TITLE:
Role of hypercoagulability in patients with thrombosis of dialysis access.
REVIEW:
Maintaining vascular access for haemodialysis is an issue of considerable importance
for patients with end stage renal disease and the healthcare resources. Studies have
variously estimated the annual cost of creating and maintaining dialysis vascular
access in US to be close to $ 1 billion (1-2).
Many studies in past have clearly shown that only 60%- 80% of the access sites
remain patent after 12 months and approximately 50%- 70% after 24 months. (3-5) It
is also widely appreciated that grafts are more likely to thrombose compared to native
fistulas. (3, 6-7) Primary native fistulae have lower rates of thrombosis with reported
rates varying from 10% to 35% per year (mean 28%). Polytetrafluoroethylene (PTFE)
grafts have a graft thrombosis rate that varies from 30 to 65% per year. (5, 8-10)
Thrombosis has been identified as the most common cause of vascular access failure
representing 80-85% of all complications and failures. (4-5, 10-15) The causes and
risk factors for vascular access thrombosis (VAT) are poorly understood. It is
however accepted that low blood flow through the graft due either to stenosis or
neointimal hyperplasia at the site of venous anastomosis is the most important
contributory factor. (5, 16-18) It is also known that whereas some patients never
experience any problems with vascular access certain others are plagued with
recurrent access thrombosis. (19).
In a significant proportion of patients with thrombosis of their vascular access, no
attributable anatomical cause is found. It is believed that hypercoagulable states may
contribute to thrombosis of the vascular access in such patients. Many past studies
have investigated hypercoagulability as a cause of vascular access thrombosis.
Various studies have studied different substances but most have been inconclusive.
Various factors, which have been thought to play a role in the thrombosis of vascular
access, are listed below along with a brief review of currently available literature on
their role in the dialysis population.
Anticardiolipin antibody (ACA) is strongly associated with venous and arterial
thrombosis in patients with Systemic Lupus Erythematosus and related disorders. (2022) Several studies have confirmed the presence of antiphospholipid antibody in
patients with ESRD on haemodialysis. (23-27) There are conflicting reports of
association between elevated titres of ACA and vascular access thrombosis in patients
on haemodialysis. (23, 28-30) Whereas some studies have shown an association
between access thrombosis and raised Immunoglobulin G-ACA titre (22, 28-29, 3132), others have failed to confirm such an association (6,23, 26-27, 33)
Antibody to bovine thrombin: Topical bovine thrombin preparations are often used
to promote haemostasis during vascular surgery, including dialysis access placement.
(34-35) These patients can develop antibody to topical bovine thrombin. (36) Certain
studies have showed an association between antibodies to topical bovine thrombin
preparation and PTFE graft thrombosis. (7, 19) In one study elevated antibody levels
to topical bovine thrombin were present in 30.7% patients. Patients with PTFE grafts
or cuffed catheters were significantly more likely to have elevated antibody levels
compared to patients with arteriovenous fistula (AVF). In this study, patients with
elevated antibody levels to topical bovine thrombin were significantly more likely to
have experienced prior access thrombosis than patients with normal antibody levels
but this was only seen in patients with PTFE grafts and similar phenomenon was not
observed in patients with fistulas or cuffed catheters. (7)
The possible mechanisms by which this antibody may lead to a hypercoagulable state
are interference with antithrombin III activity (37-38) and activation of protein C. (39)
In study by O’Shea et al (7), 32% patients with recurrent graft thrombosis had
elevated concentrations of antibody to topical bovine thrombin.
Exposure to topical bovine thrombin preparations has been showed by several authors
to induce elevated antibodies to a wide range of proteins like prothrombin, factor V,
fibrinogen and B2 glycoprotein, protein C. (39, 40-43) Autoantibodies to these plasma
proteins have been associated with an increased thrombotic risk in certain patients’
subsets. (34, 44-47) In study by Sands et al (34) over 96% of the patients with
antibodies to a bovine thrombin preparation had elevated antibody levels to one or
more of these proteins. 58% of the dialysis patients (45% for AVF and 75% for grafts)
had antibody to one or more of the plasma proteins. Authors concluded that patients
with PTFE grafts and antibody to one or more of these substances had more than 10
times the incidence of prior thrombosis and over six fold higher thrombosis rates. The
same phenomenon was not observed in patients with AVF. The sample size was small
to study the effect of each antibody independently. This study just showed an
association between the antibody to topical bovine thrombin and graft thrombosis and
doesn’t necessarily establish a causative role.
