Heparin-induced thrombocytopenia in cardiac surgery and critically ill patients

 

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Summary

Thrombocytopenia as well as anti-platelet factor 4/heparin (PF4/H) antibodies are common in cardiac surgery patients and those treated in the intensive care unit. In contrast, heparin-induced thrombocytopenia (HIT) is uncommon in these populations (∼1 % and ∼0.5 %, respectively). A stepwise approach where testing for anti-PF4/H antibodies is performed only in patients with typical clinical symptoms of HIT improves diagnostic specificity of the laboratory assays without losing sensitivity, thereby helping to avoid overdiagnosis and resulting HIT overtreatment. Short-term re-exposure to heparin, especially given intraoperatively for cardiovascular surgery, is a reasonable therapeutic option in patients with a history of HIT who subsequently test negative for HIT antibodies. Organ failure(s), enhanced bleeding risks, and other characteristics require special considerations regarding non-heparin anticoagulation: Argatroban is the alternative anticoagulant with pharmacokinetics independent of renal function, but it has a prolonged half-life in case of impaired liver function. For bivalirudin, protocols during cardiopulmonary bypass surgery are established, and it is suitable for patients with liver insufficiency. A major issue of direct thrombin inhibitors are false high activated partial thromboplastin time values in patients with comorbidities affecting prothrombin, which can result in systematic underdosing of the drugs. This is not the case for danaparoid and fondaparinux, which can be monitored by anti-factor Xa assays, but have long half-lives and no suitable antidote. This review includes also information on management of on- and off-pump cardiac surgery, ventricular assist devices, percutaneous interventions, continuous renal replacement therapy, and extracorporeal membrane oxygenation in patients with HIT.

• References

• 1 Bauer TL. et al. Prevalence of heparin-associated antibodies without thrombosis in patients undergoing cardiopulmonary bypass surgery. Circulation 1997; 95: 1242-1246.
  CrossrefPubMedGoogle Scholar
• 2 Selleng S. et al. Prevalence and clinical implications of anti-PF4/heparin antibodies in intensive care patients: a prospective observational study. J Thromb Thrombolysis 2015; 39: 60-67.
  CrossrefPubMedGoogle Scholar
• 3 Hanes SD. et al. Incidence and risk factors of thrombocytopenia in critically ill trauma patients. Ann Pharmacother 1997; 31: 285-289.
  CrossrefPubMedGoogle Scholar
• 4 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: 2530-2536.
  CrossrefPubMedGoogle Scholar
• 5 Selleng S. et al. Incidence and clinical relevance of anti-platelet factor 4/heparin antibodies before cardiac surgery. Am Heart J 2010; 160: 362-369.
  CrossrefPubMedGoogle Scholar
• 6 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: 592-597.
  CrossrefPubMedGoogle Scholar
• 7 Bennett-Guerrero E, Slaughter TF, White WD. et al. Preoperative anti-PF4/he-parin antibody level predicts adverse outcome after cardiac surgery. J Thorac Cardiovasc Surg 2005; 130: 1567-1572.
  CrossrefPubMedGoogle Scholar
• 8 Nader ND, Khadra WZ, Reich NT. et al. Blood product use in cardiac revascularization: comparison of on- and off-pump techniques. The Ann Thorac Surg 1999; 68: 1640-1643.
  PubMedGoogle Scholar
• 9 Selleng S. 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; 08: 30-36.
  CrossrefPubMedGoogle Scholar
• 10 Warkentin TE. et al. Impact of the patient population on the risk for heparin-in-duced thrombocytopenia. Blood 2000; 96: 1703-1708.
  PubMedGoogle Scholar
• 11 Yusuf AM. et al. Prognostic importance of preoperative anti-PF4/heparin antibodies in patients undergoing cardiac surgery. A systematic review. Thromb Haemost 2012; 107: 8-14.
  Article in Thieme ConnectPubMedGoogle Scholar
• 12 Warkentin TE. et al. Laboratory testing for the antibodies that cause heparin-in-duced thrombocytopenia: how much class do we need?. J Lab Clin Med 2005; 146: 341-346.
  CrossrefPubMedGoogle Scholar
• 13 Juhl D. et al. Incidence and clinical significance of anti-PF4/heparin antibodies of the IgG, IgM, and IgA class in 755 consecutive patient samples referred for diagnostic testing for heparin-induced thrombocytopenia. Eur J Haematol 2006; 76: 420-426.
