Acquired hypercoagulable state in renal transplant recipients

Amir Kazory; Didier Ducloux

doi:10.1160/TH03-09-0568

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 91(04): 646-654
DOI: 10.1160/TH03-09-0568

Review Article

Schattauer GmbH

Acquired hypercoagulable state in renal transplant recipients

Amir Kazory

¹Department of Nephrology and Renal Transplantation, Saint-Jacques Hospital, Besançon, France

,

Didier Ducloux

¹Department of Nephrology and Renal Transplantation, Saint-Jacques Hospital, Besançon, France

› Author Affiliations

Abstract

Summary

Stable renal transplant recipients manifest a chronic hypercoagulable state with an increased risk of thromboembolic complications, which appears to be multifactorial. While this group of patients could present the known risk factors for thromboembolism in the general population (e.g. diabetes, cancer, pregnancy), they may also suffer from other situations which are mostly related to transplantation and are consequently specific to them. Here, we review briefly the clinical aspects and controversies of the most important of these factors including immunosuppressive agents, antiphospholipid antibodies, hyperhomocysteinemia, pre-transplant dialysis modality, and posttransplant erythrocytosis. In addition, other more recent topics including hypercysteinemia, recurrent proteinuria, and acute CMV infection are discussed.

Keywords

Renal transplantation - thromboembolism - hypercoagulability - thrombosis

Full Text

References

References
1 Irish AB, Green FR. Environmental and genetic determinants of the hypercoagulable state and cardiovascular disease in renal transplant recipients. Nephrol Dial Transplant 1997; 12: 167-73.
2 Allen RD, Michie CA, Murie JA. et al. Deep venous thrombosis after renal transplantation. Surg Gynecol Obstet 1987; 164: 137-42.
3 Humar A, Johnson EM, Gillingham KJ. et al. Venous thromboembolic complications after kidney and kidney-pancreas transplantation. Transplantation 1998; 65 (02) 229-34.
4 Advisory committee to the renal transplant registry. The 12^th report of the human renal transplant registry. JAMA 1975; 233: 787-93.
5 European and dialysis and transplant association. Combined report on regular dialysis and transplantation in Europe. London: Pitman; 1983: 13.
6 Vanrenterghem Y, Roels L, Lerut T. et al. Thromboembolic complications and haemostatic changes in cyclosporin-treated cadaveric kidney allograft recipients. Lancet 1985; 01 (8436): 999-1002.
7 Carlsen E, Prydz H. Enhancement of procoagulant activity in stimulated mononuclear blood cells and monocytes by cyclosporine. Transplantation 1987; 43 (04) 543-8.
8 Fishman SJ B.S. W, Glickman JD. et al. Cyclosporin A augments human platelet sensitivity to aggregating agents by increasing fibrinogen receptor availability. J Surg Res 1991; 51: 93-8.
9 Bombeli T, Muller M, Werner PStraub. et al. Cyclosporine-induced detachment of vascular endothelial cells initiates the extrinsic coagulation system in plasma and whole blood. J lab Clin Med 1996; 127: 621-34.
10 Levi M, Wilmink J, Buller HR. Impaired fibrinolysis in cyclosporine-treated renal transplant patients. Transplantation 1992; 54 (06) 978-83.
11 Garcia-Maldonaldo M, Kaufman CE, Comp PC. Decrease in endothelial cell-dependent protein C activation induced by thrombomodulin by treatment by cyclosporine. Transplantation 1991; 51 (03) 701-5.
12 Petric R, Freeman D, Wallace C. et al. Effect of cyclosporine on urinary prostinoid excretion, renal blood flow and glomerotubular function. Transplantation 1998; 45: 883-9.
13 Brown Z, Neild GH. Cyclosporine inhibits prostacyclin production by cultured human endothelial cells. Transplant Proc 1987; 19: 1178-80.
14 Hornung N, Degiannis D. Up-regulation by cyclosporine(CsA) of the in vitro release of soluble CD23 and of the in vitro production of IL-6 and IgM. Scand J Immunol 1993; 38 (03) 287-92.
