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• W1991996564 abstract "Heparin-induced thrombocytopenia is a serious complication of heparin therapy that can lead to thromboembolism, cardiovascular events, and death. Hemodialysis patients are repeatedly exposed to heparin and are at risk for developing antibodies to the platelet factor 4-heparin (PF4-H) complex. We sought to determine the association between PF4-H antibodies and mortality in a prospective cohort of 419 asymptomatic hemodialysis patients. Pre-dialysis blood samples were screened for nonspecific PF4-H antibodies, and all positive and indeterminate samples were subsequently tested using immunoglobulin (Ig)G-specific PF4-H and platelet serotonin-release assays. During a median follow-up of 2.5 years there were 129 all-cause deaths. After controlling for potential confounding variables, the relative risk of death was significantly increased for patients with IgG-specific PF4-H antibodies and further elevated with an indeterminate serotonin-release assay. Our study suggests that IgG-specific PF4-H antibody formation is associated with increased mortality in hemodialysis patients. Heparin-induced thrombocytopenia is a serious complication of heparin therapy that can lead to thromboembolism, cardiovascular events, and death. Hemodialysis patients are repeatedly exposed to heparin and are at risk for developing antibodies to the platelet factor 4-heparin (PF4-H) complex. We sought to determine the association between PF4-H antibodies and mortality in a prospective cohort of 419 asymptomatic hemodialysis patients. Pre-dialysis blood samples were screened for nonspecific PF4-H antibodies, and all positive and indeterminate samples were subsequently tested using immunoglobulin (Ig)G-specific PF4-H and platelet serotonin-release assays. During a median follow-up of 2.5 years there were 129 all-cause deaths. After controlling for potential confounding variables, the relative risk of death was significantly increased for patients with IgG-specific PF4-H antibodies and further elevated with an indeterminate serotonin-release assay. Our study suggests that IgG-specific PF4-H antibody formation is associated with increased mortality in hemodialysis patients. Heparin-induced thrombocytopenia is a serious complication of systemic heparin therapy. Exposure to heparin can trigger an immune response resulting in the production of antibodies against the platelet factor 4-heparin (PF4-H) complex.1.Vun C.M. Evans S. Chesterman C.N. Anti-PF4-heparin immunoglobulin G is the major class of heparin-induced thrombocytopenia antibody: findings of an enzyme-linked immunofiltration assay using membrane-bound hPF4-heparin.Br J Haematol. 2001; 112: 69-75Crossref PubMed Scopus (10) Google Scholar, 2.Mureebe L. Silver D. Heparin-induced thrombocytopenia: pathophysiology and management.Vasc Endovascular Surg. 2002; 36: 163-170Crossref PubMed Scopus (31) Google Scholar, 3.Chong B.H. Pitney W.R. Castaldi P.A. Heparin-induced thrombocytopenia: association of thrombotic complications with heparin-dependent IgG antibody that induces thromboxane synthesis in platelet aggregation.Lancet. 1982; 2: 1246-1249Abstract PubMed Scopus (221) Google Scholar Immunoglobulin (Ig)G PF4-H antibodies have been associated with the development of both venous and arterial thrombosis. Hemodialysis patients are repeatedly exposed to heparin and are at risk for developing PF4-H antibodies. The morbidity and mortality of patients on chronic hemodialysis continues to be substantial, primarily because of vascular occlusive disease. Variables contributing to the pathophysiology underlying this vasculopathy are not well established.4.Wanner C. Zimmermann J. Quaschning T. Galle J. Inflammation, dyslipidemia and vascular risk factors in hemodialysis patients.Kidney Int Suppl. 