  CrossrefPubMedGoogle Scholar
• 14 Kress DC. et al. Positive heparin-platelet factor 4 antibody complex and cardiac surgical outcomes. Ann Thorac Surg 2007; 83: 1737-1743.
  CrossrefPubMedGoogle Scholar
• 15 Mattioli AV. et al. Heparin/PF4 antibodies formation after heparin treatment: temporal aspects and long-term follow-up. Am Heart J 2009; 157: 589-595.
  CrossrefPubMedGoogle Scholar
• 16 Linkins LA. 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 (02) Suppl e495S-530S.
  CrossrefPubMedGoogle Scholar
• 17 Mattioli AV, Bonetti L, Carletti U. et al. Thrombotic events in patients with anti-platelet factor 4/heparin antibodies. Heart 2009; 95: 1350-1354.
  CrossrefPubMedGoogle Scholar
• 18 Kerendi F, Thourani VH, Puskas JD. et al. Impact of heparin-induced thrombocytopenia on postoperative outcomes after cardiac surgery. Ann Thorac Surg 2007; 84: 1548-1555.
  CrossrefPubMedGoogle Scholar
• 19 Gluckman TJ. 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; 07: 1457-1464.
  CrossrefPubMedGoogle Scholar
• 20 Pouplard C. et al. Changes in platelet count after cardiac surgery can effectively predict the development of pathogenic heparin-dependent antibodies. Br J Haematol 2005; 128: 837-841.
  CrossrefPubMedGoogle Scholar
• 21 Lo GK. 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
• 22 Gruel Y. et al. Usefulness of pretest clinical score (4Ts) combined with immunoassay for the diagnosis of heparin-induced thrombocytopenia. Curr Opin Pulm Med 2008; 14: 397-402.
  CrossrefPubMedGoogle Scholar
• 23 Demma LJ. et al. A diagnosis of heparin-induced thrombocytopenia with combined clinical and laboratory methods in cardiothoracic surgical intensive care unit patients. Anesth Analg 2011; 113: 697-702.
  CrossrefPubMedGoogle Scholar
• 24 Dellaria SM. et al. Urgent cardiac surgery in a patient with a remote history of heparin-induced thrombocytopenia: use of the anti-PF4/heparin ELISA confirmatory test. Anesth Analg 2008; 107: 379-381.
  CrossrefPubMedGoogle Scholar
• 25 Whitlatch NL. et al. Anti-heparin/platelet factor 4 antibody optical density values and the confirmatory procedure in the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost 2008; 100: 678-684.
  Article in Thieme ConnectPubMedGoogle Scholar
• 26 Warkentin TE, Sheppard JI. No significant improvement in diagnostic specificity of an anti-PF4/polyanion immunoassay with use of high heparin confirmatory procedure. J Thromb Haemost 2006; 04: 281-282.
  CrossrefPubMedGoogle Scholar
• 27 Selleng S. et al. The diagnostic value of the anti-PF4/heparin immunoassay high-dose heparin confirmatory test in cardiac surgery patients. Anesth Analg 2011; 112: 774-776.
  CrossrefPubMedGoogle Scholar
• 28 Potzsch B. et al. Use of heparin during cardiopulmonary bypass in patients with a history of heparin-induced thrombocytopenia. N Engl J Med 2000; 343: 515.
  CrossrefPubMedGoogle Scholar
• 29 Warkentin TE, Anderson JAM. How I treat patients with a history of HIT. Blood 2016 Epub ahead of print.
  PubMedGoogle Scholar
• 30 Dyke CM. 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: 533-539.
  CrossrefPubMedGoogle Scholar
• 31 Koster A. 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: 572-577.
  CrossrefPubMedGoogle Scholar
• 32 Aouifi A. et al. Cardiac surgery with cardiopulmonary bypass in patients with type II heparin-induced thrombocytopenia. Ann Thorac Surg 2001; 71: 678-683.
  CrossrefPubMedGoogle Scholar
• 33 Antoniou T. et al. Cardiac surgery in patients with heparin-induced thrombocytopenia using preoperatively determined dosages of iloprost. Heart Surg Forum 2002; 05: 354-357.
