Approach to the treatment, characterization and diagnosis of an acquired auto-antibody directed against factors prothrombin, factor X and factor IX: a case report and review of the literature.

Bleeding disorders secondary to acquired non-inhibitory antibodies directed against vitamin K-dependent coagulation proteins are rare. In this report, the authors describe a patient with a low grade lymphoma who presented with a fatal acquired bleeding manifestation and abnormal hemostatic studies resulting from deficiencies in both prothrombin and factor X. Patient plasma samples were collected and studied for the presence of an acquired inhibitor. Levels of plasma coagulation proteins were measured using immunoassay. Patient anti-prothrombin immunoglobulin G was isolated and binding to prothrombin, prothrombin F1.2, factors IX and X was evaluated using immunoblots and competition immunoassay. Prolongation in the prothrombin time and activated partial thromboplastin time suggested a factor deficiency in the common pathway of coagulation. Functional and antigenic levels of both prothrombin and factor X were decreased. An IgG subtype-4 antibody was isolated from patient plasma using affinity chromatography on prothrombin-sepharose. This antibody was found to bind to a common metal-ion-dependent conformational epitope found on the γ-carboxyglutamic acid (Gla) domain of prothrombin, factor X and factor IX. This report represents the first description of an acquired bleeding disorder resulting from a unique cross-reactive auto-antibody against a common metal-ion-dependent antigenic structure on the Gla-domain of the vitamin K-dependent proteins.

Isolation and characterization of a hepatoma-associated abnormal (des-gamma-carboxy)prothrombin.

Hepatoma-associated abnormal (des-gamma-carboxy)prothrombin (HAPT) is a newly described tumor marker for hepatocellular carcinoma. HAPT has been measured in the blood of patients with hepatoma by immunoassay but has not been isolated or characterized. This paper describes the quantitative isolation and structural characterization of HAPT. Purified HAPT has the same molecular weight, amino-terminal sequence, and amino acid analysis (exclusive of gamma-carboxyglutamic acid) as native prothrombin and abnormal prothrombin isolated from the blood of patients taking sodium warfarin. HAPT is heterogeneous in gamma-carboxyglutamic acid (Gla) content with an average of 5 Gla residues/molecule compared to 10 Gla residues for native prothrombin and 2 Gla residues for abnormal prothrombin. HAPT is glycosylated in a manner equivalent to that for native prothrombin when evaluated by a concanavalin A-binding assay. These studies find structural identity between HAPT and abnormal prothrombin. Therefore the findings support the hypothesis that HAPT results from an acquired defect in the posttranslational vitamin K-dependent carboxylation of the prothrombin precursor and not an intrinsic defect in the prothrombin precursor molecule.

OC-14 - Baseline D-dimer levels are predictive of recurrent venous thromboembolism (VTE) at 6 months in cancer patients with VTE treated with tinzaparin.

INTRODUCTION: VTE is a major complication in cancer patients. Despite treatment with low molecular weight heparin (LMWH), 9% will have recurrent VTE within 6 months. Measurement of plasma biomarkers in cancer patients receiving LMWH may be predictive of recurrent VTE or overall survival (OS). AIM: We conducted a single arm phase 2 study to evaluate the efficacy and safety of once daily tinzaparin for the initial treatment and extended prophylaxis of VTE in cancer patients. The study included a prospective analysis of plasma biomarkers D-dimer and IL-6 to assess whether these were predictive of recurrent VTE or OS. MATERIALS AND METHODS: Consecutive patients with active cancer diagnosed with a pulmonary embolism (PE) and/or proximal deep venous thrombosis (DVT) at the University of Southern California Norris Comprehensive Cancer Center, Los Angeles County Medical Center, or New York Presbyterian - Weill Cornell Medical Center were invited to participate in this study with a target enrollment of 100 patients. Key eligibility criteria included: age ≥18, ECOG score ≤2, adequate organ function, and ≥6 month estimated survival. Patients were treated with daily subcutaneously tinzaparin 175 U/kg for 6 months on study. Tinzaparin could be continued ≤1 year at the discretion of the treating physician. All patients who received ≥1 dose were evaluable for efficacy and safety. Primary study endpoints were recurrent VTE or major bleeding. Secondary outcome measures included OS and plasma biomarkers. Biomarkers were measured at baseline, 7 days, 1 month and 6 months after tinzaparin initiation. Patients who had baseline and 1 week or 1 month samples collected were included in the biomarker analysis. RESULTS: 97 patients were enrolled. 2 patients were ineligible. 8 patients did not have baseline or follow-up biomarkers completed. 87 patients were included in the analysis. 28 (32%) of patients completed≥6 months of tinzaparin. Major bleeding occurred in 2 patients. 11 patients had recurrent VTE at 6 months (3 PE, 7 DVT, 1 central venous thrombosis not associated with a catheter). Median baseline D-dimer level was 2759 ng/mL (range: 375-37,591). Median baseline IL-6 level was 9.4 pg/mL (range: 0.8-20.9). Baseline D-dimer>median was predictive of VTE recurrence at 6 months (p=.006). Baseline IL-6>median was not predictive of VTE recurrence at 6 months. Neither 1 month D-dimer or IL-6 levels were predictive of VTE recurrence at 6 months. D-dimer and IL-6 at baseline and at 1 month were not predictive of OS. CONCLUSIONS: In patients with active cancer and VTE treated with tinzaparin, baseline D-dimer levels above the median value were predictive of VTE recurrence at 6 months.

