Treatment outcomes by tumor histology in Eastern Cooperative Group Study E4599 of bevacizumab with paclitaxel/carboplatin for advanced non-small cell lung cancer.

INTRODUCTION: The combination of paclitaxel/carboplatin (PC) and bevacizumab (B) was previously shown to extend overall survival (OS) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). An analysis of survival and safety outcomes based on histology is presented here. METHODS: Patients with cytologically or histologically confirmed metastatic NSCLC were treated with PC + B (PCB) or PC. Median OS for all patients was determined using Kaplan-Meier methodology. Hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained using an unstratified Cox proportional hazards model. Histology-by-treatment interaction was tested with an unstratified multivariate Cox regression model. RESULTS: A total of 444 patients were randomized to PC, and 434 patients were randomized to PCB (the intent-to-treat population). Median OS times were 10.3 and 12.3 months for PC and PCB, respectively, with an HR for PCB of 0.80 (95% CI: 0.69-0.93). A total of 68.8% of patients had adenocarcinoma histology; 18.9% had "not otherwise specified"; 5.5% had large cell undifferentiated; 2.6% had bronchoalveolar carcinoma; and 3.9% "other." For adenocarcinoma, median OS was 10.3 months for PC treatment (n = 302) and 14.2 months for PCB (n = 300), HR 0.69 (95%CI: 0.58-0.83). Sample sizes for other specific histologic subtypes were too small for meaningful comparisons. Safety profiles among histologies were consistent with the overall safety profile, and there were no unexpected adverse event trends. CONCLUSIONS: Addition of B to PC is associated with increased survival in previously untreated patients with nonsquamous NSCLC. Adenocarcinoma was associated with an increased survival benefit of PCB treatment. Data for other histologies are inconclusive, primarily because of small patient sample sizes and large CIs.

Pharmacokinetic analysis of irinotecan plus bevacizumab in patients with advanced solid tumors.

PURPOSE: The purpose of this study was to evaluate the effect of bevacizumab on the pharmacokinetics (PK) of irinotecan and its active metabolite. Exploratory analyses of the impact of variability in uridine diphosphate glucuronosyltransferase 1A (UGT1A) genes on irinotecan metabolism and toxicity were conducted. METHODS: This was an open-labeled, fixed-sequence study of bevacizumab with FOLFIRI (irinotecan, leucovorin, and infusional 5-fluorouracil). Pharmacokinetic assessments were conducted in cycles 1 and 3. RESULTS: Forty-five subjects were enrolled. No difference in dose-normalized AUC(0-last) for irinotecan and SN-38 between irinotecan administered alone or in combination with bevacizumab was identified. Leukopenia was associated with higher exposure to both irinotecan and SN-38. UGT1A1 polymorphisms were associated with variability in irinotecan PK. Gastrointestinal toxicity was associated with UGT1A6 genotype. No other associations between UGT1A genotypes and toxicity were detected. CONCLUSION: Bevacizumab does not affect irinotecan PK when administered concurrently. A variety of pharmacogenetic relationships may influence the pharmacokinetics of irinotecan and its toxicity.

Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial.

We sought to determine whether thrombophilic defects increase recurrent venous thromboembolism (VTE) during warfarin therapy. Six hundred sixty-one patients with unprovoked VTE who were randomized to extended low-intensity (international normalized ratio [INR], 1.5-1.9) or conventional-intensity (INR, 2.0-3.0) anticoagulant therapy were tested for thrombophilia and followed for a mean of 2.3 years. One or more thrombophilic defects were present in 42% of patients. The overall rate of recurrent VTE was 0.9% per patient-year. Recurrent VTE was not increased in the presence of factor V Leiden (hazard ratio [HR], 0.7; 95% CI, 0.2-2.6); the 20210G>A prothrombin gene mutation (HR, 0); antithrombin deficiency (HR, 0); elevated factor VIII (HR, 0.7; 95% CI, 0.1-5.4); elevated factor XI (HR, 0.7; 95% CI, 0.1-5.0), or elevated homocysteine (HR, 0.7; 95% CI, 0.1-5.3), but showed a trend to an increase with an antiphospholipid antibody (HR, 2.9; 95% CI, 0.8-10.5). Compared with patients with no thrombophilic defects, the rate of recurrence was not increased in the presence of one (HR, 0.7; 95% CI, 0.2-2.3) or more than one (HR, 0.7; 95% CI, 0.2-3.4) defect. We conclude that single or multiple thrombophilic defects are not associated with a higher risk of recurrent VTE during warfarin therapy.

Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer.

PURPOSE: We evaluated the efficacy and safety of bevacizumab in patients with platinum-resistant epithelial ovarian carcinoma (EOC) or peritoneal serous carcinoma (PSC) who had experienced disease progression during, or within 3 months of discontinuing, topotecan or liposomal doxorubicin. PATIENTS AND METHODS: No more than three prior treatment regimens were allowed. Patients received single-agent bevacizumab 15 mg/kg intravenously every 3 weeks. Response was assessed by computed tomography (CT) scan every 6 weeks using Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Of 44 patients treated, 83.7% were primarily platinum resistant, 59.1% had received liposomal doxorubicin, 25% topotecan, 15.9% both agents, and 47.7% had received three prior chemotherapy regimens. A median of five (range, two to 16) bevacizumab doses were administered. Partial responses were observed in seven patients (15.9%). Median progression-free survival was 4.4 months (95% CI, 3.1 to 5.5 months), with a median survival duration of 10.7 months at study termination. Bevacizumab-associated grade 3 to 4 events included hypertension (9.1%), proteinuria (15.9%), bleeding (2.3%), and wound-healing complications (2.3%). The incidence of GI perforation (GIP; 11.4%) was higher than reported in bevacizumab trials of other tumor types. GIP occurred in 23.8% of patients receiving three prior chemotherapy regimens, compared with 0% of patients receiving two prior chemotherapy regimens (P < .01). A trend toward higher risk of GIP was observed for patients with bowel wall thickening or bowel obstruction on CT scan. Arterial thromboembolic events occurred in three patients (6.8%). Three deaths were related to bevacizumab treatment. CONCLUSION: Bevacizumab has single-agent activity in patients with platinum-resistant EOC or PSC. A higher than expected incidence of GIP was noted in these heavily pretreated patients.

Viability of red cells prepared with S-303 pathogen inactivation treatment.

BACKGROUND: A nucleic acid-targeted pathogen inactivation process with S-303 was developed to treat red blood cells (RBCs). STUDY DESIGN AND METHODS: Three studies in healthy subjects investigated posttransfusion recovery, life span, and immunogenic potential of autologous RBCs treated with S-303 and stored for 35 days. A two-arm trial in 42 subjects (1A) examined recovery of 35-day-old S-303 RBCs after a single transfusion. A one-arm study (1B) measured recovery and immune response in 28 subjects after multiple transfusions of S-303 RBCs. A randomized, crossover study (1C) in 29 subjects compared recovery and life span of 35-day-old S-303 RBCs and conventional RBCs. RESULTS: In Studies 1A and 1B, mean recovery of S-303 RBCs ranged from 78.7 to 84.4 percent. In Phase 1C, the mean 24-hour posttransfusion recoveries of S-303 and untreated RBCs were 81.7 +/- 6.3 and 84.5 +/- 6.2 percent (p = 0.05). The median life spans (t(1/2)) of S-303 and control RBCs were identical (37.4 days, p = 0.98). No antibodies to S-303 RBCs were detected. CONCLUSION: The mean 24-hour recovery of 35-day-old S-303 RBCs was less than untreated RBCs, but greater than 75 percent. RBCs treated with S-303 and stored for 35 days exhibited median life span not different from that of conventional RBCs.

Fresh frozen plasma prepared with amotosalen HCl (S-59) photochemical pathogen inactivation: transfusion of patients with congenital coagulation factor deficiencies.

