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Arepally GM, Padmanabhan A. Heparin-Induced Thrombocytopenia: A Focus on Thrombosis. Arterioscler Thromb Vasc Biol 2021; 41:141-152. [PMID: 33267665 PMCID: PMC7769912 DOI: 10.1161/atvbaha.120.315445] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 11/13/2020] [Indexed: 01/19/2023]
Abstract
Heparin-induced thrombocytopenia is an immune-mediated disorder caused by antibodies that recognize complexes of platelet factor 4 and heparin. Thrombosis is a central and unpredictable feature of this syndrome. Despite optimal management, disease morbidity and mortality from thrombosis remain high. The hypercoagulable state in heparin-induced thrombocytopenia is biologically distinct from other thrombophilic disorders in that clinical complications are directly attributable to circulating ultra-large immune complexes. In some individuals, ultra-large immune complexes elicit unchecked cellular procoagulant responses that culminate in thrombosis. To date, the clinical and biologic risk factors associated with thrombotic risk in heparin-induced thrombocytopenia remain elusive. This review will summarize our current understanding of thrombosis in heparin-induced thrombocytopenia with attention to its clinical features, cellular mechanisms, and its management.
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Affiliation(s)
| | - Anand Padmanabhan
- Divisions of Hematopathology, Transfusion Medicine, and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN (A.P.)
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2
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Pollak U. Heparin-induced thrombocytopenia complicating extracorporeal membrane oxygenation support: Review of the literature and alternative anticoagulants. J Thromb Haemost 2019; 17:1608-1622. [PMID: 31313454 DOI: 10.1111/jth.14575] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/25/2019] [Accepted: 07/11/2019] [Indexed: 01/19/2023]
Abstract
Heparin-induced thrombocytopenia (HIT) is a life-threatening prothrombotic, immune-mediated complication of unfractionated heparin and low molecular weight heparin therapy. HIT is characterized by moderate thrombocytopenia 5-10 days after initial heparin exposure, detection of platelet-activating anti-platelet factor 4/heparin antibodies and an increased risk of venous and arterial thrombosis. Extracorporeal membrane oxygenation (ECMO) is a form of mechanical circulatory support used in critically ill patients with respiratory or cardiac failure. Systemic anticoagulation is used to alleviate the thrombotic complications that may occur when blood is exposed to artificial surfaces within the ECMO circuit. Therefore, when HIT complicates patients on ECMO support, it is associated with a high thrombotic morbidity and mortality. The risk for HIT correlates with the accumulative dosage of heparin exposure. In ECMO patients receiving continuous infusion of heparin for circuit patency, the risk for HIT is not neglected and must be thought of in the differential diagnosis of the appropriate clinical and laboratory circumstances. The following article reviews the current knowledge in HIT complicating ECMO patients and the alternative anticoagulation options in the presence of HIT.
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Affiliation(s)
- Uri Pollak
- Pediatric Cardiac Critical Care Unit, Hadassah University Medical Center, Jerusalem, Israel
- Pediatric Cardiology, Hadassah University Medical Center, Jerusalem, Israel
- Pediatric Extracorporeal Support Program, Hadassah University Medical Center, Jerusalem, Israel
- The Hebrew University Hadassah Medical School, Jerusalem, Israel
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Ibrahim W, Nakia H, Stephen M, Bruce S, Bryan W, William P. A Patient With Remote Heparin-Induced Thrombocytopenia and Antiphospholipid Syndrome Requiring Cardiopulmonary Bypass: Do Current Guidelines Apply? Semin Cardiothorac Vasc Anesth 2018; 23:256-260. [DOI: 10.1177/1089253218779081] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Anticoagulation for cardiopulmonary bypass (CPB) is required to prevent acute disseminated intravascular coagulation and clot formation within the bypass circuit. Unfractionated heparin is the standard anticoagulant for CPB due to its many advantages and long history of successful use. However, heparin has the unique drawback of triggering Heparin-PF4 (PF4) antibodies potentially leading to heparin-induced thrombocytopenia (HIT). We have limited data regarding reformation of antibodies if a patient has had a prior (remote) antibody production or full HIT. Patients with antiphospholipid antibodies undergoing CPB with unfractionated heparin have a high complication rate, even in the absence of HIT. Antiphospholipid antibodies have a multifaceted, cumulatively inhibitory effect on the normal anticoagulation armamentarium in vivo. Even more concerning is the possibility that antiphospholipid syndrome and HIT may be synergistic. We report a patient with risk factors for both thromboembolic (remote history of HIT and antiphospholipid syndrome) and hemorrhagic complications who underwent an aortic valve replacement and coronary artery bypass grafting on CPB using bivalirudin. We discuss the complex decision making regarding anticoagulant for CPB, particularly with regard to American College of Chest Physicians guidelines.