15 Dalmon J, Laurent M, Courtois G. The human beta fibrinogen promoter contains a hepatocyte nuclear factor 1-dependent interleukin-6-responsive element. Mol Cell Biol 1993; 13 (02) 1183-93.
16 Malyszko J, Malyszko JS, Pawlak K. et al. The coagulo-lytic system and endothelial function in cyclosporine-treated kidney allograft recipients. Transplantation 1996; 62 (06) 828-30.
17 van der Dropel MA, Man in’t AJVeld, Levi M. et al. Beneficail effects of conversion from cyclosporine to azathioprine on fibrinolysis in renal transplant recipients. Arterioscler Thromb Vasc Biol 1999; 19: 1555-8.
18 Huser B, Lammle B, Landmann J. et al. Von Willebrand factor and factor VIII in renal transplant recipients under immunosuppression with cyclosporine and steroids. Se-quential measurements over 4 months in 17 patients. Clin Nephrol 1990; 34 (05) 214-22.
19 Brunkwall J, Bergqvist D, Bergentz SE. et al. Postoperative deep vein thrombosis after renal transplantation. Transplantation 1987; 43 (05) 647-9.
20 Gruber SA, Pescovitz MD, Simmons RL. et al. Thromboembolic complications in renal allograft recipients. Transplantation 1987; 44: 775-8.
21 Penny MJ, Nankivell BJ, Disney APS. et al. Renal graft thrombosis. Transplantation 1994; 58 (05) 565-9.
22 Gruber SA, Chavers B. Payne et al. allograft renal vascular thrombosis-lack of increase with cyclosporine immunosuppression. Transplantation 1989; 47 (03) 475-8.
23 Irish A. Renal allograft thrombosis: can thrombophilia explain the inexplicable?. Nephrol Dial Transplant 1999; 14: 2297-303.
24 Muraki T, Sasaki Y, Giddings JC. et al. Antithrombotic effect of FK506 versus prothrombotic effect of cyclosporine in vivo. Transplantation 1995; 60: 308-10.
25 Muraki T, Taka T, Noguchi T. et al. Effects of cyclosporine and FK506 on in vitro high shear-induced platelet reactivity in rat and human non-anticoagulated blood. Transplantation 1998; 65: 1132-4.
26 Freudenbereger R, Alexis J, Gass A. et al. Antithrombotic effect of FK506 vs cyclosporine in cardiac transplant recipients: potential implications in transplant arteriopathy. J Heart Lung Transplant 1999; 18: 1228-31.
27 Pirsch JD, Miller J, Deierhoi MH. et al. A comparison of Tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. Transplantation 1997; 63: 977-83.
28 Ozsoylu S, Strauss HS, Diamond LK. Effects of corticosteroids on coagulation of the blood. Nature 1962; 195: 1214-8.
29 Wagner DD. Cell biology of von Willebrand factor. Annu Rev Cell Biol 1990; 06: 217-20.
30 Laung WE. Glucocorticoids inhibit plasminogen activator production by endothelial cells. Thromb Haemost 1983; 50: 888-91.
31 Patrassi GM, Sartori MT, Rigotti P. et al. Coagulation and fibrinolysis during the first year of immunosuppressive treatment in renal transplantation : correspondence between hypercoagulable state and steroid therapy. Clin Appl Thrombosis Hemosta 1995; 01: 277-81.
32 Patrassi GM, Sartori MT, Rigotti P. et al. Reduced fibrinolytic potential one year after kidney transplantation : relationship to longterm steroid treatment. Transplantation 1995; 59: 1416-9.
33 Sartori MT, Patrassi GM, Rigotti P. et al. Improved fibrinolytic capacity after withdrawal of steroid immunosuppression in renal transplant recipients. Transplantation 2000; 69 (10) 2116-21.
34 Sartori MT, Rigotti P, Marchini F. et al. Plasma fibrinolytic capacity in renal transplant recipients : effect of steroid-free immunosuppression therapy. Transplantation 2003; 75 (07) 994-8.
35 Salmeron A, Sanchez FMadrid, Ursa RM. et al. A conformational epitope expressed upon association of CD-3 epsilon with either CD-3 delta or CD-3 gamma is the main target for recognition by anti-CD3 monoclonal antibodies. J immunol 1991; 147: 3047-52.
36 Pradier O, Marchant A, Abramowicz D. et al. Procoagulant effect of the OKT3 monoclonal antibody : involvement of tumor necrosis factor. Kidney Int 1992; 42: 1124-9.