1997; 62: S53-S55PubMed Google Scholar,5.London G.M. Marchais S.J. Guerin A.P. et al.Inflammation, arteriosclerosis, and cardiovascular therapy in hemodialysis patients.Kidney Int Suppl. 2003; 84: S88-S93Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar Antibodies to the PF4-H complex, without clinical manifestations of heparin-induced thrombocytopenia, have been associated with both arterial and venous thrombosis.6.Boon D.M. van Vliet H.H. Zietse R. Kappers-Klunne M.C. The presence of antibodies against a PF4-heparin complex in patients on haemodialysis.Thromb Haemost. 1996; 76: 480PubMed Google Scholar, 7.Sitter T. Spannagl M. Banas B. Schiffl H. Prevalence of heparin-induced PF4-heparin antibodies in hemodialysis patients.Nephron. 1998; 79: 245-246Crossref PubMed Scopus (40) Google Scholar, 8.Greinacher A. Zinn S. Wizemann S.Z. Birk U.W. Heparin-induced antibodies as a risk factor for thromboembolism and hemorrhage in patients undergoing chronic haemodialysis.Lancet. 1996; 348: 764Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 9.Luzzatto G. Bertoli M. Cella G. et al.Platelet count, anti-heparin/platelet factor 4 antibodies and tissue factor pathway inhibitor plasma antigen level in chronic dialysis.Thromb Res. 1998; 89: 115-122Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 10.Yu A. Jacobson S.H. Bygden A. Egberg N. The presence of heparin-platelet factor 4 antibodies as a marker of hypercoagulability during hemodialysis.Clin Chem Lab Med. 2002; 40: 21-26Crossref PubMed Scopus (17) Google Scholar, 11.Mattioli A.V. Bonetti L. Sternieri S. Mattioli G. Heparin-induced thrombocytopenia in patients treated with unfractionated heparin: prevalence of thrombosis in a 1 year follow-up.Ital Heart J. 2000; 1: 39-42PubMed Google Scholar, 12.Nakamoto H. Shimada Y. Kanno T. et al.Role of platelet factor 4-heparin complex antibody (HIT antibody) in the pathogenesis of thrombotic episodes in patients on hemodialysis.Hemodial Int. 2005; 9: S2-S7Crossref PubMed Scopus (23) Google Scholar, 13.Mureebe L. Coats R.D. Silliman W.R. et al.Heparin-associated antiplatelet antibodies increase morbidity and mortality in hemodialysis patients.Surgery. 2004; 136: 848-853Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 14.Pena de la Vega L. Miller R.S. Benda M.M. et al.Association of heparin-dependent antibodies and adverse outcomes in hemodialysis patients: a Population-Based Study.Mayo Clin Proc. 2005; 80: 995-1000Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar In addition, PF4-H antibodies in asymptomatic patients have been suggested as a possible cause of increased morbidity and mortality in patients on maintenance hemodialysis.13.Mureebe L. Coats R.D. Silliman W.R. et al.Heparin-associated antiplatelet antibodies increase morbidity and mortality in hemodialysis patients.Surgery. 2004; 136: 848-853Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar,14.Pena de la Vega L. Miller R.S. Benda M.M. et al.Association of heparin-dependent antibodies and adverse outcomes in hemodialysis patients: a Population-Based Study.Mayo Clin Proc. 2005; 80: 995-1000Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar However, these studies were limited by small sample sizes and important confounding variables were not controlled for in the analyses. Accordingly, the objective of this study was to examine the association between PF4-H antibodies in asymptomatic patients and survival in a large sample of hemodialysis patients while simultaneously controlling for other potential risk factors of mortality. Of the 419 patients in this analysis, 35 (8.4%) had