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Affiliation(s)
- Warsame Ibrahim
- The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Hunter Nakia
- The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Miller Stephen
- The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | | | - Whitson Bryan
- The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Perez William
- The Ohio State University Wexner Medical Center, Columbus, OH, USA
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Salter BS, Weiner MM, Trinh MA, Heller J, Evans AS, Adams DH, Fischer GW. Heparin-Induced Thrombocytopenia: A Comprehensive Clinical Review. J Am Coll Cardiol 2017; 67:2519-32. [PMID: 27230048 DOI: 10.1016/j.jacc.2016.02.073] [Citation(s) in RCA: 129] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 02/03/2016] [Accepted: 02/08/2016] [Indexed: 12/13/2022]
Abstract
Heparin-induced thrombocytopenia is a profoundly dangerous, potentially lethal, immunologically mediated adverse drug reaction to unfractionated heparin or, less commonly, to low-molecular weight heparin. In this comprehensive review, the authors highlight heparin-induced thrombocytopenia's risk factors, clinical presentation, pathophysiology, diagnostic principles, and treatment. The authors place special emphasis on the management of patients requiring procedures using cardiopulmonary bypass or interventions in the catheterization laboratory. Clinical vigilance of this disease process is important to ensure its recognition, diagnosis, and treatment. Misdiagnosis of the syndrome, as well as misunderstanding of the disease process, continues to contribute to its morbidity and mortality.
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Affiliation(s)
- Benjamin S Salter
- Department of Anesthesiology, Mount Sinai Medical Center, New York, New York.
| | - Menachem M Weiner
- Department of Anesthesiology, Mount Sinai Medical Center, New York, New York
| | - Muoi A Trinh
- Department of Anesthesiology, Mount Sinai Medical Center, New York, New York
| | - Joshua Heller
- Department of Anesthesiology, Mount Sinai Medical Center, New York, New York
| | - Adam S Evans
- Department of Anesthesiology, Mount Sinai Medical Center, New York, New York
| | - David H Adams
- Department of Cardiac Surgery, Mount Sinai Medical Center, New York, New York
| | - Gregory W Fischer
- Department of Anesthesiology, Mount Sinai Medical Center, New York, New York
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5
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Gupta S, Tiruvoipati R, Green C, Botha J, Tran H. Heparin induced thrombocytopenia in critically ill: Diagnostic dilemmas and management conundrums. World J Crit Care Med 2015; 4:202-212. [PMID: 26261772 PMCID: PMC4524817 DOI: 10.5492/wjccm.v4.i3.202] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Revised: 02/25/2015] [Accepted: 07/14/2015] [Indexed: 02/06/2023] Open
Abstract
Thrombocytopenia is often noted in critically ill patients. While there are many reasons for thrombocytopenia, the use of heparin and its derivatives is increasingly noted to be associated with thrombocytopenia. Heparin induced thrombocytopenia syndrome (HITS) is a distinct entity that is characterised by the occurrence of thrombocytopenia in conjunction with thrombotic manifestations after exposure to unfractionated heparin or low molecular weight heparin. HITS is an immunologic disorder mediated by antibodies to heparin-platelet factor 4 (PF4) complex. HITS is an uncommon cause of thrombocytopenia. Reported incidence of HITS in patients exposed to heparin varies from 0.2% to up to 5%. HITS is rare in ICU populations, with estimates varying from 0.39%-0.48%. It is a complex problem which may cause diagnostic dilemmas and management conundrum. The diagnosis of HITS centers around detection of antibodies against PF4-heparin complexes. Immunoassays performed by most pathology laboratories detect the presence of antibodies, but do not reveal whether the antibodies are pathological. Platelet activation assays demonstrate the presence of clinically relevant antibodies, but only a minority of laboratories conduct them. Several anticoagulants are used in management of HITS. In this review we discuss the incidence, pathogenesis, diagnosis and management of HITS.