Hyperhomocysteinemia has been reported to be associated with vascular thrombosis
in patients with normal renal function. (48) Patients with chronic renal failure have
homocysteine levels much higher than patients with normal renal function. (8, 49-50)
Though few studies have failed to confirm any relationship between elevated total
plasma homocysteine and vascular access thrombosis (6,49,51), certain others have
shown hyperhomocysteinemia to be associated with cardiovascular events including
VAT. (52) Another study (7) showed that 80.6% of patients with recurrent graft
thrombosis had elevated homocysteine concentration.
Anti platelet factor 4/heparin antibody:
Heparin induced thrombocytopenia is a side effect of heparin therapy and may lead to
paradoxical thrombotic events. (53-54) The condition seems to be caused by
antibodies to heparin/platelet factor 4 (PF4) complex antigen. (53) A prevalence of
antiheparin/PF4 antibodies (Hab) of 0-3.9% has been reported in dialysis patients.
(55-58) Heparin also causes a 24-fold increase in Tissue Factor Plasma Inhibitor
(TFPI) plasma level. (59) TFPI is a protease inhibitor with strong anticoagulant
properties. In the study by Luzzatto et al (53), six out of fifty patients studied were
thrombocytopenic but none showed bleeding or thrombotic manifestations. Basal
TFPI in dialysis patients was significantly higher than in controls. 12% patients on
chronic dialysis in this study had anti heparin /PF4 antibodies, with a higher
prevalence among females and patients treated with cuprophane containing
membranes.
In study by O’Shea et al (7) 18% of the patients with recurrent graft thrombosis had
heparin induced antibodies. In another study (60) Only 1 out of 88 (13%)
haemodialysis patients tested weakly positive for anti PF4/heparin antibodies and this
was not associated with thrombocytopenia or vascular access thrombosis.
Fibrinogen
Plasma fibrinogen is previously known to be a risk factor for venous thrombosis and
cardiovascular disease in patients with chronic renal failure. (61-62) Song et al (63)
found fibrinogen level >460mg/dl was significantly associated with poor vascular
access survival. Another study by De Marchi et al (64) did not find fibrinogen to be a
risk factor for vascular access thrombosis. In study by O’Shea et al (7), 63% with
recurrent dialysis access graft thrombosis had elevated fibrinogen concentration
Song et al (63) found older age, PTFE graft, erythropoeitin therapy, higher
haematocrit, lower albumin and higher fibrinogen levels to be significantly associated
with vascular access failure whereas gender, diabetes mellitus, total cholesterol and
platelet count were not. A fibrinogen level of 460 mg/dl proved to be the cut off point
with the most predictive value (Sensitivity-61% and Specificity-67%) in this study.
Anti endothelial cell antibodies have been described in various immune and nonimmune conditions. They have been correlated with venous thrombosis in primary
antiphospholipid syndrome (65) and have also been seen in haemodialysis population.
(66) Another study found that levels of antibody to human umbilical vein endothelial
cells but not with other endothelial cell line were significantly higher in haemodialysis
patients with vascular access thrombosis (VAT) compared with patients with no VAT.
(67)
Anti modified Low Density Lipoprotein (LDL) antibody:
Antibodies to modified LDL have been seen in patients with atherosclerosis. (68)
These antibodies have been linked to thrombosis in patients with antiphospholipid
syndrome and have also been seen in haemodialysis population. (69) In study by
George et al (67) higher levels of antibodies to modified LDL were seen in
hemodialysis patients, no correlation was observed with thromboembolic events.