an indeterminate result and 54 (12.9%) had a positive result with the screening PF4-H ELISA assay. The IgG-specific PF4-H ELISA assay was positive in 9 of 89 (10.1%) patients with a positive or indeterminate screening PF4-H ELISA result. One patient with indeterminate screening PF4-H ELISA result had a positive IgG-specific PF4-H ELISA assay. The serotonin release assay (SRA) screening assay was positive in 5 of 89 (5.6%) patients with a positive PF4-H ELISA assay. Of these five subjects, all were indeterminate in the full panel SRA testing. Four of these patients were positive using the IgG-specific PF4-H antibody testing, while one patient was negative for IgG-specific PF4-H antibody. No patient had a positive full panel SRA. The baseline characteristics of patients with nonspecific PF4-H antibodies, IgG-specific PF4-H antibodies, and both IgG-specific PF4-H antibodies and SRA indeterminate results are depicted in Table 1 a, b and c. Patients with nonspecific PF4-H antibodies were more likely to be black and diabetic (Table 1a). Patients with IgG-specific PF4-H antibodies or both IgG-specific PF4-H antibodies and an indeterminate SRA were also more likely to be black (Table 1b and c). Otherwise, the patients with and without PF4-H antibodies had generally similar baseline characteristics.Table 1aBaseline characteristics of patients with nonspecific PF4-H antibodies, IgG-specific PF4-H antibodies, and both IgG-specific PF4-H antibodies and indeterminate serotonin release assayNonspecific PF4-H antibodiesCharacteristicPositive (n=54)Negative (n=365)P-valueAge, mean (s.d.), years64.9 (15.8)63.5 (16.5)0.54BMI, mean (s.d.), kg m−225.7 (6.1)25.6 (5.8)0.88Albumin, mean (s.d.), g l−135.7 (4.7)35.6 (4.1)0.92Time on dialysis, median (IQR), days470.5 (225, 1332)794 (348, 1533)0.13Hemoglobin, mean (s.d.), g dl−111.6 (0.9)11.8 (1.1)0.48Erythropoietin dose, mean (s.d.), units per week13 803 (10 243)12 059 (8455)0.24Urea reduction ratio, mean (s.d.)75.3 (7.6)75.3 (6.4)0.96Never smoked, no. (%)19 (35)118 (32)0.54Male, no. (%)28 (52)233 (64)0.09Race, no. (%)0.05 Caucasian43 (80)321 (88) Black7 (13)17 (5) Other4 (7)27 (7)Etiology of renal failure, no. (%)0.64 Diabetes16 (30)75 (21) Glomerulonephritis11 (20)75 (21) Hypertension6 (11)53 (15) Polycystic kidney disease3 (6)31 (8) Obstructive uropathy1 (2)21 (6) Other8 (15)58 (15) Unknown9 (16)52 (14)Diabetes, no. (%)25 (46)110 (30)0.02Malignancy, no. (%)10 (19)64 (18)0.86DVT/PE, no. (%)1 (2)18 (5)0.31Peripheral vascular disease, no. (%)10 (19)114 (31)0.06Angina, no. (%)18 (33)108 (30)0.58Myocardial infarction, no. (%)10 (19)100 (27)0.17Cerebrovascular accident, no. (%)8 (15)29 (8)0.09Transient ischemic attack, no. (%)1 (2)19 (5)0.28BMI, body mass index; DVT, deep vein thrombosis; IgG, immunoglobulin G; IQR, interquartile range; PE, pulmonary embolism; PF4-H, platelet factor 4-heparin. Open table in a new tab Table 1bBaseline characteristics of patients with PF4-H antibodies, IgG-specific PF4-H antibodies, and both IgG-specific PF4-H antibodies and indeterminate serotonin release assayIgG-specific PF4-H antibodiesCharacteristicPositive (n=9)Negative (n=410)P-valueAge, mean (s.d.), years64.1 (19.0)63.6 (16.3)0.93BMI, mean (s.d.), kg m−224.4 (3.8)25.7 (5.8)0.53Albumin, mean (s.d.), g l−136.7 (4.5)35.6 (4.2)0.45Time on dialysis, median (IQR), days738 (330, 1398)764 (317, 1514)0.73Hemoglobin, mean (s.d.), g dl−112.1 (1.2)11.7 (1.1)0.31Erythropoietin dose, mean (s.d.), units per week11 370 (8013)12 304 (8735)0.75Urea reduction ratio, mean (s.d.)74.9 (6.9)75.3 (6.5)0.88Never smoked, no. (%)2 (22)135 (33)0.79Male, no. (%)6 (67)255 (62)0.78Race, no. (%)<0.001 Caucasian5 (56)359 (88) Black4 (44)20 (5) Other031 (8)Etiology of renal failure, no. (%)0.83 