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Cardiac Surgery and Heparin Induced Thrombocytopaenia (HIT): A Case Report and Short Review. Heart Lung Circ 2012; 21:295-9. [DOI: 10.1016/j.hlc.2012.02.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Revised: 12/06/2011] [Accepted: 02/11/2012] [Indexed: 11/19/2022]
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Agrawal DR, Sayeed MR, Roy IRS, Somaraja K. Pre-emptive use of bivalirudin for emergent off-pump coronary artery bypass surgery in a suspected case of heparin-induced thrombocytopenia. Indian J Anaesth 2012; 56:98-9. [PMID: 22529440 PMCID: PMC3327093 DOI: 10.4103/0019-5049.93364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Dharmesh R Agrawal
- Department of Cardiac Anaesthesiology, Apollo Hospital, Bangaluru, India
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Koniari I, Siminelakis SN, Baikoussis NG, Papadopoulos G, Goudevenos J, Apostolakis E. Antiphospholipid syndrome; its implication in cardiovascular diseases: a review. J Cardiothorac Surg 2010; 5:101. [PMID: 21047408 PMCID: PMC2987921 DOI: 10.1186/1749-8090-5-101] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2010] [Accepted: 11/03/2010] [Indexed: 11/19/2022] Open
Abstract
Antiphospholipid syndrome (APLS) is a rare syndrome mainly characterized by several hyper-coagulable complications and therefore, implicated in the operated cardiac surgery patient. APLS comprises clinical features such as arterial or venous thromboses, valve disease, coronary artery disease, intracardiac thrombus formation, pulmonary hypertension and dilated cardiomyopathy. The most commonly affected valve is the mitral, followed by the aortic and tricuspid valve. For APLS diagnosis essential is the detection of so-called antiphospholipid antibodies (aPL) as anticardiolipin antibodies (aCL) or lupus anticoagulant (LA). Minor alterations in the anticoagulation, infection, and surgical stress may trigger widespread thrombosis. The incidence of thrombosis is highest during the following perioperative periods: preoperatively during the withdrawal of warfarin, postoperatively during the period of hypercoagulability despite warfarin or heparin therapy, or postoperatively before adequate anticoagulation achievement. Cardiac valvular pathology includes irregular thickening of the valve leaflets due to deposition of immune complexes that may lead to vegetations and valve dysfunction; a significant risk factor for stroke. Patients with APLS are at increased risk for thrombosis and adequate anticoagulation is of vital importance during cardiopulmonary bypass (CPB). A successful outcome requires multidisciplinary management in order to prevent thrombotic or bleeding complications and to manage perioperative anticoagulation. More work and reporting on anticoagulation management and adjuvant therapy in patients with APLS during extracorporeal circulation are necessary.
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Affiliation(s)
- Ioanna Koniari
- Cardiothoracic Surgery Department, University of Patras, School of Medicine, Patras, Greece.
