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Semin Thromb Hemost 2017; 43(07): 691-698
DOI: 10.1055/s-0037-1602664
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Heparin-Induced Thrombocytopenia in Cardiac Surgery Patients

Allyson M. Pishko
1   Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
,
Adam Cuker
1   Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
2   Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
› Author Affiliations
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Publication History

Publication Date:
08 June 2017 (online)

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Abstract

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder mediated by platelet-activating antibodies that target complexes of platelet factor 4 (PF4) and heparin. Because nearly all patients undergoing cardiopulmonary bypass (CPB) are exposed to heparin and experience a postoperative platelet count fall, it is not surprising that HIT is commonly suspected in this population. However, the incidence of HIT in cardiac surgery patients who receive intraoperative and postoperative unfractionated heparin is much lower than the incidence of suspected HIT, being approximately 1 to 2%. Clinical diagnosis may therefore be particularly challenging because of the need to distinguish the common platelet count fall associated with CPB and surgery from the much less common platelet count fall associated with HIT. A biphasic platelet count pattern is characteristic of HIT in this setting. Laboratory diagnosis is also difficult because of the high frequency of anti-PF4/heparin antibody seropositivity after cardiac surgery in patients without HIT. A unique aspect of management in the cardiac surgery setting is selecting an anticoagulant for intraoperative use in patients with a history of HIT who require cardiac surgery. In this article, we review the epidemiology, clinical diagnosis, and laboratory diagnosis of HIT in cardiac surgery patients and present a conceptual framework for selecting intraoperative anticoagulation in patients with a history of HIT.

Keywords

cardiac surgery - cardiopulmonary bypass - heparin - heparin-induced thrombocytopenia - thrombocytopenia
 

  • 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 (01) 95-96
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Rauova L, Poncz M, McKenzie SE. , et al. Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia. Blood 2005; 105 (01) 131-138
    CrossrefPubMedGoogle Scholar
  • 3 Greinacher A, Eichler P, Lubenow N, Kwasny H, Luz M. Heparin-induced thrombocytopenia with thromboembolic complications: meta-analysis of 2 prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range. Blood 2000; 96 (03) 846-851
    CrossrefPubMedGoogle Scholar
  • 4 Cuker A. Clinical and laboratory diagnosis of heparin-induced thrombocytopenia: an integrated approach. Semin Thromb Hemost 2014; 40 (01) 106-114
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Cuker A. Current and emerging therapeutics for heparin-induced thrombocytopenia. Semin Thromb Hemost 2012; 38 (01) 31-37
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Cuker A, Cines DB. How I treat heparin-induced thrombocytopenia. Blood 2012; 119 (10) 2209-2218
    CrossrefPubMedGoogle Scholar
  • 7 Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106 (08) 2710-2715
    CrossrefPubMedGoogle Scholar
  • 8 Warkentin TE, Sheppard JA, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000; 96 (05) 1703-1708
    CrossrefPubMedGoogle Scholar
