Semin Thromb Hemost 2010; 36(1): 091-102
DOI: 10.1055/s-0030-1248728
© Thieme Medical Publishers

The Management of Cardiovascular Diseases in Patients with Hemophilia

Antonio Coppola1 , Annarita Tagliaferri2 , Massimo Franchini3
  • 1Regional Reference Centre for Coagulation Disorders, Federico II University Hospital, Naples, Italy
  • 2Regional Reference Centre for Inherited Bleeding Disorders, University Hospital, Parma, Italy
  • 3Department of Pathology and Laboratory Medicine, Immunohaematology and Transfusion Centre, University Hospital, Parma, Italy
Further Information

Publication History

Publication Date:
13 April 2010 (online)

ABSTRACT

Morbidity and mortality for cardiovascular disease are likely to be lower in patients with hemophilia than in the general male population. However, their clinical impact is increasing in parallel with the increase of life expectancy due to modern safe replacement treatments and the improvement of comprehensive care of these patients. No rigorous trial concerning treatment of ischemic coronary disease is currently available, and such studies are probably not feasible in this setting. Given the lack of evidence-based guidelines, the analysis of case reports describing management of coronary artery disease and cardiac surgery in hemophilic patients suggests that treatment strategies should be similar to those used in nonhemophilic subjects, provided that an adequate concentrate replacement is administered. On the whole, treatment should be tailored for balancing the actual thrombotic risk and the preexisting bleeding tendency, enhanced by the use of antithrombotic agents. In this review, the available information is discussed, together with the recent suggestions of experts developed to provide more uniform approaches and collection of data. Treatment of cardiovascular disease reflects the evolving scenario in which clinicians who treat hemophilia will have to extend their interactions with other specialists to confront the new challenges of the comprehensive care of aging hemophilic patients.