Risk of recurrent venous thromboembolism and major hemorrhage in cancer-associated incidental pulmonary embolism among treated and untreated patients: a pooled analysis of 926 patients.

UNLABELLED: ESSENTIALS: We performed a pooled analysis of 926 patients with cancer-associated incidental pulmonary embolism (IPE). Vitamin K antagonists (VKA) are associated with a higher risk of major hemorrhage. Recurrence risk is comparable after subsegmental and more proximally localized IPE. Our results support low molecular weight heparins over VKA and similar management of subsegmental IPE. BACKGROUND: Incidental pulmonary embolism (IPE) is defined as pulmonary embolism (PE) diagnosed on computed tomography scanning not performed for suspected PE. IPE has been estimated to occur in 3.1% of all cancer patients and is a growing challenge for clinicians and patients. Nevertheless, knowledge about the treatment and prognosis of cancer-associated IPE is scarce. We aimed to provide the best available evidence on IPE management. METHODS: Incidence rates of symptomatic recurrent venous thromboembolism (VTE), major hemorrhage, and mortality during 6-month follow-up were pooled using individual patient data from studies identified by a systematic literature search. Subgroup analyses based on cancer stage, thrombus localization, and management were performed. RESULTS: In 926 cancer patients with IPE from 11 cohorts, weighted pooled 6-month risks of recurrent VTE, major hemorrhage and mortality were 5.8% (95% confidence interval [CI] 3.7-8.3%), 4.7% (95% CI 3.0-6.8%), and 37% (95% CI 28-47%). VTE recurrence risk was comparable under low molecular weight heparins (LMWH) and vitamin K antagonists (VKAs) (6.2% vs. 6.4%; hazard ratio [HR] 0.9; 95% CI 0.3-3.1), while 12% in untreated patients (HR 2.6; 95% CI 0.91-7.3). Risk of major hemorrhage was higher under VKAs than under LMWH (13% vs. 3.9%; HR 3.9; 95% CI 1.6-10). VTE recurrence risk was comparable in patients with an subsegmental IPE and those with a more proximally localized IPE (HR 1.1; 95% CI 0.50-2.4). CONCLUSION: These results support the current recommendation to anticoagulate cancer-associated IPE with LMWH and argue against different management of subsegmental IPE.

Phase I/II clinical and pharmacokinetic evaluation of liposomal daunorubicin.

PURPOSE: Since liposomal encapsulation of anticancer drugs may enhance antitumor activity while reducing toxicity in vitro, we evaluated liposomally encapsulated daunorubucin (DaunoXome; Vestar, Inc, San Dimas, CA) for safety, pharmacokinetics, and potential efficacy in patients with AIDS-related Kaposi's sarcoma (AIDS-KS). PATIENTS AND METHODS: Forty patients with advanced AIDS-KS were accrued. Successive cohorts received DaunoXome at doses of 10, 20, 30, and 40 mg/m2 given once every 3 weeks, and 40, 50, and 60 mg/m2 given once every 2 weeks. Selected KS and solid-tumor patients underwent pharmacokinetic evaluation. RESULTS: The area under the plasma concentration curve (AUC) ranged from 16.9 micrograms.h/mL to 375.3 micrograms./mL and the alpha half-life ranged from 7.8 to 8.3 hours at 10 mg/m2 to 60 mg/m2, respectively. Both pharmacokinetic profiles were significantly better compared with free daunorubicin. DaunoXome was well tolerated with no significant alopecia, mucositis, or vomiting. Neutropenia (< 1,000/microL occurred in 17% of cycles and was severe (< 500/microL) in only 2%. Anemia and thrombocytopenia were uncommon. Other adverse events included mild to moderate fatigue, nausea, and diarrhea. Even after cumulative doses greater than 1,000 mg/m2, no significant declines in cardiac function were observed. Twenty-two patients who received 50 and 60 mg/m2 were assessable for tumor response; 12 (55%) had a partial response (PR) or clinical complete response (CR). The median survival duration in all patients was 9 months. Prognostic factors for short survival were low CD4 lymphocyte counts (P = .004) and prior anthracycline therapy (P = .02). CONCLUSION: DaunoXome has an improved pharmacokinetic profile compared with free daunorubicin, and is well tolerated. DaunoXome can be given safely at doses up to 60 mg/m2 every 2 weeks and has significant antitumor activity in patients with AIDS-KS.