Other factors that have variously been studied by different researchers are C reactive
protein measured, antithrombin III activity, Factor VII, Factor VIII, Erythropoietin
therapy, thermolabile methylenetetrahydrofolate reductase, 3’-untranslated
prothrombin gene polymorphism, factor V Leiden, IgG anti CMV antibody,
Parathyroid hormone level and anti β2 glycoprotein I antibody (7, 67, 70, 71)
REFERENCES:
1. Besarab A, Dorrell S, Moritz M, et al. What can be done to preserve vascular
access for dialysis? Semin Dial 1991; 4: 155-6.
2. US Renal Data System. The economic cost of ESRD, vascular access procedures,
and Medicare spending for alternative modalities of treatment. Am J Kidney Dis
1997; 30(suppl): S160-77.
3. Song IS, Yang WS, Kim SB, Lee JH, Kwon TW, Park JS. Association of plasma
fibrinogen concentration with vascular access failure in hemodialysis patients.
Nephrol Dial Transplant 1999; 14: 137-41.
4. Munda R, First R, Alexander JW, Linnemann CC, Fidler JP, Kittur D.
Polytetrafluoroethylene graft survival in hemodialysis. JAMA 1983; 249: 219-222.
5. Winsett OE, Wolma FJ. Complications of vascular access for hemodialysis. South
Med J 1985; 78: 513-17.
6. Manns BJ, Burgess ED, Parsons HG, Schaefer JP, Hyndman ME, Scott-D NW.
Hyperhomocysteinemia, anticardiolipin antibody status, and risk for vascular access
thrombosis in hemodialysis patients. Kidney International 1999; 55: 315-20.
7. O’Shea SI, Lawson JH, Reddan D, Murphy M, Ortel TL. Hypercoagulable states
and antithrombotic strategies in recurrent vascular access site thrombosis. J Vasc Surg
2003; 38: 541-8.
8. Sirrs S, Duncan L, Djurdejv O, Nussbaumer G, Ganz G, Frohlich J, Levin A.
Homocysteine and vascular access complications in haemodialysis patients: insights
into a complex metabolic relationship. Nephrol Dial Transplant 1999: 14: 738-43.
9. Churchill DN, Taylor DW, Cook RJ, et al. Canadian Hemodialysis Morbidity
Study. Am J Kidney Dis 1992; 19: 214-34.
10. Fan PY, Schwab SJ. Vascular access: concept for the 1990s. J Am Soc Nephrol
1992; 3: 1-11.
11. NKF-DOQI clinical practice guidelines for vascular access. Am J Kidney Disease
1997; 30: S150-189.
12. Palder SB, Kirkman RL, Whittenmore AD, et al. Vascular access for
hemodialysis. Ann Surg 1985; 202: 235-9.
13. Raju S. PTFE grafts for hemodialysis access: techniques for insertion and
management of complications. Ann Surg 1987; 206: 666-73.
14. Schwab SJ, Harrington JT, Singh A, et al. Vascular access for hemodialysis.
Kidney Int 1999; 55: 2078-90.
15. Albers FJ. Causes of hemodialysis access failure. Adv Renal Replace
Ther 1994; 1: 107-18.
16. Sreedhara R, Himmelfarb J, Lazarus JM, Hakim RM. Antiplatelet therapy
Antiplatelet therapy in graft thrombosis: Results of a prospective, randomized,
double-blind study. Kidney Int 1994; 45: 1477-1483.
17. Kanterman RY, Vesely TM, Pilgram TK, et al. Dialysis access grafts: anatomic
location of venous stenosis and results of angioplasty. Radiology
1995; 95: 135-9.
18. Glanz S, Bashist B, Gordon DH, et al. Angiography of upper extremity access
fistulas for dialysis. Radiology 1982; 143: 45-52.
19. Sands JJ, Nudo SA, Ashford RG, Moore KD, Ortel TL. Antibodies to topical
bovine thrombin correlate with access thrombosis. Am J Kidney Dis 2000; 35(5);
796-801.
20. Harris EN, Chan JKH, Asherson RA, Aber VR, Gharavi AE, Hughes GRV.
Thrombosis, recurrent fetal loss, and thrombocytopenia: Predictive value of
anticardiolipin antibody test. Arch Intern med 1986; 146: 2153-6.