REFERENCES

  • 1 Mannucci P M, Tuddenham E G. The hemophilias—from royal genes to gene therapy.  N Engl J Med. 2001;  344(23) 1773-1779
  • 2 Mejia-Carvajal C, Czapek E E, Valentino L A. Life expectancy in hemophilia outcome.  J Thromb Haemost. 2006;  4(3) 507-509
  • 3 Franchini M, Tagliaferri A, Mannucci P M. The management of hemophilia in elderly patients.  Clin Interv Aging. 2007;  2(3) 361-368
  • 4 Stewart J W, Acheson J D. Atherosclerosis in a haemophiliac.  Lancet. 1957;  272 1121-1122
  • 5 Meili E O, Straub P W, Lichtlen P, Frick P G. Myocardial infarction in a haemophiliac. Demonstration of coronary sclerosis by selective angiography.  Helv Med Acta. 1968;  34(3) 239-243
  • 6 Small M, Jack A S, Lowe G D, Mutch A F, Forbes C D, Prentice C R. Coronary artery disease in severe haemophilia.  Br Heart J. 1983;  49(6) 604-607
  • 7 Rosendaal F R, Varekamp I, Smit C et al.. Mortality and causes of death in Dutch haemophiliacs, 1973–86.  Br J Haematol. 1989;  71(1) 71-76
  • 8 Triemstra M, Rosendaal F R, Smit C, Van der Ploeg H M, Briët E. Mortality in patients with hemophilia. Changes in a Dutch population from 1986 to 1992 and 1973 to 1986.  Ann Intern Med. 1995;  123(11) 823-827
  • 9 Srámek A, Kriek M, Rosendaal F R. Decreased mortality of ischaemic heart disease among carriers of haemophilia.  Lancet. 2003;  362(9381) 351-354
  • 10 Plug I, Van Der Bom J G, Peters M et al.. Mortality and causes of death in patients with hemophilia, 1992–2001: a prospective cohort study.  J Thromb Haemost. 2006;  4(3) 510-516
  • 11 Koumbarelis E, Rosendaal F R, Gialeraki A et al.. Epidemiology of haemophilia in Greece: an overview.  Thromb Haemost. 1994;  72(6) 808-813
  • 12 Darby S C, Kan S W, Spooner R J et al.. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV.  Blood. 2007;  110(3) 815-825
  • 13 Soucie J M, Nuss R, Evatt B The Hemophilia Surveillance System Project Investigators et al. Mortality among males with hemophilia: relations with source of medical care.  Blood. 2000;  96(2) 437-442
  • 14 Kulkarni R, Soucie J M, Evatt B L. Hemophilia Surveillance System Project Investigators . Prevalence and risk factors for heart disease among males with hemophilia.  Am J Hematol. 2005;  79(1) 36-42
  • 15 Tuinenburg A, Mauser-Bunschoten E P, Verhaar M C, Biesma D H, Schutgens R EG. Cardiovascular disease in patients with hemophilia.  J Thromb Haemost. 2009;  7(2) 247-254
  • 16 Srámek A, Reiber J HC, Gerrits W BJ, Rosendaal F R. Decreased coagulability has no clinically relevant effect on atherogenesis: observations in individuals with a hereditary bleeding tendency.  Circulation. 2001;  104(7) 762-767
  • 17 Sartori M T, Bilora F, Zanon E et al.. Endothelial dysfunction in haemophilia patients.  Haemophilia. 2008;  14(5) 1055-1062
  • 18 Franchini M. Thrombotic complications in patients with hereditary bleeding disorders.  Thromb Haemost. 2004;  92(2) 298-304
  • 19 Schimpf K L, Zeltsch C, Zeltsch P. Myocardial infarction complicating activated prothrombin complex concentrate substitution in a patient with hemophilia A.  Lancet. 1982;  2 1043
  • 20 Gruppo R A, Bove K E, Donaldson V H. Fatal myocardial necrosis associated with prothrombin-complex concentrate therapy in hemophilia A.  N Engl J Med. 1983;  309(4) 242-243
  • 21 Sullivan D W, Purdy L J, Billingham M, Glader B E. Fatal myocardial infarction following therapy with prothrombin complex concentrates in a young man with hemophilia A.  Pediatrics. 1984;  74(2) 279-281
  • 22 Chavin S I, Siegel D M, Rocco Jr T A, Olson J P. Acute myocardial infarction during treatment with an activated prothrombin complex concentrate in a patient with factor VIII deficiency and a factor VIII inhibitor.  Am J Med. 1988;  85(2) 245-249
  • 23 Karayalcin G, Goldberg B, Cherrick I, Kurer C, Bierman F, Lanzkowsky P. Acute myocardial infarction complicating prothrombin complex concentrate therapy in an 8-year-old boy with hemophilia A and factor VIII inhibitor.  Am J Pediatr Hematol Oncol. 1993;  15(4) 416-419
  • 24 Köhler M, Hellstern P, Lechler E, Uberfuhr P, Müller-Berghaus G. Thromboembolic complications associated with the use of prothrombin complex and factor IX concentrates.  Thromb Haemost. 1998;  80(3) 399-402