Diabetes3 (33)88 (21) Glomerulonephritis1 (11)85 (21) Hypertension1 (11)58 (14) Polycystic kidney disease034 (8) Obstructive uropathy1 (11)21 (5) Other1 (11)65 (16) Unknown2 (22)59 (14)Diabetes, no. (%)3 (33)132 (32)0.94Malignancy, no. (%)2 (22)72 (18)0.72DVT/PE, no. (%)019 (5)0.51Peripheral vascular disease, no. (%)2 (22)122 (30)0.62Angina, no. (%)2 (22)124 (30)0.60Myocardial infarction, no. (%)2 (22)108 (26)0.78Cerebrovascular accident, no. (%)3 (33)34 (8)0.09Transient ischemic attack, no. (%)020 (5)0.49BMI, body mass index; DVT, deep vein thrombosis; IgG, immunoglobulin G; IQR, interquartile range; PE, pulmonary embolism; PF4-H, platelet factor 4-heparin. Open table in a new tab Table 1cBaseline characteristics of patients with PF4-H antibodies, IgG-specific PF4-H antibodies, and both IgG-specific PF4-H antibodies and indeterminate serotonin release assayIgG-specific PF4-H antibodies and indeterminate serotonin release assayCharacteristicPositive (n=4)Negative (n=415)P-valueAge, mean (s.d.), years69.3 (14.4)63.6 (16.4)0.49BMI, mean (s.d.), kg m−224.7 (3.8)25.6 (5.8)0.76Albumin, mean (s.d.), g l−134.8 (5.6)35.6 (4.2)0.68Time on dialysis, median (IQR), days499 (144, 1068)775 (319, 1533)0.33Hemoglobin, mean (s.d.), g dl−112.2 (1.7)11.7 (1.1)0.45Erythropoietin dose, mean (s.d.), units per week7917 (7026)12 326 (8723)0.31Urea reduction ratio, mean (s.d.)73.9 (8.2)75.3 (6.5)0.67Never smoked, no. (%)1 (25)136 (33)0.51Male, no. (%)3 (75)258 (62)0.60Race, no. (%)0.01 Caucasian2 (50)362 (87) Black2 (50)22 (5) Other031 (8)Etiology of renal failure, no. (%)0.44 Diabetes1 (25)90 (22) Glomerulonephritis086 (21) Hypertension1 (25)58 (14) Polycystic kidney disease034 (8) Obstructive uropathy022 (5) Other066 (16) Unknown2 (50)59 (14)Diabetes, no. (%)1 (25)134 (32)0.76Malignancy, no. (%)2 (50)72 (17)0.09DVT/PE, no. (%)019 (5)0.66Peripheral vascular disease, no. (%)0124 (30)0.19Angina, no. (%)0126 (30)0.19Myocardial infarction, no. (%)0110 (27)0.23Cerebrovascular accident, no. (%)1 (25)36 (9)0.25Transient ischemic attack, no. (%)020 (5)0.65BMI, body mass index; DVT, deep vein thrombosis; IgG, immunoglobulin G; IQR, interquartile range; PE, pulmonary embolism; PF4-H, platelet factor 4-heparin. Open table in a new tab BMI, body mass index; DVT, deep vein thrombosis; IgG, immunoglobulin G; IQR, interquartile range; PE, pulmonary embolism; PF4-H, platelet factor 4-heparin. BMI, body mass index; DVT, deep vein thrombosis; IgG, immunoglobulin G; IQR, interquartile range; PE, pulmonary embolism; PF4-H, platelet factor 4-heparin. BMI, body mass index; DVT, deep vein thrombosis; IgG, immunoglobulin G; IQR, interquartile range; PE, pulmonary embolism; PF4-H, platelet factor 4-heparin. One hundred and twenty-nine (31%) patients died during a median follow-up of 2.5 years. No patients were lost to follow-up. Fourteen of 54 (26%) patients with nonspecific PF4-H antibodies died during follow-up. In the group of patients with IgG-specific PF4-H antibodies, 5/9 (56%) died during follow-up. Three of five patients (60%) died of cardiovascular complications (myocardial infarction, n=2; ischemic bowel, n=1). Finally, 3/4 (75%) deaths occurred in the group of patients with IgG-specific PF4-H antibodies and indeterminate SRA result. Two of these patients died of cardiovascular complications (myocardial infarction, n=1; ischemic bowel, n=1). We found a significant association between PF4-H antibodies and mortality. For patients with IgG-specific PF4-H antibodies, the risk of death was increased over two-fold (unadjusted hazard ratio 2.40; 95% confidence interval 0.98–5.89; P=0.06) (Table 2). After controlling for age; gender; race; smoking status; diabetes; etiology of renal failure; time on