  • 9 Warkentin TE, Levine MN, Hirsh J. , et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332 (20) 1330-1335
    CrossrefPubMedGoogle Scholar
  • 10 Lubenow N, Hinz P, Thomaschewski S. , et al. The severity of trauma determines the immune response to PF4/heparin and the frequency of heparin-induced thrombocytopenia. Blood 2010; 115 (09) 1797-1803
    CrossrefPubMedGoogle Scholar
  • 11 Pouplard C, May MA, Iochmann S. , et al. Antibodies to platelet factor 4-heparin after cardiopulmonary bypass in patients anticoagulated with unfractionated heparin or a low-molecular-weight heparin : clinical implications for heparin-induced thrombocytopenia. Circulation 1999; 99 (19) 2530-2536
    CrossrefPubMedGoogle Scholar
  • 12 Walls JT, Curtis JJ, Silver D, Boley TM, Schmaltz RA, Nawarawong W. Heparin-induced thrombocytopenia in open heart surgical patients: sequelae of late recognition. Ann Thorac Surg 1992; 53 (05) 787-791
    CrossrefPubMedGoogle Scholar
  • 13 Singer RL, Mannion JD, Bauer TL, Armenti FR, Edie RN. Complications from heparin-induced thrombocytopenia in patients undergoing cardiopulmonary bypass. Chest 1993; 104 (05) 1436-1440
    CrossrefPubMedGoogle Scholar
  • 14 Selleng S, Malowsky B, Strobel U. , et al. Early-onset and persisting thrombocytopenia in post-cardiac surgery patients is rarely due to heparin-induced thrombocytopenia, even when antibody tests are positive. J Thromb Haemost 2010; 8 (01) 30-36
    CrossrefPubMedGoogle Scholar
  • 15 Schenk S, El-Banayosy A, Prohaska W. , et al. Heparin-induced thrombocytopenia in patients receiving mechanical circulatory support. J Thorac Cardiovasc Surg 2006; 131 (06) 1373-81.e4
    CrossrefPubMedGoogle Scholar
  • 16 Schenk S, El-Banayosy A, Morshuis M. , et al. IgG classification of anti-PF4/heparin antibodies to identify patients with heparin-induced thrombocytopenia during mechanical circulatory support. J Thromb Haemost 2007; 5 (02) 235-241
    CrossrefPubMedGoogle Scholar
  • 17 Koster A, Huebler S, Potapov E. , et al. Impact of heparin-induced thrombocytopenia on outcome in patients with ventricular assist device support: single-institution experience in 358 consecutive patients. Ann Thorac Surg 2007; 83 (01) 72-76
    CrossrefPubMedGoogle Scholar
  • 18 Murphy DA, Hockings LE, Andrews RK. , et al. Extracorporeal membrane oxygenation-hemostatic complications. Transfus Med Rev 2015; 29 (02) 90-101
    CrossrefPubMedGoogle Scholar
  • 19 Hassan S, Qureshi W, Badami A. , et al. Heparin-induced thrombocytopenia: is it a graft-threatening complication?. Transpl Int 2013; 26 (04) 385-391
    CrossrefPubMedGoogle Scholar
  • 20 Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006; 4 (04) 759-765
    CrossrefPubMedGoogle Scholar
  • 21 Bryant A, Low J, Austin S, Joseph JE. Timely diagnosis and management of heparin-induced thrombocytopenia in a frequent request, low incidence single centre using clinical 4T's score and particle gel immunoassay. Br J Haematol 2008; 143 (05) 721-726
    CrossrefPubMedGoogle Scholar
  • 22 Denys B, Stove V, Philippé J, Devreese K. A clinical-laboratory approach contributing to a rapid and reliable diagnosis of heparin-induced thrombocytopenia. Thromb Res 2008; 123 (01) 137-145
    CrossrefPubMedGoogle Scholar
  • 23 Cuker A, Arepally G, Crowther MA. , et al. The HIT Expert Probability (HEP) Score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion. J Thromb Haemost 2010; 8 (12) 2642-2650
    CrossrefPubMedGoogle Scholar