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9
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Wong JK, Tian Y, Shuttleworth P, Caffarelli AD, Reitz BA, Mora-Mangano CT. A Thrombus in the Venous Reservoir While Using Bivalirudin in a Patient with Heparin-Induced Thrombocytopenia Undergoing Heart Transplantation. Anesth Analg 2010; 111:609-12. [DOI: 10.1213/ane.0b013e3181e9ead3] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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10
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Ing C, Spellman J, Nishanian E. Cerebrospinal fluid drainage with bivalirudin and rFactor VIIa for thoracic aortic aneurysm surgery using left atrial-femoral artery bypass. J Cardiothorac Vasc Anesth 2010; 24:828-30. [PMID: 20138549 DOI: 10.1053/j.jvca.2009.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2009] [Indexed: 11/11/2022]
Affiliation(s)
- Caleb Ing
- Department of Anesthesia, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
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Jović MD, Nezić DG, Calija BM, Nenadić DS, Knezević AM, Borzanović MD, Krivokapić BM, Petrović IM, Djukanović BP. [Cardiac surgery in patients with heparin-induced thrombocytopenia (HIT II)]. ACTA CHIRURGICA IUGOSLAVICA 2009; 56:47-52. [PMID: 19504989 DOI: 10.2298/aci0901047j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Heparin-induced thrombocytopenia (HIT) might be life-threatening in patients undergoing open heart surgery, due to thromboembolic events, thrombocytopenia and bleeding. If cardiac surgery with cardiopulmonary bypass (CPB) is necessary, anticoagulation therapy will be based on usage of danaparoid or direct thrombin inhibitors. Female patient was switched from per oral anticoagulant therapy to low molecular heparin therapy preparing for reredo mitral valve replacement due to endocarditis and artificial valve thrombosis. In next 10 days, thrombocytopenia was obvious (Tr 302,000 mm3 to 11,000 mm3) , and diagnoses of HIT were done. Anticoagulant therapy was continued with danaparoid, 750 IU/12 h sc. During the surgery, reredo mitral valve replacement and aortocoronary bypass on anterior descending coronary artery, blood salvage technique with rhirudin (intravenous bolus 0.4 mg/kg, in CPB prajming solution 0.4 mg/kg and continuous infusion during CPB 0.15 mg/kg/h) during cardiopulmonary bypass was used. Active coagulation time and +++ were monitored, without any sign of micro thrombosis in circuit. Postoperatively, per oral anticoagulation therapy was initiated with prolonged postoperative treatment due to basic disease, endocarditis. Patient was discharged from hospital on 21st postoperative day without any complication.
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Affiliation(s)
- M D Jović
- Klinika za anesteziju i intenzivno lecenje Beograd
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Crouch MA, Kasirajan V, Cahoon W, Katlaps GJ, Gunnerson KJ. Successful Use and Dosing of Bivalirudin After Temporary Total Artificial Heart Implantation: A Case Series. Pharmacotherapy 2008; 28:1413-20. [DOI: 10.1592/phco.28.11.1413] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Butenas S, Orfeo T, Brummel-Ziedins KE, Mann KG. Influence of bivalirudin on tissue factor-triggered coagulation. Blood Coagul Fibrinolysis 2007; 18:407-14. [PMID: 17581314 DOI: 10.1097/mbc.0b013e32814fcdb8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Bivalirudin, a synthetic analog of the carboxy-terminus of hirudin, is a reversible thrombin inhibitor used during coronary balloon angioplasty. The objective of this study was to evaluate the influence of bivalirudin on thrombin generation. Three in-vitro models (numerical simulations, synthetic coagulation proteome and whole blood) of contact pathway-independent blood coagulation triggered with tissue factor were used in this study. Increasing concentrations of bivalirudin prolong the initiation phase of thrombin generation in a concentration-dependent manner. At subpharmacologic bivalirudin concentrations (0.5-2 micromol/l), total thrombin generation was significantly increased. At a pharmacologic concentration (5 micromol/l), bivalirudin suppressed thrombin generation in the synthetic coagulation proteome; in numerical simulations and contact pathway-inhibited whole blood, no thrombin generation was detected over 1200-2000 s and platelet activation was inhibited by 80%. The addition of a pharmacologic concentration (9 micromol/l) of a naturally occurring protease inhibitor aprotinin in the presence of at least 0.5 micromol/l bivalirudin provided limited enhancement of the bivalirudin inhibitory effect. In conclusion, bivalirudin at pharmacologic concentrations is an efficient inhibitor of thrombin generation, platelet activation and clot formation, which acts not as a modulator but as an 'on-off' switch of blood coagulation.