BACKGROUND: Photochemical treatment (PCT) with amotosalen HCl (S-59) was developed to inactivate pathogens and white blood cells in plasma (PCT-FFP) used for transfusion support. STUDY DESIGN AND METHODS: An open-label, multicenter trial was conducted in patients with congenital coagulation factor deficiencies (factors [F]I, FII, FV, FVII, FX, FXI, and FXIII and protein C) to measure the kinetics of specific coagulation factors, hemostatic efficacy, and safety of PCT-FFP. Posttransfusion prothrombin time (PT), partial thromboplastin time (PTT), and clinical hemostasis were evaluated before and after PCT-FFP transfusions. RESULTS: Thirty-four patients received 107 transfusions of PCT-FFP for kinetic studies or therapeutic indications (mean dose, 12.8 +/- 8.5 mL/kg). Incremental factor recoveries ranged from 0.9 to 2.4 IU per dL per IU per kg (FII, FV, FVII, FX, FXI, and protein C). Mean pretransfusion PT (20.7 +/- 22.2 sec) corrected after PCT-FFP (13.8 +/- 2.4 sec, p < 0.001). Mean pretransfusion PTT (51.2 +/- 29.3 sec) corrected after PCT-FFP (32.0 +/- 5.1 sec, p < 0.001). Thirteen patients required 77 transfusions for therapeutic indications. PCT-FFP provided effective hemostasis and was well tolerated. CONCLUSIONS: Replacement coagulation factors in PCT-FFP exhibited kinetics and therapeutic efficacy consistent with conventional FFP.

Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer.

PURPOSE: Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA), a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody that inhibits tumor angiogenesis, has demonstrated survival benefit in patients with previously untreated metastatic colorectal cancer when combined with irinotecan/fluorouracil (FU)/leucovorin (LV; IFL). Three randomized clinical studies have evaluated bevacizumab in combination with FU/LV alone. A combined analysis of raw data from these studies was performed to better assess the efficacy of bevacizumab with FU/LV. PATIENTS AND METHODS: The analysis used primary efficacy data from three independent studies, including 241 patients in a combined control group receiving either FU/LV or IFL and 249 patients receiving FU/LV/bevacizumab (5 mg/kg once every 2 weeks). The efficacy data included response rate, progression-free survival, and overall survival. RESULTS: The median duration of survival was 17.9 months in the FU/LV/bevacizumab group, compared with 14.6 months in the combined control group, corresponding to a hazard ratio for death of 0.74 (P = .008). The median duration of progression-free survival was 8.8 months in the FU/LV/bevacizumab group, compared with 5.6 months in the combined control group, corresponding to a hazard ratio for disease progression of 0.63 (P < or = .0001). The addition of bevacizumab also improved the response rate (34.1% v 24.5%; P = .019). CONCLUSION: The addition of bevacizumab to FU/LV provides a statistically significant and clinically relevant benefit to patients with previously untreated metastatic colorectal cancer.

Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer.

PURPOSE: In a phase III trial, combining bevacizumab (BV)--a recombinant, humanized, monoclonal antibody targeting vascular endothelial growth factor--with irinotecan, bolus fluorouracil (FU), and leucovorin (LV; IFL) increased survival compared with IFL alone in first-line treatment of patients with metastatic colorectal cancer (CRC). Results for the parent study of IFL/BV versus IFL/placebo are reported elsewhere. Here, we describe efficacy and safety results for the third patient cohort in this trial, who received BV combined with FU/LV, and compare them with results for concurrently enrolled patients who received IFL. METHODS: Patients (N = 923) were randomly assigned to receive IFL/placebo (control), IFL/BV, or FU/LV/BV. Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) 5 mg/kg was administered intravenously every 2 weeks. Before an interim analysis confirmed acceptable safety for IFL/BV, 313 patients were concurrently randomly assigned to these three arms; after this analysis, the FU/LV/BV arm was discontinued. RESULTS: Median overall survivals were 18.3 and 15.1 months with FU/LV/BV (n = 110) and IFL/placebo (n = 100), respectively. Median progression-free survivals were 8.8 and 6.8 months, respectively. Overall response rates were 40.0% and 37.0%, and median response durations were 8.5 and 7.2 months, respectively. Adverse events consistent with those expected from FU/leucovorin- or IFL-based regimens were seen, as were modest increases in hypertension and bleeding in the bevacizumab arm, which were generally easily managed. CONCLUSION: The FU/LV/BV regimen seems as effective as IFL and has an acceptable safety profile. FU/LV/BV is an active alternative treatment regimen for patients with previously untreated metastatic CRC.

The influence of ethnicity on warfarin dosage requirement.