37 Lozano M, Oppenheimer F, Cofan F. et al. Platelet procoagulant activity induced in vivo by munomorab-CD3 infusion in uremic patients. Thromb Res 2001; 104: 405-11.
38 Abramowicz D, Pradier O, Marchant A. et al. Induction of thromboses within renal grafts by high-dose prophylactic OKT3. Lancet 1992; 339: 777-8.
39 Abramowicz D, Pradier O, De Pauw L. et al. High-dose glucocorticoids increase the procoagulant effects of OKT3. Kidney 1994; 46 (06) 1596-602.
40 Shankar R, Bastani B, Salinas-Madrigal L. et al. Acute thrombosis of the renal transplant artery after a single dose of OKT3. Am J Nephrol 2001; 21 (02) 141-4.
41 Babinska A, Markell MS, Salifu MO. et al. Enhancement of human platelet aggregation and secretion induced by rapamycin. Nephrol Dial Transplant 1998; 13: 3153-9.
42 Data on file. Wyeth Ayerst Pharmaceuticals. 2002
43 Dunkelberg JC, Trotter JF, Wachs M. et al. Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications. Liver Transplant 2003; 09 (05) 463-8.
44 MacDonald AS. for the Rapamune® global Study Group. A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 2001; 71: 271-80.
45 Langer RM, Kahan BD. Sirolimus does not increase the risk for postoperative thromboembolic events among renal transplant recipients. Transplantation 2003; 76 (02) 318-23.
46 Klein BC, Bach D, Rehfeld I. et al. Influence of Mycophenolic Acid and FK-506 on human platelet activation in vitro. Kidney Blood Press Res 2000; 23: 119-24.
47 Malyszko J, Malyszko JS. Mysliwiec. Effects of Mycophenolate Mofetil and Mycophenolic Acid on platelet aggregation in vitro. Transplant Proc 2000; 32: 1347-9.
48 Cherney DZI, Zaltzman JS. Mycophenolate mofetil causing deep venous thrombosis in a renal transplant patient with factor V Leiden. Nephrol Dial Transplant 2001; 16: 1702-4.
49 Harris EN, Gharari AE, Boey ML. Anti-cardiolipin antibodies: detection by radioimmunoassay and association with thrombosis. Lancet 1983; 02: 12112-4.
50 Rysava R, Zabka J, Peregrin JH. et al. Acute renal failure due to bilateral renal artery thrombosis associated with primary antiphspholipid syndrome. Nephrol Dial Transplant 1998; 13: 2645-7.
51 Harris EN, Asherson RA, Hugues GR. Antiphospholipid antibodies: autoantibodies with a difference. Annu Rev Med 1988; 39: 261-4.
52 Khamashta MA, Harris EN, Gharavi AE. et al. Immune mediated mechanism for thrombosis: antiphospholipid antibody binding to platelet membranes. Ann Rheum Dis 1988; 47: 849-52.
53 Carreras LO, Defreyn G, Machin SJ. et al. Arterial thrombosis, intrauterine death and the lupus anticoagulant: detection of immunoglobulin interfering with prostacyclin formation. Lancet 1981; 01: 244-6.
54 Ruiz-Arguelles GJ, Ruiz-Arguelles A, Deleze M. et al. Acquired protein C deficiency in a patient with ptimary phospholipid syndrome: relationship to reactivity of anticardioplipin antibody with thrombomodulin. J Rheumatol 1989; 16: 381-4.
55 Ducloux D, Bourrinet E, Motte G. et al. Antiphospholipid antibodies as a risk factor for atherosclerotic events in renal transplant recipients. Kidney Int 2003; 64: 1065-70.
56 Ducloux D, Pellet E, Fournier V. et al. Prevalence and clinical significance of antiphospholipid antibodies in renal transplant recipients. Transplantation 1999; 67 (01) 90-3.
57 Knight RJ, Schanzer H, Rand JH. et al. Renal allograft thrombosis associated with the antiphospholipid antibody syndrome. Transplantation 1995; 60 (06) 614-5.
58 Mondragon-Rameriz G, Bochicchio T, Garcia-Torres R. et al. Recurrent renal thrombotic angiopathy after kidney transplantation in two patients with primary antiphospholipid syndrome. Clin Transplant 1994; 08: 93-6.
59 Wagenknecht DR, Becker DG, LeFor WM. et al. Antiphospholipid antibodies are a risk factor for early renal allograft failure. Transplantation 1999; 68 (02) 241-6.
60 Nygard O, Nordrehaug NE, Refsum H. et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997; 337 (04) 230-6.
61 Boushey CJ, Beresfor SSA, GS O. et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995; 274: 1049-57.