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Affiliation(s)
- Saulius Butenas
- Department of Biochemistry, University of Vermont, College of Medicine, Burlington, Vermont, USA
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Levy JH, Tanaka KA, Hursting MJ. Reducing thrombotic complications in the perioperative setting: an update on heparin-induced thrombocytopenia. Anesth Analg 2007; 105:570-82. [PMID: 17717208 DOI: 10.1213/01.ane.0000277497.70701.47] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Heparins are widely used in the perioperative setting. Immune heparin-induced thrombocytopenia (HIT) is a serious, antibody-mediated complication of heparin therapy that occurs in approximately 0.5%-5% of patients treated with heparin for at least 5 days. An extremely prothrombotic disorder, HIT confers significant risks of thrombosis and devastating consequences on affected patients: approximately 38%-76% develop thrombosis, approximately 10% with thrombosis require limb amputation, and approximately 20%-30% die within a month. HIT antibodies are transient and typically disappear within 3 mo. In patients with lingering antibodies, however, re-exposure to heparin can be catastrophic. In the perioperative setting, heightened awareness is important for the prompt recognition, diagnosis, and treatment of HIT. HIT should be considered if the platelet count decreases 50% and/or thrombosis occurs 5-14 days after starting heparin, with other diagnoses excluded. On strong clinical suspicion of HIT, heparin should be discontinued and a parenteral alternative anticoagulant initiated, even before laboratory confirmation of HIT is obtained. Subsequent laboratory test results may help with the decision to continue with nonheparin therapy or switch back to heparin. Heparin avoidance in patients with current or previous HIT is feasible in most clinical situations, except perhaps in cardiovascular surgery. If the surgery cannot be delayed until HIT antibodies have disappeared, intraoperative alternative anticoagulation is recommended.
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Affiliation(s)
- Jerrold H Levy
- Emory University School of Medicine, Atlanta, Georgia 30322, USA
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Bartholomew JR. Bivalirudin for the Treatment of Heparin-Induced?Thrombocytopenia. HEPARIN-INDUCED THROMBOCYTOPENIA 2007. [DOI: 10.3109/9781420045093.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Kress DC, Aronson S, McDonald ML, Malik MI, Divgi AB, Tector AJ, Downey FX, Anderson AJ, Stone M, Clancy C. Positive Heparin-Platelet Factor 4 Antibody Complex and Cardiac Surgical Outcomes. Ann Thorac Surg 2007; 83:1737-43. [PMID: 17462391 DOI: 10.1016/j.athoracsur.2006.12.011] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2006] [Revised: 12/08/2006] [Accepted: 12/11/2006] [Indexed: 11/15/2022]
Abstract
BACKGROUND Given the large number of patients undergoing cardiac operations annually, it is important to identify populations at high risk for adverse outcomes. This observational study was conducted to determine the incidence of preoperative heparin-platelet factor 4 (HPF4) antibodies and to assess the associated risk of postoperative adverse outcomes in a nonselected cardiac surgery patient population. METHODS Between March 2002 and December 2004, 1114 (92%) of 1209 patients undergoing cardiac surgery with heparin were tested in an unselected manner for HPF4 antibodies. Main outcome measures were HPF4 antibody seropositivity and fatal and nonfatal adverse clinical outcomes after cardiac surgery. RESULTS Of those screened, 60 (5.4%) of 1114 had positive HPF4 antibodies preoperatively. These patients had longer mean postoperative length of stay (14.0 days versus 9.8 days, p = 0.05), a higher incidence of prolonged (> or = 96 hours) mechanical ventilation (20.3% versus 9.2%, p = 0.02), acute limb ischemia (5.1% versus 0.9%, p = 0.03), renal complications including dialysis (20.3% versus 10.5%, p = 0.03), and gastrointestinal complications (15.3% versus 5.9%, p = 0.01). Stepwise logistic regression analysis showed positive HPF4 antibody status to be an independent predictor for adverse outcome and was associated with a higher risk for renal complications, including dialysis (adjusted odds ratio 2.2; 95% confidence interval, 1.1 to 4.3), than was diabetes. CONCLUSIONS In this large patient series, the presence of HPF4 antibodies before surgical heparin administration was an independent and clinically significant risk factor for postoperative adverse events after cardiac surgery. An optimal preoperative cardiac surgery risk profile should include HPF4 antibody status.