dialysis; history of malignancy; history of angina, myocardial infarction, stroke, transient ischemic attack, or peripheral vascular disease; hemoglobin; albumin; urea reduction ratio; erythropoietin dose; and any thrombophilia, IgG-specific PF4-H antibodies were found to be an independent predictor of mortality (adjusted hazard ratio 2.68; 95% confidence interval 1.08–6.63; P=0.03) (Table 2). An even greater risk of death was seen in patients with both an IgG-specific PF4-H antibody and an indeterminate serotonin-release assay (unadjusted hazard ratio 3.61; 95% confidence interval 1.14–11.43; P=0.02) (Table 2). After controlling for the same variables listed above, the presence of an IgG-specific PF4-H antibody and an indeterminate serotonin-release assay remained a significant predictor of mortality (adjusted hazard ratio 6.32; 95% confidence interval 1.68–23.7; P=0.01) (Table 2). The risk of death was not significantly increased in patients with nonspecific PF4-H antibodies (Table 2).Table 2Cox regression analysis examining the risk of death associated with PF4-H antibodiesModelHazard ratio95% Confidence intervalP-valueNonspecific PF4-H antibodies Univariate0.870.50–1.520.64 MultivariateaMultivariate models were controlled for age; gender; race; smoking status; diabetes; etiology of renal failure; time on dialysis; history of malignancy; history of angina, myocardial infarction, stroke, transient ischemic attack, or peripheral vascular disease; hemoglobin; albumin; urea reduction ratio; erythropoietin dose; and any thrombophilia.0.650.36–1.150.14IgG-specific PF4-H antibodies Univariate2.400.98–5.890.06 MultivariateaMultivariate models were controlled for age; gender; race; smoking status; diabetes; etiology of renal failure; time on dialysis; history of malignancy; history of angina, myocardial infarction, stroke, transient ischemic attack, or peripheral vascular disease; hemoglobin; albumin; urea reduction ratio; erythropoietin dose; and any thrombophilia.2.681.08–6.630.03IgG-specific PF4-H antibodies and indeterminate serotonin release assay Univariate3.611.14–11.430.02 MultivariateaMultivariate models were controlled for age; gender; race; smoking status; diabetes; etiology of renal failure; time on dialysis; history of malignancy; history of angina, myocardial infarction, stroke, transient ischemic attack, or peripheral vascular disease; hemoglobin; albumin; urea reduction ratio; erythropoietin dose; and any thrombophilia.6.321.68–23.70.01IgG, immunoglobulin G; PF4-H, platelet factor 4-heparin.a Multivariate models were controlled for age; gender; race; smoking status; diabetes; etiology of renal failure; time on dialysis; history of malignancy; history of angina, myocardial infarction, stroke, transient ischemic attack, or peripheral vascular disease; hemoglobin; albumin; urea reduction ratio; erythropoietin dose; and any thrombophilia. Open table in a new tab IgG, immunoglobulin G; PF4-H, platelet factor 4-heparin. In the secondary analyses, we only found a significant association between IgG-specific PF4-H antibodies and minor cardiovascular event (Table 3). However, the point estimates were similar and in the same direction as the hazard ratios found for mortality.Table 3Cox regression analysis examining the risk of cardiovascular events associated with PF4-H antibodiesModelHazard ratio95% Confidence intervalP-valueNonspecific PF4-H antibodies Major cardiovascular eventaMajor cardiovascular event was defined as myocardial infarction, cerebrovascular accident, pulmonary embolism, or deep vein thrombosis.1.100.55–2.230.78 MultivariatebMultivariate models were controlled for: age; gender; race; smoking status; diabetes; etiology of renal failure; time on