62 den Heijer M, Koster T, Blom HJ. et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Eng J Med 1996; 334: 759-62.
63 Ducloux D, Motte G, Chalopin JM. Homocysteine in renal disease. Clin Lab 2000; 46: 141-51.
64 Bostom AG, Gohh RY, Tsai MY. et al. Excess prevalence of fasting and PML hyper-homocysteinemia in stable renal transplant recipients. Arterioscler Thromb Vasc Biol 1997; 17: 1894-900.
65 Ducloux D, Motte G, Challier B. et al. Serum total homocysteine and cardiovascular disease occurrence in chronic stable renal transplant recipients: a prospective study. J Am Soc Nephrol 2000; 11: 134-7.
66 Ducloux D, Ruedin C, Gibey R. et al. Prevalence, determinants, and clinical significance of hyperhomocysteinemia in renal transplant recipients. Nephrol Dial Transplant 1998; 13: 2890-3.
67 Arnadottir M, Hultberg B, Vladov V. et al. Hyperhomocysteinemia in cyclosporinetreated renal transplant recipients. Transplantation 1996; 61: 509-12.
68 Cole DE, Ross HJ, Evrovski J. et al. Correlation between total homocysteine and cyclosporine concentrations in cardiac transplant recipients. Clin Chem 1998; 44 (11) 2307-12.
69 Bostom AG, Gohh RY, Beaulieu AJ. et al. Determinants of fasting total homocysteine levels among chronic stable renal transplant recipients. Transplantation 1999; 68 (02) 257-61.
70 Cattaneo M. Hyperhomocysteinemia, atherosclerosis and thrombosis. Thromb Haemost 1999; 81: 165-76.
71 Cattaneo M, Tsai MY, Bucciarelli P. et al. A common methylenetetrahydrofolate reductase gene (C667T) increase the risk for deep-vein thrombosis in patients with mutant factor V (factor V: Q506). Arterioscler Thromb Vasc Biol 1997; 17: 1662-6.
72 Abdelfatah A, Ducloux D, Toubin G. et al. Treatment of hyperhomocysteinemia with folic acid reduces oxidative stress in renal transplant recipients. Transplantation 2002; 73 (04) 663-5.
73 Marcucci R, Brunelli T, Giusti B. et al. The role of cysteine and homocysteine in venous and arterial thrombotic disease. Am J Clin Pathol 2001; 116 (01) 56-60.
74 Marcucci R, Fedi S, Brunelli T. et al. High cysteine levels in renal transplant recipients : relationship with hyperhomocysteinemia and 5,10-MTHFR polymorphism. Transplantation 2001; 71 (06) 746-51.
75 Thervet E, Anglicheau D, Legendre C. Recent issues concerning renal transplantation in systemic lupus erythematosus patients. Nephrol Dial Transplant 2001; 16: 12-4.
76 Stone JH, Amend WJ, Criswell LA. Antiphospholipid antibody syndrome in renal transplantation: occurrence of clinical events in 96 consecutive patients with systemic lupus erythematosus. Am J Kidney Dis 1999; 34 (06) 1040-7.
77 Radhakrishnan J, Williams GS, Appel GB. et al. Renal transplantation in anticardiolipin antibody-positive lupus erythematosus patients. Am J Kidney Dis 1994; 23 (02) 286-9.
78 Karassa FB, Konstandina A, Pappas P. et al. Late renal transplant thrombosis in a patient with systemic lupus erythematosus and antiphospholipid syndrome. Nephrol Dial Transplant 1999; 14: 472-4.
79 Friedman GS, Wik D, Silva L. et al. Allograft loss in renal transplant recipients with Fabry’s disease and activated protein C resistance. Transplantation 2000; 69 (10) 2099-2102.
80 Chang HS, Ro LS, Chen ST. Fabry’s disease: report of a case. J Formosan Medical Association 1995; 94 (06) 346-50.
81 Hirshfield G, Collier JD, Brown K. et al. Donor factor V Leiden mutation and vascular thrombosis following liver transplantation. Liver Transplant Surg 1998; 04 (01) 58-9.
82 Kanfer A. Thromboses and Hemostasis disorders in nephrotic syndrome. Nophrologie 1992; 13: 347-59.
83 Mannucci PM, Valsecchi C, Bottasso B. et al. High plasma levels of protein C activity and antigen in the nephrotic syndrome. Thromb Haemost 1986; 55: 31-3.
84 Sagripanti A, Barsotti G. Hypercoagulability, intraglomerular coagulation, and thromboembolism in nephrotic syndrome. Nephron 1995; 70: 271-81.