  • 25 Iannaccaro P, Santoro R, Sottilotta G, Papaleo G, Muleo G. Thrombosis in hemophiliacs with prothrombotic molecular defect.  Clin Appl Thromb Hemost. 2005;  11(3) 359-360
  • 26 Siboni S M, Mannucci P M, Gringeri A et al.. Health status and quality of life of elderly persons with severe hemophilia born before the advent of modern replacement therapy.  J Thromb Haemost. 2009;  7(5) 780-786
  • 27 Miesbach W, Alesci S, Krekeler S, Seifried E. Comorbidities and bleeding pattern in elderly haemophilia A patients.  Haemophilia. 2009;  15(4) 894-899
  • 28 Girolami A, Ruzzon E, Fabris F et al.. Myocardial infarction and other arterial occlusions in hemophilia A patients. A cardiological evaluation of all 42 cases reported in the literature.  Acta Haematol. 2006;  116 120-125
  • 29 Girolami A, Randi M L, Ruzzon E, Zanon E, Girolami B. Myocardial infarction, other arterial thrombosis and invasive coronary procedures, in hemaophilia B: a critical evaluation of reported cases.  J Thromb Thrombolysis. 2005;  20(1) 43-46
  • 30 Aledort L M. Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activity.  J Thromb Haemost. 2004;  2(10) 1700-1708
  • 31 Negrier C, Goudemand J, Sultan Y, Bertrand M, Rothschild C, Lauroua P. Multicenter retrospective study on the utilization of FEIBA in France in patients with factor VIII and factor IX inhibitors. French FEIBA Study Group. Factor Eight Bypassing Activity.  Thromb Haemost. 1997;  77(6) 1113-1119
  • 32 Ehrlich H J, Henzl M J, Gomperts E D. Safety of factor VIII inhibitor bypass activity (FEIBA): 10-year compilation of thrombotic adverse events.  Haemophilia. 2002;  8(2) 83-90
  • 33 Franchini M, Zaffanello M, Veneri D. Recombinant factor VIIa. An update on its clinical use.  Thromb Haemost. 2005;  93(6) 1027-1035
  • 34 Roberts H R. Recombinant factor VIIa (NovoSeven) and the safety of treatment.  Semin Hematol. 2001;  38(4, suppl 12) 48-50
  • 35 Lippi G, Montagnana M, Salvagno G L, Guidi G C. Potential value for new diagnostic markers in the early recognition of acute coronary syndromes.  CJEM. 2006;  8(1) 27-31
  • 36 Antithrombotic Trialists’ Collaboration . Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.  BMJ. 2002;  324(7329) 71-86
  • 37 Harrington R A, Becker R C, Cannon C P American College of Chest Physicians et al. Antithrombotic therapy for non-ST-segment elevation acute coronary syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;  133(6, suppl) 670S-707S
  • 38 Goodman S G, Menon V, Cannon C P, Steg G, Ohman E M, Harrington R A. American College of Chest Physicians . Acute ST-segment elevation myocardial infarction: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;  133(6, suppl) 708S-775S
  • 39 Moscucci M, Fox K A, Cannon C P et al.. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE).  Eur Heart J. 2003;  24(20) 1815-1823
  • 40 Warkentin T E, Kelton J G. Temporal aspects of heparin-induced thrombocytopenia.  N Engl J Med. 2001;  344(17) 1286-1292
  • 41 Merlini P A, Rossi M, Menozzi A et al.. Thrombocytopenia caused by abciximab or tirofiban and its association with clinical outcome in patients undergoing coronary stenting.  Circulation. 2004;  109(18) 2203-2206
  • 42 Mielke Jr C H, Britten A F. Use of aspirin or acetaminophen in hemophilia.  N Engl J Med. 1970;  282(22) 1270
  • 43 Quick A J. No aspirin for hemophiliacs.  N Engl J Med. 1971;  284(4) 218
  • 44 MacKinlay N, Taper J, Renisson F, Rickard K. Cardiac surgery and catheterization in patients with haemophilia.  Haemophilia. 2000;  6(2) 84-88
  • 45 Forman M B, Kopelman H A, Gleaton J H, Janco R L, Perry J M. Percutaneous transluminal coronary angioplasty in hemophilia.  Am Heart J. 1986;  111(1) 169-172
  • 46 Helft G, Metzger J P, Samama M M, Rothschild C, Batisse J P, Vacheron A. Coronary stenting in a hemophilic patient.  Thromb Haemost. 1997;  77(5) 1044-1045
  • 47 Peerlinck K, Vermylen J. Acute myocardial infarction following administration of recombinant activated factor VII (Novo Seven) in a patient with haemophilia A and inhibitor.  Thromb Haemost. 1999;  82(6) 1775-1776
  • 48 Alsolaiman M M, Chang K, Arjomand H, Oza R, Costacurta G. Acute left anterior descending artery occlusion in a hemophiliac A patient during recombinant factor VIII infusion: treatment with coronary angioplasty.  Catheter Cardiovasc Interv. 2000;  50(4) 468-472