21. Love PE, Santoro SA. Antiphospholipid antibodies: Anticardiolipin and the lupus
anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders:
Prevalence and clinical significance. Ann Intern Med 1990; 112: 682-98.
22. Kalunian KC, Peter JB, Middlekauff HR, Sayre J, Ando DG, Mangotich M, Hahn
BH. Clinical significance of a single test for anticardiolipin antibodies in patients with
systemic lupus erythematosus. Am J Med 1988; 85: 602-8.
23. Sitter T, Schiffl H. Anticardiolipin antibodies in patients on regular hemodialysis:
an epiphenomenon? Nephron 1992; 64: 655-6.
24. Quereda C, Pardo A, Lamas S, Orofino L, Garcia-Avello A, Marcen R, Teruel JL,
Ortuno J. Lupus like in vitro anticoagulant activity in end stage renal disease.
Nephron 1988; 49: 39-44.
25. Gronhagen-Riska C, Teppo AM, Helentera A, Honkanen E, Julkunen H. Raised
concentration of antibodies to cardiolipin in patients receiving dialysis. BMJ 1990;
300: 1696-7.
26. Garcia-Martin F, DE Arriba G, Carrascosa T, Moldenhauer F, Martin-Escobar E,
Val J, Saiz F. anticardiolipin antibodies and lupus anticoagulant in end stage renal
disease. Nephrol Dial Transplant 1991; 6: 543-47.
27. Sitter T, Spannagl M, Schiffl H. Anticardiolipin antibodies and lupus
anticoagulant in patients treated with different methods of renal replacement therapy
in comparison to patients with systemic lupus erythematosus. Ann Hematol 1992; 65:
79-82.
28. Prakash R, Miller CC, Suki WN. Anticardiolipin antibody in patients on
maintenance hemodialysis and its association with recurrent arteriovenous graft
thrombosis. Am J Kidney Dis 1995; 26: 347-52.
29. Prieto LN, Suki WN. Frequent hemodialysis graft thrombosis: Association with
antiphospholipid antibodies. Am J Kidney Dis 1994; 23: 587-90.
30. Brunet P, Aillaud MF, San Marco M, et al. Antiphospholipids in hemodialysis
patients: relationship between lupus anticoagulant and thrombosis. Kidney Int 1995;
48: 794-800.
31. Valeri A, Joseph R, Radhakrishnan J. A large prospective survey of anticardiolipin antibodies in chronic hemodialysis patients. Clin Nephrol 1999; 51:11621.
32. Page B, Yazbeck F, Zingraff J, Zins B, Bourquelot P. Clotting of vascular access
in dialysis patients associated to anticardiolipin antibodies. Nephrol Dial Transplant
1992(abstr); 7: 733.
33. Chew SL, Lins RL, Daelemans R, Zachee P, De Clerck LS, Vermylen J. Are
antiphospholipid antibodies clinically relevant in dialysis patients? Nephrol Dial
Transplant 1992; 14: 1194-98.
34. Sands JJ, Nudo SA, Moore KD, Ortel TL. Antibodies to Prothrombin, Factor V
and 2-Glycoprotein I and vascular access thrombosis. ASAIO Journal 2001; 47: 507510.
35. Shireman PK, Greisler HP. Fibrin sealant in vascular surgery: A review. J Long
Term Effects Med Implants 1998; 8: 117-32.
36. Banninger H, Hardegger T, Tobler A, Barth A, Schupback P, Reinhart W,
Lammle B, Furlan M. Fibrin glue in surgery: Frequent development of inhibitors of
bovine thrombin and human factor V. Br J Haematol 1993; 85: 528-532.
37. Ortel TL, Neal MC, Thames EH, et al. Immunologic impact and clinical outcomes after
surgical exposure to bovine thrombin. Ann Surg 2001; 233: 88-96.
38. Lawson JH, Pennell BJ, Olson JD, Mann KG. Isolation and characterization of an
acquired Antithrombin antibody. Blood 1990; 76: 2249-2257.