  PubMedGoogle Scholar
• 34 Koster A. et al. One-year experience with the platelet glycoprotein IIb/IIIa antagonist tirofiban and heparin during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II. J Thorac Cardiovasc Surg 2001; 122: 1254-1255.
  CrossrefPubMedGoogle Scholar
• 35 Jaben EA. et al. Use of plasma exchange in patients with heparin-induced thrombocytopenia: a report of two cases and a review of the literature. J Clin Apher 2011; 26: 219-224.
  CrossrefPubMedGoogle Scholar
• 36 Welsby IJ. et al. Plasmapheresis and heparin reexposure as a management strategy for cardiac surgical patients with heparin-induced thrombocytopenia. An-esth Analg 2010; 110: 30-35.
  CrossrefPubMedGoogle Scholar
• 37 Voeller RK. et al. Novel use of plasmapheresis in a patient with heparin-induced thrombocytopenia requiring urgent insertion of a left ventricular assist device under cardiopulmonary bypass. J Thorac Cardiovasc Surg 2010; 140: e56-58.
  CrossrefPubMedGoogle Scholar
• 38 Follis F. et al. Argatroban as a substitute of heparin during cardiopulmonary bypass: a safe alternative?. Interact Cardiovasc Thorac Surg 2010; 10: 592-596.
  CrossrefPubMedGoogle Scholar
• 39 Agarwal S. et al. Challenges encountered with argatroban anticoagulation during cardiopulmonary bypass. J Anaesthesiol Clin Pharmacol 2012; 28: 106-110.
  CrossrefPubMedGoogle Scholar
• 40 Magnani HN, Gallus A. Heparin-induced thrombocytopenia (HIT). A report of 1,478 clinical outcomes of patients treated with danaparoid (Orgaran) from 1982 to mid-2004. Thromb Haemost 2006; 95: 967-981.
  Article in Thieme ConnectPubMedGoogle Scholar
• 41 Carrier M. et al. Heparin versus danaparoid in off-pump coronary bypass grafting: results of a prospective randomized clinical trial. J Thorac Cardiovasc Surg 2003; 125: 325-329.
  CrossrefPubMedGoogle Scholar
• 42 Cannon MA. et al. Failure of argatroban anticoagulation during off-pump coronary artery bypass surgery. Ann Thorac Surg 2004; 77: 711-713.
  CrossrefPubMedGoogle Scholar
• 43 Dyke CM. 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: 836-839.
  CrossrefPubMedGoogle Scholar
• 44 Smedira NG. et al. Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: the results of the EVOLUTION-OFF study. J Thorac Car-diovasc Surg 2006; 131: 686-692.
  CrossrefPubMedGoogle Scholar
• 45 Lange P. et al. Bivalirudin vs Heparin in Patients Who Undergo Transcatheter Aortic Valve Implantation. Can J Cardiol 2015; 31: 998-1003.
  CrossrefPubMedGoogle Scholar
• 46 Dangas GD. et al. Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement: The Randomized BRAVO-3 Trial. J Am Coll Cardiol 2015; 66: 2860-2868.
  CrossrefPubMedGoogle Scholar
• 47 Alsidawi S, Effat M. Peri-procedural management of anti-platelets and antico-agulation in patients undergoing MitraClip procedure. J Thromb Thrombolysis 2014; 38: 416-419.
  CrossrefPubMedGoogle Scholar
• 48 Stone GW. et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218-2230.
  CrossrefPubMedGoogle Scholar
• 49 Toeg H. et al. Anticoagulation strategies for left ventricular assist devices. Curr Opin Cardiol 2015 Epub ahead of print.
  PubMedGoogle Scholar
• 50 Koster A. et al. Prevalence and persistence of heparin/platelet factor 4 antibodies in patients with heparin coated and noncoated ventricular assist devices. ASAIO J 2000; 46: 319-322.
  CrossrefPubMedGoogle Scholar
• 51 Schenk S. et al. Heparin-induced thrombocytopenia in patients receiving mechanical circulatory support. J Thorac Cardiovasc Surg 2006; 131: 1373-1381 e4.
  CrossrefPubMedGoogle Scholar
• 52 Warkentin TE. et al. Heparin-induced thrombocytopenia in patients with ventricular assist devices: are new prevention strategies required?. Ann Thorac Surg 2009; 87: 1633-1640.