85 Colle JP, Mishal Z, Lesty C. et al. Abnormal fibrin clot architecture in nephrotic patients is related to hypofibrinolysis: influence of plasma biochemical modifications: a possible mechanism for the high thrombotic tendency?. Thromb Haemost 1999; 82: 1482-9.
86 Biesenbach G, Janko O, Hubmann R. et al. The incidence of thrombovenous and thromboembolic complications in kidney transplant patients with recurrent glomerulonephritis is dependent on the occurrence of severe proteinuria. Clin Nephrol 2000; 54 (05) 382-7.
87 Bertoli M, Gasparotto ML, Vertolli U. et al. Does hypercoagulability exist in CAPD patients?. Perit Dial Bull 1984; 04: 237-9.
88 Kobayashi M, Yorioka N, Yamakido M. Hypercoagulability and secondary hyperfibrinolysis may be related to abnormal lipid metabolism in patients treated with continuous ambulatory peritoneal dialysis. Nephron 1997; 76: 56-61.
89 Van Der Vliet JA, Barendregt WB, Hoitsma AJ. et al. Increased incidence of renal allograft thrombosis after continuous ambulatory peritoneal dialysis. Clin Transplant 1996; 10: 51-4.
90 Ojo AO, Hanson JA, Wolfe RA. et al. Dialysis modality and and the risk of allograft thrombosis in adult renal transplant recipients. Kidney Int 1999; 55: 1952-60.
91 Snyder JJ, Kasiske BL, Gilbertson DT. et al. A comparison of transplant outcomes in peritoneal and hemodialysis patients. Kidney Int 2002; 62: 1423-30.
92 Sumrani NB, Daskalakis P, Miles AM. et al. Erythrocytosis after renal transplantation: a prospective analysis. ASAIO J 1993; 39: 51-5.
93 Qunibi WY, Barri Y, Devol A. et al. Factors predictive of post-transplant erythrocytosis. Kidney Int 1991; 40: 1153-9.
94 Kahan BD, Ponticelli C, Aroldi A. et al. Musculoskeletal, ocular and hematological complications. In: Kahan BD, Ponticelli C. eds. Principles and practice of renal transplantation. Martin Dunitz; London: 2000: 693-719.
95 Wickre CG, Norman DJ, Bennison A. et al. Postrenal transplant erythrocytosis : a review of 53 patients. Kidney Int 1983; 23: 731-7.
96 Hestin D, Legrand E, Mertes M. et al. Polycythemia after kidney transplantation. Presse Med 1992; 21 (41) 1973-4.
97 EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation. Section IV: long-term management of the transplant recipient. IV.9.3 Haematological complications. Erythrocytosis. Nephrol Dial Transpl 2002; 17 (Suppl. 04) 49-50.
98 Montanaro D, Groupuzzo M, Boscutti G. et al. Long-term therapy for postrenal transplant erythrocytosis with ACE inhibitors: efficacy, safety, and action mechanisms. Clin Nephrol 2000; 53 (04) suppl 47-51.
99 Julian BA, Brantley RRJ, Barker CV. et al. Losartan, an angiotensin II type 1 receptor antagonist lowers hematocrit in post-transplant erythrocytosis. J Am Soc Nephrol 1998; 09: 1104-8.
100 Bakris GL, Sauter ER, Hussey JL. et al. Effects of theophylline on erythropoietin production in normal subjects and in patients with erythrocytosis after renal transplantation. N Eng J Med 1990; 323: 86-90.
101 Bruggeman CA, Debie WN, Muller AD. et al. Cytomegalovirus alters von Willebrand factor content in human endothelial cells. Thromb Haemost 1988; 59: 264-70.
102 Van Dam-Mieras MCE, Muller AD, Van Hinsbergh VWM. et al. The procoagulant response of cytomegalovirus infected endothelial cells. Thromb Haemost 1992; 68: 364.
103 Toyoda M, Galfayan K, Galera OA. et al. CMV infection induces anti-endothelial cell antibodies in cardiac and renal graft recipients. Transplant Immun 1997; 05: 104-11.
104 Neumann FJ, Kastrati A, Miethke T. et al. Previous cytomegalovirus infection and risk of coronary thrombotic events after stent placement. Circulation 2000; 101: 11-3.
105 Abgueguen P, Delbos V, Chennebault JM. et al. Vascular thrombosis and acute cytomegalovirus infection in immunocompetent patients: report of 2 cases and literature review. Clin Infect Dis 2003; 36: 134-9.
106 Muldoon J, O’Riordan K, Rao S. et al. Ischemic colitis secondary to venous thrombosis. Transplantation 1996; 61 (11) 1651-3.