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Affiliation(s)
- David C Kress
- Department of Thoracic and Cardiovascular Surgery, St. Luke's Medical Center, Milwaukee, Wisconsin, USA.
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Koster A, Dyke CM, Aldea G, Smedira NG, McCarthy HL, Aronson S, Hetzer R, Avery E, Spiess B, Lincoff AM. 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; 83:572-7. [PMID: 17257990 DOI: 10.1016/j.athoracsur.2006.09.038] [Citation(s) in RCA: 156] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2006] [Revised: 09/08/2006] [Accepted: 09/11/2006] [Indexed: 10/23/2022]
Abstract
BACKGROUND The coronary artery bypass grafting (CABG) heparin-induced thrombocytopenia thrombosis syndrome (HITTS) on- and off-pump safety and efficacy (CHOOSE-ON) trial was designed as a safety and efficacy trial of bivalirudin for use in anticoagulation during cardiopulmonary bypass (CPB) in patients with confirmed or suspected HIT and (or) antiplatelet factor 4/heparin (anti-PF4/H) antibodies. METHODS In an open-label, multicenter trial, 50 patients were enrolled prospectively. The primary study endpoint was in-hospital acute procedural success, defined as the absence of death, Q-wave myocardial infarction (MI), repeat operation for coronary revascularization, and stroke at day seven after surgery or hospital discharge, whichever occurred first. The secondary study endpoints were procedural success, defined as the absence of death, Q-wave MI, repeat operation for coronary revascularization, and stroke, at 30 days and 12 weeks after surgery. Perioperative blood loss, transfusions, and the incidence of major bleeding events were also captured. RESULTS There were 49 patients treated with bivalirudin of which 43 had acute HIT and thrombosis syndrome (HITTS) with antibodies at time of surgery. Procedural success in-hospital or at 7 days was achieved in 46 (94%) patients. At day 30 procedural success was achieved in 42 (86%) patients, and after 12 weeks in 40 (82%) patients. Mean intraoperative blood loss was 575 +/- 524 mL, and mean 24-hour postoperative blood loss was 998 +/- 595 mL. Forty-one (84%) patients received transfusions before day 7 or discharge with a mean of 5.6 +/- 3.8 units of red blood cells, 8.6 +/- 7.2 units of platelets, and 6.0 +/- 4.7 units of fresh frozen plasma. No differences in outcome among bivalirudin-treated patients were observed between those in the overall group and those with moderately impaired renal function (n = 10). CONCLUSIONS The current investigation expands the experience of safe and effective anticoagulation with bivalirudin during CPB to patients with confirmed or suspected HIT and anti-PF4/H antibodies, including in the setting of impaired renal function.
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Affiliation(s)
- Andreas Koster
- Department of Anesthesia, Deutsches Herzzentrum Berlin, Germany.
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19
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Abstract
Heparin-induced thrombocytopenia (HIT) is a serious, yet treatable prothrombotic disease that develops in approximately 0.5% to 5% of heparin-treated patients and dramatically increases their risk of thrombosis (odds ratio, 37). The antibodies that mediate HIT (ie, heparin-platelet factor 4 antibodies) occur more frequently than the overt disease itself, and, even in the absence of thrombocytopenia, are associated with increased thrombotic morbidity and mortality. HIT should be suspected whenever the platelet count drops more than 50% from baseline (or to <150 x 10(9)/L) beginning 5 to 14 days after starting heparin (or sooner if there was prior heparin exposure) or new thrombosis occurs during, or soon after heparin treatment, with other causes excluded. When HIT is strongly suspected, with or without complicating thrombosis, heparins should be discontinued, and a fast-acting, nonheparin alternative anticoagulant such as argatroban should be initiated immediately. With prompt recognition, diagnosis, and treatment of HIT, the clinical outcomes and health economic burdens of this prothrombotic disease are improved significantly.
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Affiliation(s)
- Jerrold H Levy
- Department of Anesthesiology, Emory University School of Medicine, 1364 Clifton Road N.E., Atlanta, GA 30322, USA.