  • 24 Tawfik NM, Hegazy MA, Hassan EA, Ramadan YK, Nasr AS. Egyptian experience of reliability of 4T's score in diagnosis of heparin induced thrombocytopenia syndrome. Blood Coagul Fibrinolysis 2011; 22 (08) 701-705
    CrossrefPubMedGoogle Scholar
  • 25 Nader ND, Khadra WZ, Reich NT, Bacon DR, Salerno TA, Panos AL. Blood product use in cardiac revascularization: comparison of on- and off-pump techniques. Ann Thorac Surg 1999; 68 (05) 1640-1643
    CrossrefPubMedGoogle Scholar
  • 26 Gruel Y, Pouplard C. Post-operative platelet count profile: the most reliable tool for identifying patients with true heparin-induced thrombocypenia after cardiac surgery. J Thromb Haemost 2010; 8 (01) 27-29
    CrossrefPubMedGoogle Scholar
  • 27 Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001; 344 (17) 1286-1292
    CrossrefPubMedGoogle Scholar
  • 28 Warkentin TE. Clinical presentation of heparin-induced thrombocytopenia. Semin Hematol 1998; 35 (04) (Suppl. 05) 9-16 , discussion 35–36
    PubMedGoogle Scholar
  • 29 Warkentin TE, Roberts RS, Hirsh J, Kelton JG. An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients. Arch Intern Med 2003; 163 (20) 2518-2524
    CrossrefPubMedGoogle Scholar
  • 30 Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996; 101 (05) 502-507
    CrossrefPubMedGoogle Scholar
  • 31 Nand S, Wong W, Yuen B, Yetter A, Schmulbach E, Gross Fisher S. Heparin-induced thrombocytopenia with thrombosis: incidence, analysis of risk factors, and clinical outcomes in 108 consecutive patients treated at a single institution. Am J Hematol 1997; 56 (01) 12-16
    CrossrefPubMedGoogle Scholar
  • 32 Wallis DE, Lewis BE, Walenga JM. Failure of current strategies in the prevention of thrombosis in patients with heparin-induced thrombocytopenia: a clinician's perspective. Semin Thromb Hemost 1999; 25 (Suppl. 01) 3-7
    PubMedGoogle Scholar
  • 33 Greinacher A, Farner B, Kroll H, Kohlmann T, Warkentin TE, Eichler P. Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis. A retrospective analysis of 408 patients. Thromb Haemost 2005; 94 (01) 132-135
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Vonderheide RH, Thadhani R, Kuter DJ. Association of thrombocytopenia with the use of intra-aortic balloon pumps. Am J Med 1998; 105 (01) 27-32
    CrossrefPubMedGoogle Scholar
  • 35 Matthai Jr WH. Thrombocytopenia in cardiovascular patients: diagnosis and management. Chest 2005; 127 (2, Suppl): 46S-52S
    CrossrefPubMedGoogle Scholar
  • 36 Lee GM, Welsby IJ, Phillips-Bute B, Ortel TL, Arepally GM. High incidence of antibodies to protamine and protamine/heparin complexes in patients undergoing cardiopulmonary bypass. Blood 2013; 121 (15) 2828-2835
    CrossrefPubMedGoogle Scholar
  • 37 Bakchoul T, Zöllner H, Amiral J. , et al. Anti-protamine-heparin antibodies: incidence, clinical relevance, and pathogenesis. Blood 2013; 121 (15) 2821-2827
    CrossrefPubMedGoogle Scholar
  • 38 Pouplard C, Leroux D, Rollin J, Amiral J, May MA, Gruel Y. Incidence of antibodies to protamine sulfate/heparin complexes in cardiac surgery patients and impact on platelet activation and clinical outcome. Thromb Haemost 2013; 109 (06) 1141-1147
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Cuker A, Cines DB. Protamine-induced thrombocytopenia?. Blood 2013; 121 (15) 2818-2819
    CrossrefPubMedGoogle Scholar
  • 40 Warkentin TE, Heddle NM. Laboratory diagnosis of immune heparin-induced thrombocytopenia. Curr Hematol Rep 2003; 2 (02) 148-157
    PubMedGoogle Scholar
  • 41 Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood 2012; 120 (20) 4160-4167
    CrossrefPubMedGoogle Scholar