dialysis; history of malignancy; history of angina, myocardial infarction, stroke, transient ischemic attack or peripheral vascular disease; hemoglobin; albumin; urea reduction ratio; erythropoietin dose; any thrombophilia.0.910.44–1.850.79 Minor cardiovascular eventcMinor cardiovascular event was defined as transient ischemic attack or angina.1.720.79–3.720.17 MultivariatebMultivariate models were controlled for: age; gender; race; smoking status; diabetes; etiology of renal failure; time on dialysis; history of malignancy; history of angina, myocardial infarction, stroke, transient ischemic attack or peripheral vascular disease; hemoglobin; albumin; urea reduction ratio; erythropoietin dose; any thrombophilia.1.770.82–3.840.15IgG-specific PF4-H antibodies Major cardiovascular eventaMajor cardiovascular event was defined as myocardial infarction, cerebrovascular accident, pulmonary embolism, or deep vein thrombosis.1.710.42–6.990.46 MultivariatebMultivariate models were controlled for: age; gender; race; smoking status; diabetes; etiology of renal failure; time on dialysis; history of malignancy; history of angina, myocardial infarction, stroke, transient ischemic attack or peripheral vascular disease; hemoglobin; albumin; urea reduction ratio; erythropoietin dose; any thrombophilia.2.470.59–10.30.21 Minor cardiovascular eventcMinor cardiovascular event was defined as transient ischemic attack or angina.2.870.69–11.90.15 MultivariatebMultivariate models were controlled for: age; gender; race; smoking status; diabetes; etiology of renal failure; time on dialysis; history of malignancy; history of angina, myocardial infarction, stroke, transient ischemic attack or peripheral vascular disease; hemoglobin; albumin; urea reduction ratio; erythropoietin dose; any thrombophilia.5.121.21–21.80.03IgG-specific PF4-H antibodies and indeterminate serotonin release assay Major cardiovascular eventaMajor cardiovascular event was defined as myocardial infarction, cerebrovascular accident, pulmonary embolism, or deep vein thrombosis.1.760.24–12.70.58 MultivariatebMultivariate models were controlled for: age; gender; race; smoking status; diabetes; etiology of renal failure; time on dialysis; history of malignancy; history of angina, myocardial infarction, stroke, transient ischemic attack or peripheral vascular disease; hemoglobin; albumin; urea reduction ratio; erythropoietin dose; any thrombophilia.2.780.38–20.60.32 Minor cardiovascular eventcMinor cardiovascular event was defined as transient ischemic attack or angina.,dThere were no events in the positive group.———IgG, immunoglobulin G; PF4-H, platelet factor 4-heparin.a Major cardiovascular event was defined as myocardial infarction, cerebrovascular accident, pulmonary embolism, or deep vein thrombosis.b Multivariate models were controlled for: age; gender; race; smoking status; diabetes; etiology of renal failure; time on dialysis; history of malignancy; history of angina, myocardial infarction, stroke, transient ischemic attack or peripheral vascular disease; hemoglobin; albumin; urea reduction ratio; erythropoietin dose; any thrombophilia.c Minor cardiovascular event was defined as transient ischemic attack or angina.d There were no events in the positive group. Open table in a new tab IgG, immunoglobulin G; PF4-H, platelet factor 4-heparin. To our knowledge, this is the largest and the most comprehensive examination of the association between PF4-H antibodies and survival in hemodialysis patients. After adjusting for important variables, we found that the presence of IgG-specific PF4-H antibodies was associated with a significant increase in mortality for patients on maintenance hemodialysis. The hypercoagulable state of heparin-induced thrombocytopenia is responsible for the marked increase in morbidity and mortality seen with this condition. Venous and arterial thrombotic events are common consequences.15.Warkentin T.E. Levine M.N. Hirsh J. et al.Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.N Engl J Med. 1995; 332: 1330-1336Crossref PubMed Scopus (2148) Google Scholar PF4-H antibodies in asymptomatic patients have also been associated with both arterial and venous thrombosis.6.Boon D.M. van Vliet H.H. Zietse R. Kappers-Klunne M.C. The presence of antibodies against a PF4-heparin complex in patients on haemodialysis.Thromb Haemost. 1996; 76: 480PubMed Google Scholar, 7.Sitter T. Spannagl M. Banas B. Schiffl H. Prevalence of heparin-induced PF4-heparin antibodies in hemodialysis patients.Nephron. 1998; 79: 245-246Crossref PubMed Scopus (40) Google Scholar, 8.Greinacher A. Zinn S. Wizemann S.Z. Birk U.W. Heparin-induced antibodies as a risk factor for thromboembolism and hemorrhage in patients undergoing chronic haemodialysis.Lancet. 1996; 348: 764Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 9.Luzzatto G. Bertoli M. Cella G. et al.Platelet count, anti-heparin/platelet factor 4 antibodies and tissue factor pathway inhibitor plasma antigen level in chronic dialysis.Thromb Res. 1998; 89: 115-122Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 10.Yu A. Jacobson S.H. Bygden A. Egberg N. The presence of heparin-platelet factor 4 antibodies as a marker of hypercoagulability during hemodialysis.Clin Chem Lab Med. 2002; 40: 21-26Crossref PubMed Scopus (17) Google Scholar, 11.Mattioli A.V. Bonetti L. Sternieri S. Mattioli G. Heparin-induced thrombocytopenia in patients treated with unfractionated heparin: prevalence of thrombosis in a 1 year follow-up.Ital Heart J. 2000; 1: 39-42PubMed Google Scholar, 12.Nakamoto H. Shimada Y. Kanno T. et al.Role of platelet factor 4-heparin complex antibody (HIT antibody) in the pathogenesis of thrombotic episodes in patients on hemodialysis.Hemodial Int. 2005; 9: S2-S7Crossref PubMed Scopus (23) Google Scholar, 13.Mureebe L. Coats R.D. Silliman W.R. et al.Heparin-associated antiplatelet antibodies increase morbidity and mortality in hemodialysis patients.Surgery. 2004; 136: 848-853Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 14.Pena de la Vega L. Miller R.S. Benda M.M. et al.Association of heparin-dependent antibodies and adverse outcomes in hemodialysis patients: a Population-Based Study.Mayo Clin Proc. 2005; 80: 995-1000Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Patients on hemodialysis have a reduced survival compared to healthy controls. Therefore, it makes biological sense that PF4-H antibodies contribute to the pathophysiology underlying the vasculopathy causing an increased mortality and morbidity in patients on maintenance hemodialysis. Asymptomatic patients on hemodialysis with a positive heparin-induced platelet aggregation assay have been shown to have a 6.6-fold increased mortality compared to controls.13.Mureebe L. Coats R.D. Silliman W.R. et al.Heparin-associated antiplatelet antibodies increase morbidity and mortality in hemodialysis patients.Surgery. 2004; 136: 848-853Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar The mortality was due to thromboembolic complications such as pulmonary emboli and mesenteric ischemia.13.Mureebe L. Coats R.D. Silliman W.R. et al.Heparin-associated antiplatelet antibodies increase morbidity and mortality in hemodialysis patients.Surgery. 