  CrossrefPubMedGoogle Scholar
• 53 Koster A. et al. Successful use of bivalirudin as anticoagulant for ECMO in a patient with acute HIT. Ann Thorac Surg 2007; 83: 1865-1867.
  CrossrefPubMedGoogle Scholar
• 54 Pappalardo F. et al. Argatroban anticoagulation for heparin induced thrombocytopenia in patients with ventricular assist devices. Minerva Anestesiol 2012; 78: 330-335.
  PubMedGoogle Scholar
• 55 Samuels LE. et al. Argatroban as a primary or secondary postoperative anticoagulant in patients implanted with ventricular assist devices. Ann Thorac Surg 2008; 85: 1651-1655.
  CrossrefPubMedGoogle Scholar
• 56 Hillebrand J. et al. Implantation of left ventricular assist devices under extracor-poreal life support in patients with heparin-induced thrombocytopenia. J Artif Organs 2015; 18: 291-299.
  CrossrefPubMedGoogle Scholar
• 57 Pieri M. et al. Primary anticoagulation with bivalirudin for patients with implantable ventricular assist devices. Artif Organs 2014; 38: 342-346.
  CrossrefPubMedGoogle Scholar
• 58 Garland C, Somogyi D. Successful implantation of a left ventricular assist device in a patient with heparin-induced thrombocytopenia and thrombosis. J Extra Corpor Technol 2014; 46: 162-165.
  PubMedGoogle Scholar
• 59 Morshuis M. et al. A modified technique for implantation of the HeartWare left ventricular assist device when using bivalirudin anticoagulation in patients with acute heparin-induced thrombocytopenia. Interact Cardiovasc Thorac Surg 2013; 17: 225-226.
  CrossrefPubMedGoogle Scholar
• 60 Crowther MA. et al. Thrombocytopenia in medical-surgical critically ill patients: prevalence, incidence, and risk factors. J Crit Care 2005; 20: 348-353.
  CrossrefPubMedGoogle Scholar
• 61 Verma AK. et al. Frequency of heparin-induced thrombocytopenia in critical care patients. Pharmacotherapy 2003; 23: 745-753.
  CrossrefPubMedGoogle Scholar
• 62 Greinacher A, Selleng K. Thrombocytopenia in the intensive care unit patient. Hematology Am Soc Hematol Educ Program 2010; 2010: 135-143.
  CrossrefPubMedGoogle Scholar
• 63 Levine RL. et al. Heparin-platelet factor 4 antibodies in intensive care patients: an observational seroprevalence study. J Thromb Thrombolysis 2010; 30: 142-148.
  CrossrefPubMedGoogle Scholar
• 64 Crowther M. et al. Heparin-induced thrombocytopenia in the critically ill: interpreting the 4Ts test in a randomized trial. J Crit Care 2014; 29: 470. e7-15.
  PubMedGoogle Scholar
• 65 Fiorenza MA. et al. Assessment of a modified 4T scoring system for heparin-in-duced thrombocytopenia in critically ill patients. J Crit Care 2014; 29: 426-431.
  CrossrefPubMedGoogle Scholar
• 66 Junqueira DR. et al. Unfractionated heparin versus low molecular weight heparin for avoiding heparin-induced thrombocytopenia in postoperative patients. Cochrane Database Syst Rev 2012; 09: CD007557.
  PubMedGoogle Scholar
• 67 Cook D. et al. Protect Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med 2011; 364: 1305-1314.
  CrossrefPubMedGoogle Scholar
• 68 Warkentin TE. Heparin-induced thrombocytopenia in critically ill patients. Semin Thromb Hemost 2015; 41: 49-60.
  Article in Thieme ConnectPubMedGoogle Scholar
• 69 Hong AP. et al. Central venous catheters and upper-extremity deep-vein thrombosis complicating immune heparin-induced thrombocytopenia. Blood 2003; 101: 3049-3051.
  CrossrefPubMedGoogle Scholar
• 70 Tardy-Poncet B. et al. Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial. Crit Care 2015; 19: 396.
  CrossrefPubMedGoogle Scholar
• 71 Choi TS. et al. Modified plasma-based ecarin clotting time assay for monitoring of recombinant hirudin during cardiac surgery. Am J Clin Pathol 2006; 125: 290-295.
  CrossrefPubMedGoogle Scholar
• 72 Love JE. et al. Monitoring direct thrombin inhibitors with a plasma diluted thrombin time. Thromb Haemost 2007; 98: 234-242.