BACKGROUND: The optimal dose of warfarin varies among individuals, and the prediction of a maintenance dose is difficult. Ethnicity has been reported to influence warfarin dosing. OBJECTIVE: To quantitate the influence of ethnicity on warfarin dose requirement. METHODS: We conducted a retrospective cohort study at a university anticoagulation clinic to evaluate the influence of ethnicity on warfarin dose. Inclusion criteria included age > or = 18 years, target international normalized ratio (INR) 2-3, and warfarin management within the clinic for > or = 3 months with a minimum of 5 clinic visits. We collected clinical and demographic data including age, gender, weight, ethnicity, disease states, concomitant medications, indication, weekly warfarin dosage, and INR. To assess potential confounders, multivariate, repeated-measures regression analysis was used to identify and adjust for variables that may influence the maintenance dose of warfarin. RESULTS: Of the 345 patients who met the inclusion criteria, 27% were Asian American, 6% Hispanic, 54% white, and 14% African American. The adjusted mean (95% CI) weekly warfarin doses for patients with an INR goal of 2 to 3 were Asian Americans 24 mg (21 to 27), Hispanics 31 mg (25 to 37), whites 36 mg (34 to 39), and African Americans 43 mg (39 to 47) (p < 0.001). Additional factors found to influence warfarin dose requirement included age, weight, concomitant use of amiodarone, and diagnosis of venous thromboembolism. CONCLUSIONS: Warfarin dose requirements vary across ethnic groups even when adjusted for confounding factors, suggesting that genetic variation contributes to interpatient variability.

Cost-effectiveness of testing for hypercoagulability and effects on treatment strategies in patients with deep vein thrombosis.

PURPOSE: Among patients with deep vein thrombosis, hypercoagulable conditions impart a substantial risk of recurrent thrombosis. We sought to determine the cost-effectiveness of testing for these disorders, as well as which tests should be selected and how results should be used. METHODS: Using a Markov state-transition model, strategies of testing or not testing for a hypercoagulable state followed by anticoagulation for 6 to 36 months were compared in a hypothetical cohort of patients with apparently idiopathic deep vein thrombosis who were followed for life. Strategies were compared based on lifetime costs, quality-adjusted life-years (QALYs), and marginal cost-effectiveness. RESULTS: In the base case, testing followed by 24 months of anticoagulation in patients with a hypercoagulable condition was more cost-effective ($54,820; 23.76 QALYs) than usual care, which comprised 6 months of anticoagulation without testing ($55,260; 23.72 QALYs). All hypercoagulable conditions tested were common enough and associated with a sufficient risk of recurrence to justify inclusion in a test panel. Twenty-four months of initial anticoagulation was preferred (<$50,000/QALY) for most conditions, whereas lifetime anticoagulation was preferred for patients with antiphospholipid antibody syndrome ($2928/QALY) or homozygous factor V Leiden mutation ($3804/QALY). Models using newer evidence on recurrence suggested 18 to 36 months of anticoagulation without testing as the preferred approach. CONCLUSION: Testing for hypercoagulable disorders in patients with idiopathic deep vein thrombosis followed by 2 years of anticoagulation in affected patients is cost-effective. A simpler approach of treating all patients with prolonged anticoagulation without testing is justified if data confirm the persistent risk of recurrent thrombosis.

Reversal of direct thrombin inhibition after cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia.

UNLABELLED: We treated persistent hemorrhage after cardiopulmonary bypass in a heart transplant recipient who had received anticoagulation with the direct thrombin inhibitor bivalirudin by a combination therapy aimed at reducing the plasma concentration of the thrombin antagonist (hemodialysis and modified ultrafiltration), increasing the concentration of thrombin at bleeding sites (recombinant factor VIIa), and increasing the plasma concentration of other coagulation factors (fresh frozen plasma and cryoprecipitate). The bleeding was controlled, and there was no thrombotic complication. IMPLICATIONS: A combination of modified ultrafiltration, hemodialysis, and the administration of recombinant factor VIIa, fresh frozen plasma, and cryoprecipitate may reverse the anticoagulant effect of bivalirudin.

Joint range-of-motion limitations among young males with hemophilia: prevalence and risk factors.

