients on dialysis. Thromb Haemost 2008; 100: 498-504.
  Article in Thieme ConnectPubMedGoogle Scholar
• 63 Hutchison CA, Dasgupta I. National survey of heparin-induced thrombocy-topenia in the haemodialysis population of the UK population. Nephrol Dial Transplant 2007; 22: 1680-1684.
  CrossrefPubMedGoogle Scholar