2004; 136: 848-853Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Patients on hemodialysis with PF4-H antibodies in the highest tertile, but less than that required for the serologic diagnosis of heparin-induced thrombocytopenia, have also been shown to have an increased rate of cardiovascular and all-cause mortality.14.Pena de la Vega L. Miller R.S. Benda M.M. et al.Association of heparin-dependent antibodies and adverse outcomes in hemodialysis patients: a Population-Based Study.Mayo Clin Proc. 2005; 80: 995-1000Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Our results are consistent with previously published literature13.Mureebe L. Coats R.D. Silliman W.R. et al.Heparin-associated antiplatelet antibodies increase morbidity and mortality in hemodialysis patients.Surgery. 2004; 136: 848-853Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar,14.Pena de la Vega L. Miller R.S. Benda M.M. et al.Association of heparin-dependent antibodies and adverse outcomes in hemodialysis patients: a Population-Based Study.Mayo Clin Proc. 2005; 80: 995-1000Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar and demonstrate an increase in all-cause mortality for patients undergoing hemodialysis with IgG-specific PF4-H antibodies suggesting an associative phenomenon. However, our study is not suited to suggest causality. A majority of deaths in these subgroups were attributed to cardiovascular events. Although previous research suggests a link between the presence of PF4-H antibodies and cardiovascular events,13.Mureebe L. Coats R.D. Silliman W.R. et al.Heparin-associated antiplatelet antibodies increase morbidity and mortality in hemodialysis patients.Surgery. 2004; 136: 848-853Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar,14.Pena de la Vega L. Miller R.S. Benda M.M. et al.Association of heparin-dependent antibodies and adverse outcomes in hemodialysis patients: a Population-Based Study.Mayo Clin Proc. 2005; 80: 995-1000Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar our results show only a trend toward increased major cardiovascular events in patients with PF4-H antibodies. Therefore, our observed mortality rates cannot be completely explained by subclinical heparin-induced thrombocytopenia and increased major cardiovascular events. It is possible that our study was underpowered to detect these secondary outcomes or that another mechanism with elevated PF4-H antibodies remains to be determined. Whereas some suggest that cessation of heparin-like products and use of other anticoagulants may be warranted in patients with asymptomatic PF4-H antibodies on maintenance hemodialysis,13.Mureebe L. Coats R.D. Silliman W.R. et al.Heparin-associated antiplatelet antibodies increase morbidity and mortality in hemodialysis patients.Surgery. 2004; 136: 848-853Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar,16.Chang J.J.Y. Parikh C.R. When heparin causes thrombosis: significance, recognition, and management of heparin-induced thrombocytopenia in dialysis patients.Semin Dial. 2006; 19: 297-304Crossref PubMed Google Scholar others do not.17.Leehey D.J. Kanak R.J. Messmore H.L. et al.Heparin-associated thrombocytopenia in maintenance hemodialysis patients.Int J Artif Organs. 1987; 10: 390-392PubMed Google Scholar,18.Sonawane S. Kasbekar N. Berns J.S. The safety of heparins in end-stage renal disease.Semin Dial. 2006; 19: 305-310Crossref PubMed Scopus (33) Google Scholar Direct thrombin inhibitors are an option for anticoagulation in hemodialysis patients with heparin-induced thrombocytopenia. Case reports and case series repo" @default.
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• W1991996564 date "2008-01-01" @default.
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• W1991996564 title "Increased mortality in hemodialysis patients having specific antibodies to the platelet factor 4-heparin complex" @default.
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