Chronic joint disease from repeated bleeding into joints is a serious complication of hemophilia. To measure the extent of and to identify risk factors for deviations from normal in joint range of motion (ROM), we used cross-sectional data collected from 4343 males with hemophilia aged 2 to 19 years who received care at 136 US hemophilia treatment centers (HTCs). Factors examined included age, race/ethnicity, family history, insurance status, age at diagnosis and first HTC visit, frequency of HTC visits, hemophilia type, bleeding frequency, prophylaxis use, inhibitor status, body mass index (BMI), and recent orthopedic procedures. Trained personnel using a standard protocol obtained ROM measurements on 10 joints (hips, knees, shoulders, elbows, and ankles). Analyses used multiple linear regression to model overall ROM limitation separately by disease severity. For persons in all severity groups, joint ROM limitation was positively associated with older age, nonwhite race, and increased BMI. For those with severe disease, ROM limitation was also positively associated with number of bleeds and was greater for those with inhibitors or recent orthopedic procedures. We conclude that ROM limitations begin at an early age, especially for those with severe and moderate disease, and that BMI is an important, potentially modifiable risk factor.

Coagulopathy, marantic endocarditis, and cerebrovascular accidents as paraneoplastic features in medullary thyroid cancer--case report and review of the literature.

Medullary thyroid cancers account for approximately 7% of primary thyroid malignancies and are often associated with paraneoplastic syndromes. We discuss the case of a 59-year-old man who presented with a hypercoagulable state, nonbacterial endocarditis, and recurrent strokes in the setting of widespread medullary thyroid cancer. The patient was anticoagulated and underwent thyroidectomy, modified radical neck dissection, and subsequent axillary lymphadenectomy. Despite no recurrent thromboembolic events, the patient ultimately succumbed to his disease 8 months after diagnosis and 6 months after initial thyroidectomy. This is the first report, to our knowledge, of this unique presentation in a patient with thyroid cancer. The literature pertaining to the diagnosis and management of hypercoagulability states in patients with cancer, in general, and thyroid cancer, in particular, is reviewed.

Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism.

BACKGROUND: Warfarin is very effective in preventing recurrent venous thromboembolism but is also associated with a substantial risk of bleeding. After three months of conventional warfarin therapy, a lower dose of anticoagulant medication may result in less bleeding and still prevent recurrent venous thromboembolism. METHODS: We conducted a randomized, double-blind study, in which 738 patients who had completed three or more months of warfarin therapy for unprovoked venous thromboembolism were randomly assigned to continue warfarin therapy with a target international normalized ratio (INR) of 2.0 to 3.0 (conventional intensity) or a target INR of 1.5 to 1.9 (low intensity). Patients were followed for an average of 2.4 years. RESULTS: Of 369 patients assigned to low-intensity therapy, 16 had recurrent venous thromboembolism (1.9 per 100 person-years), as compared with 6 of 369 assigned to conventional-intensity therapy (0.7 per 100 person-years; hazard ratio, 2.8; 95 percent confidence interval, 1.1 to 7.0). A major bleeding episode occurred in nine patients assigned to low-intensity therapy (1.1 events per 100 person-years) and eight patients assigned to conventional-intensity therapy (0.9 event per 100 person-years; hazard ratio, 1.2; 95 percent confidence interval, 0.4 to 3.0). There was no significant difference in the frequency of overall bleeding between the two groups (hazard ratio, 1.3; 95 percent confidence interval, 0.8 to 2.1). CONCLUSIONS: Conventional-intensity warfarin therapy is more effective than low-intensity warfarin therapy for the long-term prevention of recurrent venous thromboembolism. The low-intensity warfarin regimen does not reduce the risk of clinically important bleeding.

Home monitoring of anticoagulation.

Small portable devices that generate a prothrombin time/INR from fingerstick capillary blood simplify warfarin management by allowing selected patients to monitor and manage their own warfarin dose. Early studies established that patients can self-test at home, with results as accurate as those obtained by practitioners. Point-of-care testing of elderly patients resulted in tighter INR control and a lower incidence of major hemorrhage, especially at the initiation of anticoagulant therapy. Patients can also successfully self-manage warfarin therapy. Larger, prospective, randomized intervention studies have shown that patient self-management led to greater time spent within the therapeutic INR range. However, a shift toward patient self-testing will likely require centralized implementation of patient education, training, and follow up that will need to be established in the clinic setting or by a third party.

Pharmacokinetic study of FFP photochemically treated with amotosalen (S-59) and UV light compared to FFP in healthy volunteers anticoagulated with warfarin.