  Article in Thieme ConnectPubMedGoogle Scholar
• 73 Martinez LA, Burnett AE. Catheter-directed thrombolysis with alteplase and bivalirudin in a patient with heparin-induced thrombocytopenia. Am J Health Syst Pharm 2015; 72: 707-710.
  CrossrefPubMedGoogle Scholar
• 74 Lubenow N. et al. Results of a systematic evaluation of treatment outcomes for heparin-induced thrombocytopenia in patients receiving danaparoid, ancrod, and/or coumarin explain the rapid shift in clinical practice during the 1990s. Thromb Res 2006; 117: 507-515.
  CrossrefPubMedGoogle Scholar
• 75 Warkentin TE. et al. Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series. J Thromb Haemost 2011; 09: 2389-2396.
  CrossrefPubMedGoogle Scholar
• 76 Siegal DM. et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med 2015; 373: 2413-2424.
  CrossrefPubMedGoogle Scholar
• 77 Greinacher A. et al. Reversal of anticoagulants: an overview of current developments. Thromb Haemost 2015; 113: 931-942.
  Article in Thieme ConnectPubMedGoogle Scholar
• 78 Schilder L. et al. Citrate anticoagulation versus systemic heparinisation in continuous venovenous hemofiltration in critically ill patients with acute kidney injury: a multi-center randomized clinical trial. Crit Care 2014; 18: 472.
  CrossrefPubMedGoogle Scholar
• 79 Bai M. et al. Citrate versus heparin anticoagulation for continuous renal replacement therapy: an updated meta-analysis of RCTs. Intensive Care Med 2015 Epub ahead of print.
  PubMedGoogle Scholar
• 80 Kiser TH. et al. Safety, efficacy, and dosing requirements of bivalirudin in patients with heparin-induced thrombocytopenia. Pharmacotherapy 2008; 28: 1115-1124.
  CrossrefPubMedGoogle Scholar
• 81 Kiser TH. et al. Bivalirudin versus unfractionated heparin for prevention of he-mofilter occlusion during continuous renal replacement therapy. Pharmacotherapy 2010; 30: 1117-1126.
  CrossrefPubMedGoogle Scholar
• 82 Link A. et al. Argatroban for anticoagulation in continuous renal replacement therapy. Crit Care Med 2009; 37: 105-110.
  CrossrefPubMedGoogle Scholar
• 83 Abel EE. et al. Direct thrombin inhibitors for management of heparin-induced thrombocytopenia in patients receiving renal replacement therapy: comparison of clinical outcomes. Am J Health Syst Pharm 2012; 69: 1559-1567.
  CrossrefPubMedGoogle Scholar
• 84 de Pont AC. et al. Pharmacokinetics and pharmacodynamics of danaparoid during continuous venovenous hemofiltration: a pilot study. Crit Care 2007; 11: R102.
  CrossrefPubMedGoogle Scholar
• 85 Langenecker SA. et al. Anticoagulation with prostacyclin and heparin during continuous venovenous hemofiltration. Crit Care Med 1994; 22: 1774-1781.
  CrossrefPubMedGoogle Scholar
• 86 Balik M. et al. Prostacyclin versus citrate in continuous haemodiafiltration: an observational study in patients with high risk of bleeding. Blood Purif 2005; 23: 325-329.
  CrossrefPubMedGoogle Scholar
• 87 Esper SA. et al. Extracorporeal membrane oxygenation in the adult: a review of anticoagulation monitoring and transfusion. Anesth Analg 2014; 118: 731-743.
  CrossrefPubMedGoogle Scholar
• 88 Bauer C. et al. Extracorporeal membrane oxygenation with danaparoid sodium after massive pulmonary embolism. Anesth Analg 2008; 106: 1101-1103.
  CrossrefPubMedGoogle Scholar
• 89 Pieri M. et al. Bivalirudin versus heparin as an anticoagulant during extracor-poreal membrane oxygenation: a case-control study. J Cardiothorac Vasc An-esth 2013; 27: 30-34.
  CrossrefPubMedGoogle Scholar
• 90 Beiderlinden M. et al. Argatroban in extracorporeal membrane oxygenation. Artif Organs 2007; 31: 461-465.
  CrossrefPubMedGoogle Scholar