  • 42 Berry C, Tcherniantchouk O, Ley EJ. , et al. Overdiagnosis of heparin-induced thrombocytopenia in surgical ICU patients. J Am Coll Surg 2011; 213 (01) 10-17 , discussion 17–18
    CrossrefPubMedGoogle Scholar
  • 43 Nagler M, Fabbro T, Wuillemin WA. Prospective evaluation of the interobserver reliability of the 4Ts score in patients with suspected heparin-induced thrombocytopenia. J Thromb Haemost 2012; 10 (01) 151-152
    CrossrefPubMedGoogle Scholar
  • 44 Lillo-Le Louët A, Boutouyrie P, Alhenc-Gelas M. , et al. Diagnostic score for heparin-induced thrombocytopenia after cardiopulmonary bypass. J Thromb Haemost 2004; 2 (11) 1882-1888
    CrossrefPubMedGoogle Scholar
  • 45 Messmore HL, Fabbrini N, Bird ML. , et al. Simple scoring system for early management of heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 2011; 17 (02) 197-201
    CrossrefPubMedGoogle Scholar
  • 46 Nagler M, Bachmann LM, ten Cate H, ten Cate-Hoek A. Diagnostic value of immunoassays for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood 2016; 127 (05) 546-557
    CrossrefPubMedGoogle Scholar
  • 47 Sun L, Gimotty PA, Lakshmanan S, Cuker A. Diagnostic accuracy of rapid immunoassays for heparin-induced thrombocytopenia. A systematic review and meta-analysis. Thromb Haemost 2016; 115 (05) 1044-1055
    Article in Thieme ConnectPubMedGoogle Scholar
  • 48 Yusuf AM, Warkentin TE, Arsenault KA, Whitlock R, Eikelboom JW. Prognostic importance of preoperative anti-PF4/heparin antibodies in patients undergoing cardiac surgery. A systematic review. Thromb Haemost 2012; 107 (01) 8-14
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Bauer TL, Arepally G, Konkle BA. , et al. Prevalence of heparin-associated antibodies without thrombosis in patients undergoing cardiopulmonary bypass surgery. Circulation 1997; 95 (05) 1242-1246
    CrossrefPubMedGoogle Scholar
  • 50 Everett BM, Yeh R, Foo SY. , et al. Prevalence of heparin/platelet factor 4 antibodies before and after cardiac surgery. Ann Thorac Surg 2007; 83 (02) 592-597
    CrossrefPubMedGoogle Scholar
  • 51 Mattioli AV, Bonetti L, Zennaro M, Ambrosio G, Mattioli G. Heparin/PF4 antibodies formation after heparin treatment: temporal aspects and long-term follow-up. Am Heart J 2009; 157 (03) 589-595
    CrossrefPubMedGoogle Scholar
  • 52 Gluckman TJ, Segal JB, Schulman SP. , et al. Effect of anti-platelet factor-4/heparin antibody induction on early saphenous vein graft occlusion after coronary artery bypass surgery. J Thromb Haemost 2009; 7 (09) 1457-1464
    CrossrefPubMedGoogle Scholar
  • 53 Cuker A, Ortel TL. ASH evidence-based guidelines: is the IgG-specific anti-PF4/heparin ELISA superior to the polyspecific ELISA in the laboratory diagnosis of HIT?. Hematology (Am Soc Hematol Educ Program) 2009; 250-252
    PubMedGoogle Scholar
  • 54 Raschke RA, Curry SC, Warkentin TE, Gerkin RD. Improving clinical interpretation of the anti-platelet factor 4/heparin enzyme-linked immunosorbent assay for the diagnosis of heparin-induced thrombocytopenia through the use of receiver operating characteristic analysis, stratum-specific likelihood ratios, and Bayes theorem. Chest 2013; 144 (04) 1269-1275
    CrossrefPubMedGoogle Scholar
  • 55 Cuker A. Heparin-induced thrombocytopenia (HIT) in 2011: an epidemic of overdiagnosis. Thromb Haemost 2011; 106 (06) 993-994
    Article in Thieme ConnectPubMedGoogle Scholar
  • 56 Kerendi F, Thourani VH, Puskas JD. , et al. Impact of heparin-induced thrombocytopenia on postoperative outcomes after cardiac surgery. Ann Thorac Surg 2007; 84 (05) 1548-1553 , discussion 1554–1555