BACKGROUND: To date, no clinical trials have characterized FFP infusion efficacy, and infusion still carries infectious risk. This single-blinded crossover study compared postinfusion kinetics of FVII in photochemically treated FFP to standard FFP. STUDY DESIGN AND METHODS: Subjects donated plasma by apheresis. Half of the collected plasma was treated with the psoralen amotosalen hydrochloride (S-59) and UVA light, and half were prepared as standard plasma. Subjects received warfarin over 4 days to lower FVII levels. On Day 4, subjects received 1 L of either treated or standard FFP. After 2 weeks, subjects underwent a regimen identical to that with the other type of FFP. RESULTS: After warfarin ingestion, the mean FVII concentration was 0.33 IU per mL. Both types of FFP exhibited comparable FVII kinetics, with a mean peak increment of 0.10 to 0.12 IU per mL occurring at the end of infusion. The effect disappeared after 8 hours. DISCUSSION: Study data of warfarin-treated healthy volunteers demonstrate that psoralen plus UV-treated FFP provides an equivalent in vivo coagulation response to control plasma. A 1-L dose of FFP in adults may provide an initial increment of 0.10 IU per mL of FVII. In the absence of bleeding, FVII levels return to baseline after 8 hours.

Coagulation: consultative hemostasis.

Clinical hematologists are frequently consulted for the care of hospitalized patients with complicated coagulopathies. This chapter provides an update on the scientific and clinical advances noted in disseminated intravascular coagulation (DIC) and discusses the challenges in hemostasis consultation. In Section I, Dr. Marcel Levi reviews advances in our understanding of the pathogenic mechanisms of DIC. Novel therapeutic strategies that have been developed and evaluated in patients with DIC are discussed, as are the clinical trials performed in patients with sepsis. In Section II, Dr. Lawrence Leung provides an overview of the challenging problems in thrombosis encountered in the inpatient setting. Patients with deep vein thrombosis that is refractory to conventional anticoagulation and those with extensive mesenteric thrombosis as well as the evaluation of a positive PF4/heparin ELISA in a post-operative setting are discussed. Novel treatments for recurrent catheter thrombosis in dialysis patients is addressed as well. In Section III, Dr. Julie Hambleton reviews the hemostatic complications of solid organ transplantation. Coagulopathy associated with liver transplantation, contribution of underlying thrombophilia to graft thrombosis, drug-induced microangiopathy, and the indication for postoperative prophylaxis are emphasized. Dr. Hambleton reviews the clinical trials evaluating hemostatic agents in patients undergoing liver transplantation.

Total knee arthroplasty in hemophilic arthropathy.

BACKGROUND: Arthropathy of the knee frequently develops in patients with hemophilia, who may require a total knee arthroplasty at a young age. Hemophilic patients, who require regular intravenous replacement of coagulation factor, have a higher prevalence of human immunodeficiency virus (HIV) infection, which can compromise the outcome of the arthroplasty. The purpose of this study was to evaluate prosthetic survival following total knee arthroplasty and identify factors associated with failures of the arthroplasties in hemophilic patients. METHODS: The results of fifty-three total knee arthroplasties performed in thirty-eight patients (twenty-nine of whom were seropositive for HIV) to treat hemophilic arthropathy between 1976 and 1998 were retrospectively reviewed. Inpatient and outpatient medical records were studied to determine the HIV status, CD4 lymphocyte count, type of prosthesis, duration of prosthetic survival, cause of failure, and cause of death. If an arthroplasty failed, the outcome of the treatment of the failed arthroplasty was also determined. RESULTS: The rate of survival of the prostheses was 90% after five years. Eleven total knee arthroplasties failed. The most common cause of failure was infection (seven knees), which developed at an average of sixty months (range, three to 138 months) after the arthroplasty. There was no significant difference in the CD4 lymphocyte counts between the patients in whom infection developed and those in whom it did not. The HIV status also did not appear to be related to the development of infection. Thirteen patients died, and the most common cause of death was complications associated with acquired immunodeficiency syndrome (AIDS). CONCLUSIONS: Total knee arthroplasty performed to treat hemophilic arthropathy has a high risk of failure as a result of infection. Most infections developed late and were frequently caused by Staphylococcus epidermidis, suggesting that a likely cause of failure due to infection was hematogenous spread during administration of coagulation factor. It may be difficult to salvage a prosthesis complicated by infection. However, the life expectancy of hemophilic patients is lower than that of the general population of patients treated with total knee arthroplasty, and the improvement in the quality of life after total knee arthroplasty for hemophilic arthropathy may outweigh the risk of failure.