39. Chouhan VD, De la Cadena RA, Nagaswami C, Weisel JW. Kajani M, Rao AK.
Simultaneous occurrence of human antibodies directed against fibrinogen, thrombin,
and factor V following exposure to bovine thrombin: Effects on blood coagulation,
protein C activation and platelet function. Thromb Haemost 1997; 77: 343-349.
40. Ortel TL, Charles LA, Keller FG, et al. Topical thrombin and acquired
coagulation factor inhibitors: Clinical spectrum and laboratory diagnosis. Am J
Hematol 1994; 45: 128-135.
41. Cmolik BL, Spero JA, Magovern GJ, Clark RE, Reid C. Redo cardiac surgery:
Late bleeding complications from topical thrombin induced factor V deficiency. J
Thorac Cardiovasc Surg 1993; 105: 222-228.
42. Rapaport SI, Zivelin A, Minow RA, Hunter CS, Donnelly K. Clinical significance
of antibodies to bovine and human thrombin and factor V after surgical use of bovine
thrombin. Am J Clin Pathol 1992; 97: 84-91.
43. Ortel TL, Moore KD, Neal MC, Thames EH, Lawson JH. Anticardiolipin
antibodies developing after bovine thrombin exposure during surgery are associated
with antibodies to bovine factors II and V. Lupus 1998 (abstr); 7: S199A.
44. Vaarala O, Puurunen M, Manttari M, Manninnen V, Aho K, Palosuo T.
Antibodies to prothrombin imply a risk of myocardial infarction in middle aged men.
Thromb Haemost 1996; 75: 456-459.
45. Kapur A, Kelsey PR, Isaacs PET. Factor V inhibitor in thrombosis. Am J Hematol
1993; 42: 384-388.
46. Kamphuisen PW, Haan J, Rosekrans PCM, Van der meer FJM. Deep vein
thrombosis and coumarin skin necrosis associated with a factor V inhibitor with lupus
like features. Am J Hematol 1998; 57: 176-178.
47. Zivelin A, Gitel S, Griffin JH, Xu X, Fernandez JA, Martinowitz U, Cohen Y,
Halkin H, Seligsohn U, Inbal A. Extensive venous and arterial thrombosis associated
with an inhibitor to activated protein C. Blood 1999; 94: 895-901.
48. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative
assessment of plasma homocysteine as a risk factor for vascular disease. JAMA1995;
274: 1049-1057.
49. Ducloux D, Pascal B, Jamali M, Gibey R, Chalopin J-M. Is
hyperhomocysteinemia is a risk factor for recurrent vascular access thrombosis in
haemodialysis patients? Nephrol Dial Transplant 1997; 12: 2037.
50. Bostom AG, Lathrop L. Hyperhomocysteinemia in end stage renal disease:
prevalence, etiology, and potential relationship to arteriosclerotic outcomes. Kidney
Int 1997; 52: 10-20.
51. Bowden RG, Wyatt FB, Wilson R. Homocysteine and vascular access thrombosis
in end stage renal disease patients: A retrospective study. J Nephrol 2002; 15: 666-70.
52. Moustapha A, Naso A, Nahlawi M et al. Prospective study of
hyperhomocysteinemia as an adverse cardiovascular risk factor in end stage renal
disease. Circulation 1998; 97: 138-141.
53. Luzzatto G, Bertoli M, Cella G, Fabris F, Zaia B, Girolami. Platelet count, antiheparin/platelet factor 4 antibodies and tissue factor pathway inhibitor plasma antigen
level in chronic dialysis. Thromb Res 1998; 89: 115-122.
54. Patrassi GM, Luzzatto G. Heparin-induced thrombocytopenia with thrombosis of
the aorta, iliac arteries and right axillary vein successfully treated by low-molecular
weight heparin. Acta Haematol 1994; 91: 55-6.
55. De Sancho M, Lema MG, Amiral J, Rand J. Frequency of antibodies direct
against heparin-platelet factor 4 in patients exposed to heparin through chronic
haemodialysis. Thromb Haemost 1996; 75: 695-696.