    CrossrefPubMedGoogle Scholar
  • 57 Mattioli AV, Bonetti L, Carletti U, Ambrosio G, Mattioli G. Thrombotic events in patients with antiplatelet factor 4/heparin antibodies. Heart 2009; 95 (16) 1350-1354
    CrossrefPubMedGoogle Scholar
  • 58 Welsby IJ, Krakow EF, Heit JA. , et al. The association of anti-platelet factor 4/heparin antibodies with early and delayed thromboembolism after cardiac surgery. J Thromb Haemost 2017; 15 (01) 57-65
    CrossrefPubMedGoogle Scholar
  • 59 Cuker A. Management of the multiple phases of heparin-induced thrombocytopenia. Thromb Haemost 2016; 116 (05) 835-842
    Article in Thieme ConnectPubMedGoogle Scholar
  • 60 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; 141: e495S-e530S
    CrossrefPubMedGoogle Scholar
  • 61 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; 159: 528-540
    PubMedGoogle Scholar
  • 62 Greinacher A. CLINICAL PRACTICE. Heparin-induced thrombocytopenia. N Engl J Med 2015; 373 (03) 252-261
    CrossrefPubMedGoogle Scholar
  • 63 Dyke CM, Smedira NG, Koster A. , et al. A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: the EVOLUTION-ON study. J Thorac Cardiovasc Surg 2006; 131 (03) 533-539
    CrossrefPubMedGoogle Scholar
  • 64 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 (03) 540-544
    CrossrefPubMedGoogle Scholar
  • 65 Koster A, Dyke CM, Aldea G. , et al. Bivalirudin during cardiopulmonary bypass in patients with previous or acute heparin-induced thrombocytopenia and heparin antibodies: results of the CHOOSE-ON trial. Ann Thorac Surg 2007; 83 (02) 572-577
    CrossrefPubMedGoogle Scholar
  • 66 Dyke CM, Aldea G, Koster A. , et al. Off-pump coronary artery bypass with bivalirudin for patients with heparin-induced thrombocytopenia or antiplatelet factor four/heparin antibodies. Ann Thorac Surg 2007; 84 (03) 836-839
    CrossrefPubMedGoogle Scholar
  • 67 Warkentin TE, Sheppard JA, Chu FV, Kapoor A, Crowther MA, Gangji A. Plasma exchange to remove HIT antibodies: dissociation between enzyme-immunoassay and platelet activation test reactivities. Blood 2015; 125 (01) 195-198
    CrossrefPubMedGoogle Scholar
  • 68 Welsby IJ, Um J, Milano CA, Ortel TL, Arepally G. Plasmapheresis and heparin reexposure as a management strategy for cardiac surgical patients with heparin-induced thrombocytopenia. Anesth Analg 2010; 110 (01) 30-35
    CrossrefPubMedGoogle Scholar
  • 69 Pötzsch B, Klövekorn WP, Madlener K. Use of heparin during cardiopulmonary bypass in patients with a history of heparin-induced thrombocytopenia. N Engl J Med 2000; 343 (07) 515
    CrossrefPubMedGoogle Scholar
  • 70 Selleng S, Haneya A, Hirt S, Selleng K, Schmid C, Greinacher A. Management of anticoagulation in patients with subacute heparin-induced thrombocytopenia scheduled for heart transplantation. Blood 2008; 112 (10) 4024-4027
    CrossrefPubMedGoogle Scholar
  • 71 Warkentin TE, Anderson JA. How I treat patients with a history of heparin-induced thrombocytopenia. Blood 2016; 128 (03) 348-359
    CrossrefPubMedGoogle Scholar
  • 72 McGowan KE, Makari J, Diamantouros A. , et al. Reducing the hospital burden of heparin-induced thrombocytopenia: impact of an avoid-heparin program. Blood 2016; 127 (16) 1954-1959
    CrossrefPubMedGoogle Scholar
  • 73 McMahon CM, Tanhehco YC, Cuker A. Inappropriate documentation of heparin allergy in the medical record because of misdiagnosis of heparin-induced thrombocytopenia: frequency and consequences. J Thromb Haemost 2017; 15 (02) 370-374
    CrossrefPubMedGoogle Scholar