  • 49 Au W Y, Jim M H, Lam C C. Unusual case of coronary artery disease in a patient with severe hemophilia B.  Am J Hematol. 2002;  69(2) 152-153
  • 50 Bovenzi F, De Luca L, Signore N, Fusco F, de Luca I. Abciximab for the treatment of an acute thrombotic coronary occlusion during stent implantation in a patient with severe hemophilia B.  Ital Heart J. 2003;  4(10) 728-730
  • 51 Kerkhoffs J L, Atsma D E, Oemrawsingh P V, Eikenboom J, Van der Meer F JM. Acute myocardial infarction during substitution with recombinant factor VIII concentrate in a patient with mild haemophilia A.  Thromb Haemost. 2004;  92(2) 425-426
  • 52 Virtanen R, Kauppila M, Itälä M. Percutaneous coronary intervention with stenting in a patient with haemophilia A and an acute myocardial infarction following a single dose of desmopressin.  Thromb Haemost. 2004;  92(5) 1154-1156
  • 53 Arora U K, Dhir M, Cintron G, Strom J A. Successful multi-vessel percutaneous coronary intervention with bivalirudin in a patient with severe hemophilia A: a case report and review of literature.  J Invasive Cardiol. 2004;  16(6) 330-332
  • 54 Krolick M A. Successful percutaneous coronary intervention in a patient with severe haemophilia A using bivalirudin as the sole procedural anticoagulant.  Haemophilia. 2005;  11(4) 415-417
  • 55 Smolka G, Kulach A, Dabek J, Szulc A, Gasior Z. Percutaneous coronary intervention with stent implantation in haemophilic A patient with unstable angina.  Haemophilia. 2007;  13(4) 428-431
  • 56 Ferrario C, Renders F, Cairoli A, Vuffray A, Spertini O, Angelillo-Scherrer A. Management of an acute coronary syndrome in a patient with severe haemophilia A.  Haemophilia. 2007;  13(6) 763-765
  • 57 Quintero D, Biria M, Meyers D G. Percutaneous coronary intervention in a patient with acute ST-elevation myocardial infarction and hemophilia A.  J Invasive Cardiol. 2008;  20(5) 240-241
  • 58 Coppola A, De Simone C, Di Capua M et al.. Management of ischemic heart disease in hemophilic patients: new challenges from a case report and review of the literature [abstract].  Haemophilia. 2008;  14(Suppl 2) 127
  • 59 Rivolta G F, Di Perna C, Franchini M et al.. Management of coronary artery disease in a severe haemophilia patient with high titre inhibitor and anaphylaxis.  Haemophilia. 2009;  15(5) 1161-1163
  • 60 Schutgens R EG, Tuinenburg A, Roosendaal G, Guyomi S H, Mauser-Bunschoten E P. Treatment of ischaemic heart disease in haemophilia patients: an institutional guideline.  Haemophilia. 2009;  15(4) 952-958
  • 61 Shaw S M, Fildes J E, Yonan N, Williams S G. Pleiotropic effects and cholesterol-lowering therapy.  Cardiology. 2009;  112(1) 4-12
  • 62 Antman E M, Cohen M, Radley D et al.. Assessment of the treatment effect of enoxaparin for unstable angina/non-Q-wave myocardial infarction. TIMI 11B-ESSENCE meta-analysis.  Circulation. 1999;  100(15) 1602-1608
  • 63 Ferguson J J, Califf R M, Antman E M SYNERGY Trial Investigators et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial.  JAMA. 2004;  292(1) 45-54
  • 64 Karthikeyan G, Mehta S R, Eikelboom J W. Fondaparinux in the treatment of acute coronary syndromes: evidence from OASIS 5 and 6.  Expert Rev Cardiovasc Ther. 2009;  7(3) 241-249
  • 65 Bittl J A, Chaitman B R, Feit F, Kimball W, Topol E J. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: Final report reanalysis of the Bivalirudin Angioplasty Study.  Am Heart J. 2001;  142(6) 952-959
  • 66 Maroo A, Lincoff A M. Bivalirudin in PCI: an overview of the REPLACE-2 trial.  Semin Thromb Hemost. 2004;  30(3) 329-336
  • 67 Harker L A, Boissel J P, Pilgrim A J, Gent M. Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE. CAPRIE Steering Committee and Investigators. Clopidogrel versus aspirin in patients at risk of ischaemic events.  Drug Saf. 1999;  21(4) 325-335
  • 68 Cid A R, Zorio E, Haya S et al.. Treatment in a haemophiliac A patient with paroxysmal atrial fibrillation and ischemic heart disease.  Haemophilia. 2007;  13(6) 760-762
  • 69 Patrono C, Baigent C, Hirsh J, Roth G. American College of Chest Physicians . Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;  133(6, suppl) 199S-233S
  • 70 Levine G N, Kern M J, Berger P B et al.. Management of patients undergoing percutaneous coronary revascularization.  Ann Intern Med. 2003;  139(2) 123-136