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20
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Lewis BE, Hursting MJ. Direct thrombin inhibition during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia. Expert Rev Cardiovasc Ther 2007; 5:57-68. [PMID: 17187457 DOI: 10.1586/14779072.5.1.57] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Patients with or at risk of heparin-induced thrombocytopenia (HIT) who are undergoing percutaneous coronary intervention (PCI) are at particular risk of thrombosis due to the prothrombotic nature of HIT and the endovascular disruption from PCI. Patients require aggressive anticoagulation during PCI, and alternative, nonheparin anticoagulation is recommended over heparin in patients with acute or previous HIT. Argatroban, bivalirudin, and lepirudin are nonheparin, fast-acting, parenteral direct thrombin inhibitors (DTIs). Multicenter, prospective studies have demonstrated that argatroban and lepirudin each reduce thrombosis in HIT and that argatroban and bivalirudin each provide adequate anticoagulation during PCI in patients with or at risk of HIT. We review current therapeutic practices with direct thrombin inhibitors in patients with or at risk of HIT during PCI, including individuals requiring periprocedural anticoagulation, and the factors influencing the choice of DTI in this setting.
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Affiliation(s)
- Bruce E Lewis
- Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA.
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Leissner KB, Ketchedjian A, Crowley R, Ortega R, Hesselvik JF, Shemin RJ. Deep Hypothermic Circulatory Arrest and Bivalirudin Use in a Patient With Heparin-Induced Thrombocytopenia and Antiphospholipid Syndrome. J Card Surg 2007; 22:78-82. [PMID: 17239224 DOI: 10.1111/j.1540-8191.2007.00351.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND Patients with heparin-induced thrombocytopenia II (HIT II) need an alternative nonheparin-based method of anticoagulation for cardiopulmonary bypass (CPB) to prevent thrombosis and thrombosis related complications. METHODS Bivalirudin was used during CPB and deep hypothermic circulatory arrest (DHCA) for resection of multiple right atrial masses in a patient with HIT II and antiphospholipid antibodies syndrome (APS). Anticoagulation was monitored with the activated clotting time (ACT) and a target ACT of 450 seconds or greater was maintained. RESULTS Surgical removal of multiple right atrial masses was successful and there was no evidence of thromboembolic events. Clot was noticed in the cardiotomy and venous reservoir after CPB was discontinued and the system flushed. The postoperative course was uneventful. CONCLUSIONS Anticoagulation was successfully managed with bivalirudin, a new short-acting, and direct thrombin inhibitor. Further studies are necessary to evaluate the safety of bivalirudin during DHCA.
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Affiliation(s)
- Kay B Leissner
- Department of Anesthesiology, Boston University Medical Center, Boston University, Boston, Massachusetts 02118, USA.
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Nielsen VG, Kirklin JK. Hydroxyethyl starch enhances argatroban-mediated decreases in clot propagation and strength by diminishing thrombin–fibrinogen interactions. Blood Coagul Fibrinolysis 2007; 18:49-54. [PMID: 17179827 DOI: 10.1097/mbc.0b013e3280111aa4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Direct thrombin inhibitors (DTIs) have been administered for anticoagulation during cardiopulmonary bypass for patients with heparin-induced thrombocytopenia. While DTIs prolonged clot initiation and decreased clot propagation, clot strength did not change. Hydroxyethyl starches (HES), however, significantly decreased clot propagation and strength. We hypothesized that DTI with HES could significantly decrease hemostasis more than DTI alone. Plasma was exposed to 0 or 5 microg/ml argatroban with 0 or 30% dilution with 0.9% NaCl, 10% pentastarch or 6% Voluven. Additional argatroban-exposed samples diluted with HES had addition of alpha-thrombin (0.25 U/ml) and fibrinogen (150 mg/ml). Clot kinetics were determined via thrombelastography. While dilution with 0.9% NaCl significantly (P < 0.05) decreased the clot strength by 17% compared with samples only exposed to argatroban, dilution with pentastarch and Voluven significantly (P < 0.05) markedly decreased clot strength (53 and 78%, respectively). Voluven dilution significantly increased the time to clot initiation and decreased the velocity of clot propagation compared with samples only exposed to argatroban. Addition of alpha-thrombin/fibrinogen restored clot strength. DTI/HES administration diminished hemostasis to a greater extent than DTI exposure alone. Further investigation is warranted to determine whether this therapeutic approach can improve the safety of anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia.