56. Boon DMS, Van Vliet HHDM, Zietse R, Kappers-Klunne MC. The presence of
antibodies against a PF4/heparin complex in patients on haemodialysis. Thromb
Haemost 1996; 76: 480.
57. Yamamoto S, Koide M, Matsuo M, Suzuki S, Ohtaka M, Saika S, Matsuo T.
Heparin induced thrombocytopenia in hemodialysis patients. Am J Kidney Dis 1996;
28: 82-5.
58. Greinacher A, Zinn S, Wizemann, Birk UW. Heparin induced antibodies as a risk
factor for thromboembolism and haemorrhage in patients undergoing chronic
haemodialysis. The Lancet 1996; 348:764.
59. Broze GJ. Tissue factor pathway inhibitor. Thromb Haemost 1995; 4: 90-93.
60. O’shea SI, Sands JJ, Nudo SA, Ortel TL. Frequency of ant heparin-platelet factor
4 antibodies in hemodialysis patients and correlation with recurrent vascular access
thrombosis. Am J Hematology 2002; 69: 72-73.
61. Kamphuisen PW, Eikenboom JC, Vos HL, et al. Increased levels of factor VIII
and fibrinogen in patients with venous thrombosis are not caused by acute phase
reactions. Thromb Haemost 1999; 81: 680-683.
62. Tomura S, Nakamura Y, Doi M, et al. Fibrinogen, coagulation factor VII, tissue
plasminogen activator, plasminogen activator inhibitor-1, and lipid as cardiovascular
risk factors in chronic hemodialysis and continuous ambulatory peritoneal dialysis
patients. Am J Kidney Dis 1996; 27: 848-854.
63 Song IS, Yang WS, Kim SB, et al. Association of plasma fibrinogen concentration
with vascular access failure in hemodialysis patients. Nephrol Dial Transplant 1999;
14: 137-141.
64. De Marchi S, Falleti E, Giacomello R, et al. Risk factors for vascular disease and
arteriovenous fistula dysfunction in hemodialysis patients. J Am Soc Nephrol 1996; 7:
1169-1177.
65. McCrae KR, DeMichele A, Samuels P, Roth D, Kuo A, Meng QH, Rauch J, Cines
DB. Detection of endothelial cell reactive immunoglobulin in patients with antiphospholipid antibodies. Br J Haematol 1991; 79: 595-606.
66. Direskeneli H, Ozgun S, Ozener C, Lawrence R, Erman M, Sarsmaz N, Akoglu E.
Anti-lymphocyte, anti-monocyte and anti-endothelial cell antibodies in chronic
haemodialysis patients. Nephrol Dial Transplant 1992; 7: 422-426.
67. George J, Aron A, Levy Y, Gilburd B, Ben-David A, Renaudineau Y, ZonanaNachach A, Youinou P, Harats D, Shoenfeld Y. Anti-cardiolipin, anti-endothelial-cell
and anti-malondialdehyde-LDL antibodies in uremic patients undergoing
hemodialysis: Relationship with vascular access thrombosis and thromboembolic
events. Hum Antibodies 1999; 9: 125-131.
68. Salonen JT, Yia-Herttuala S, Yamamoto R, Butler S, Korpela H, Salonen R,
Nyyssonen K, Paliniski W, Witztum JL. Antibodies against oxidized LDL and the
progression of carotid Atherosclerosis. Lancet 1992; 339: 883-887.
69. Maggi E, Bellazzi R, Gazo A, Seccia M, Bellomo G. Autoantibodies against
oxidatively modified LDL in uremic patients undergoing dialysis. Kidney Int 1994;
46: 869-876.
70. Braskin E, Duman O, Besbas N, Ozen S. Hypercoagulability in a haemodialysis
patient: Are elevations in factor VII and VIII effective? Nephron 1999; 83: 180.
71. Grandaliano G, Teutonico A, Allegretti A, Losappio R, Mancini A, Gesualdo L,
Schena FP, Pertosa G. The role of hyperparathyroidism, erythropoeitin therapy, and
CMV infection in the failure of arteriovenous fistula in hemodialysis. Kidney
International 2003; 64: 715-719.