  • 71 Iakovou I, Schmidt T, Bonizzoni E et al.. Incidence, prediction and outcome of thrombosis after successful implantation of drug-eluting stents.  JAMA. 2005;  293(17) 2126-2130
  • 72 Banerjee S, Varghese C, Samuel J et al.. Comparison of the impact of short (<1 year) and long-term (>or = 1 year) clopidogrel use following percutaneous coronary intervention on mortality.  Am J Cardiol. 2008;  102(9) 1159-1162
  • 73 Agostoni P, Biondi-Zoccai G G, de Benedictis M L et al.. Radial versus femoral approach for percutaneous coronary diagnostic and interventional procedures: systematic overview and meta-analysis of randomized trials.  J Am Coll Cardiol. 2004;  44 349-356
  • 74 Kinnaird T, Anderson R, Hill J, Thomas M. Bleeding during percutaneous intervention: tailoring the approach to minimise risk.  Heart. 2009;  95(1) 15-19
  • 75 Cantor W J, Puley G, Natarajan M K et al.. Radial versus femoral access for emergent percutaneous coronary intervention with adjunct glycoprotein IIb/IIIa inhibition in acute myocardial infarction—the RADIAL-AMI pilot randomized trial.  Am Heart J. 2005;  150(3) 543-549
  • 76 Koreny M, Riedmuller E, Nikfardjam M, Siostrzonek P, Mullner M. Arterial puncture closing devices compared with standard manual compression after cardiac catheterization: systematic review and meta-analysis.  JAMA. 2004;  291 350-357
  • 77 Kwa A T, Rogers J H. Current update on glycoprotein IIb-IIIa and direct thrombin inhibition in percutaneous coronary intervention for non-ST elevation acute coronary syndromes: balancing bleeding risk and antiplatelet efficacy.  J Interv Cardiol. 2008;  21(2) 107-117
  • 78 Lickfett L, Hagendorff A, Jung W, Pizzulli L, Brackmann H H, Lüderitz B. Acute posterior wall infarct after factor VIII concentrate administration to a patient with severe hemophilia A [in German].  Dtsch Med Wochenschr. 1998;  123(21) 658-662
  • 79 Tang M, Wierup P, Terp K, Ingerslev J, Sørensen B. Cardiac surgery in patients with haemophilia.  Haemophilia. 2009;  15(1) 101-107
  • 80 Legget P L, Doyle D, Smith W B et al.. Elective cardiac operation in a patient with severe haemophilia and acquired factor VIII antibodies.  J Thorac Cardiovasc Surg. 1984;  87(4) 556-560
  • 81 Mazzucco A, Stellin G, Cantele P, Boschello M, Traldi A, Gallucci V. Repair of ventricular septal defect and aortic regurgitation associated with severe hemophilia B.  Ann Thorac Surg. 1986;  42(1) 97-99
  • 82 Raish R J, Witte D L, Goldsmith J C. Successful cardiac surgery following plasmapheresis in a patient with hemophilia B.  Transfusion. 1985;  25(2) 128-130
  • 83 Vander Woude J C, Milam J D, Walker W E, Houchin D P, Weiland A P, Cooley D A. Cardiovascular surgery in patients with congenital plasma coagulopathies.  Ann Thorac Surg. 1988;  46(3) 283-288
  • 84 Palanzo D A, Sadr F S. Coronary artery bypass grafting in a patient with haemophilia B.  Perfusion. 1995;  10 265-270
  • 85 De Bels D, Demeere J L, Dugauquier J, Louis P, Van der Vorst E. Continuous infusion of factor VIIIc during heart surgery in a patient with haemophilia A.  Eur J Anaesthesiol. 2004;  21(12) 984-986
  • 86 Palareti G, Leali N, Coccheri S Italian Study on Complications of Oral Anticoagulant Therapy et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT).  Lancet. 1996;  348(9025) 423-428
  • 87 Kaminishi Y, Aizawa K, Saito T, Misawa Y, Madoiwa S, Sakata Y. Modified Bentall operation in a patient with hemophilia A.  Jpn J Thorac Cardiovasc Surg. 2003;  51(2) 68-70
  • 88 Ghosh K, Shetty S. Anticoagulation in haemophilia patients with prosthetic valve replacement.  Haemophilia. 2004;  10(6) 743
  • 89 Dargaud Y, Meunier S, Negrier C. Haemophilia and thrombophilia: an unexpected association!.  Haemophilia. 2004;  10(4) 319-326
  • 90 Franchini M, Lippi G. Together we care: new challenges for global haemophilia treatment centers.  Indian J Med Res. 2009;  129(4) 345-347
  • 91 Mauser-Bunschoten E P, Fransen Van De Putte D E, Schutgens R EG. Co-morbidity in the ageing haemophilia patient: the down side of increased life expectancy.  Haemophilia. 2009;  15(4) 853-863

Massimo FranchiniM.D. 

Immunohematology and Transfusion Center

Department of Pathology and Laboratory Medicine, University Hospital of Parma, Parma, Italy

Email: mfranchini@ao.pr.it

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