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Affiliation(s)
- Vance G Nielsen
- Department of Anesthesiology, The University of Alabama at Birmingham, Alabama 35249-6810, USA.
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Oh JJ, Akers WS, Lewis D, Ramaiah C, Flynn JD. Recombinant factor VIIa for refractory bleeding after cardiac surgery secondary to anticoagulation with the direct thrombin inhibitor lepirudin. Pharmacotherapy 2006; 26:569-577. [PMID: 16553518 DOI: 10.1592/phco.26.4.576] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
A 56-year-old man with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS) received anticoagulation with recombinant hirudin (lepirudin) for emergency coronary artery bypass graft (CABG) surgery and aortic valve replacement. The patient experienced life-threatening refractory bleeding that was successfully treated with recombinant factor VIIa. He had a history of infective endocarditis that resulted in severe aortic insufficiency, three-vessel coronary artery disease, and acute renal failure requiring hemodialysis. The patient was transferred from another hospital for the emergency surgery, but before his transfer, he developed HITTS secondary to therapeutic heparin for a deep vein thrombosis of the lower extremity. The presence of HITTS, the urgent nature of the case, and the availability of the direct thrombin inhibitor led the surgical team to select lepirudin for anticoagulation to facilitate cardiopulmonary bypass. After separation from cardiopulmonary bypass, the patient was in a coagulopathic state due to the inability to reverse the lepirudin and the slowed elimination of the drug secondary to inadequate renal function. As a result, the patient experienced excessive generalized oozing that was unresponsive to traditional therapies and blood product transfusions. Recombinant factor VIIa 35 microg/kg was given as rescue therapy. The bleeding slowed, which allowed placement of chest tubes and closing of the sternum. The patient was transferred to the intensive care unit in stable condition with no evidence of thrombosis in the freshly placed bypass grafts or on the bioprosthetic valve. Recombinant factor VIIa appears to be a suitable option as salvage therapy in patients with refractory bleeding secondary to anticoagulation with a direct thrombin inhibitor during cardiac surgery.
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Affiliation(s)
- Jennifer J Oh
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536, USA
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Abstract
Bivalirudin (Hirulog, Angiomax) is a specific, reversible and direct thrombin inhibitor with a predictable anticoagulant effect. It is cleared by both proteolytic cleavage and renal mechanisms, predominantly glomerular filtration. Bivalirudin inhibits both circulating thrombin and fibrin bound thrombin directly by binding to thrombin catalytic site and anion-binding exosite I in a concentration-dependent manner. Bivalirudin prolongs activated partial thromboplastin time, prothrombin time, thrombin time and activated clotting time (ACT). ACT levels with bivalirudin do not correlate with its clinical efficacy. Bivalirudin with a provisional GpIIb/IIIa inhibitor is indicated in elective contemporary percutaneous coronary intervention (PCI). In respect to combined ischemic and hemorrhagic endpoints of death, myocardial infarction, unplanned urgent revascularization and major bleeding during PCI (including subgroups of patients with renal impairment and diabetes) bivalirudin is not inferior to unfractioned heparin and planned GpIIb/IIIa inhibitors. In addition, bivalirudin has been consistently shown to have significantly less in-hospital major bleeding than heparin alone or heparin in combination with a GpIIb/IIIa inhibitor. Bivalirudin appears to be also safe and effective during PCI in patients with heparin-induced thrombocytopenia. Finally, data from PCI studies support the safety and efficacy of bivalirudin, although its direct randomized comparison with unfractionated heparin is lacking.
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Affiliation(s)
- Nicolas W Shammas
- Midwest Cardiovascular Research Foundation, Cardiovascular Medicine, PC, 1236 E. Rusholme, Suite 300, Davenport, IA 52803, USA.
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