Deficiency of the specific granule proteins, R-binder/transcobalamin I and lactoferrin, in plasma and saliva: a new disorder.

The mechanisms of hereditary deficiency of R binder, which originates in neutrophils and exocrine gland epithelium, are unknown and may be multiple. This led us to examine if defective R binder synthesis also involves proteins that colocalize with it in neutrophil-specific granules and exocrine epithelial cells and may be under common regulatory control. Stored plasma and saliva samples from five unrelated R binder-deficient patients and control subjects were assayed for R binder, lactoferrin, cationic antimicrobial protein-18, neutrophil gelatinase-associated lipocalin, gelatinase, lysozyme, and myeloperoxidase. One patient, patient A, had lactoferrin levels below the limits of detection in both plasma and saliva in addition to his R binder deficiency. Although his deficiency involved lactoferrin as well, he had no history of predisposition to infection. PCR amplification of his R binder gene promoter region and the beginning of the first exon revealed no DNA abnormalities. His son and the son of his equally deficient brother, both presumptive heterozygotes, had mild deficiency of both R binder and lactoferrin. The results show that R binder deficiency exists in at least two forms. One, presumably the less common of the two forms, is the new hereditary entity described here, which is characterized by deficiency of more than one specific granule protein in both plasma and saliva. Despite this more widely distributed absence of the proteins than is found in congenital specific granule deficiency, infection posed no clinical problem in the affected patient.

Excessive fibrinolysis in amyloidosis associated with elevated plasma single-chain urokinase.

Severe bleeding resulting from excessive fibrinolysis has been observed in patients with primary amyloidosis. The authors studied a patient with this hemostatic disorder before and during therapy with epsilon-aminocaproic acid. Excessive fibrinolysis was associated with depressed plasma concentrations of coagulation Factors XII, XI, high-molecular-weight kininogen, and Factors VIII and V; and plasminogen and alpha-2-plasmin inhibitor. These deficiencies were corrected with treatment. The functional and antigenic concentrations of tissue plasminogen activator and plasminogen activator inhibitor in the patient's plasma were normal. Urokinase-type activator activity and antigen were three to five times elevated in the patient's plasma. Results of immunoprecipitation showed that single-chain urokinase-type activator was the primary urokinase-type activator species in the patient's plasma. Excessive fibrinolysis in patients with amyloidosis results from increased plasma single-chain urokinase-type activator activity.

Population pharmacokinetic analysis of didanosine (2',3'-dideoxyinosine) plasma concentrations obtained in phase I clinical trials in patients with AIDS or AIDS-related complex.

Plasma didanosine concentration data from 36 patients receiving once-a-day therapy and from 33 patients receiving twice-a-day therapy were subject to population pharmacokinetic analysis with the computer program NONMEM. Once- or twice-a-day regimens of didanosine were administered intravenously (i.v.) (dose: 0.8-33 mg/kg) during the first 2 weeks of therapy, and orally (dose: 1.6-66 mg/kg) for the remaining 4 weeks of therapy. Plasma pharmacokinetics were determined after the first and last (steady-state) i.v. and oral doses. Population pharmacokinetic parameters for the combined i.v. and oral steady-state data were (mean [%CV]): systemic clearance, CL, 0.70 (5.2) L/h/kg; central compartment volume, Vc, 0.18 (32) L/kg; steady-state distribution volume, Vdss, 0.84 (6.8) L/kg; first-order absorption rate constant, Ka, 1.3 (9.5) hr-1; and bioavailable fraction, F, 0.34 (8.5). Interindividual variability (omega) was (%CV) 22.3 and 71.0 for CL and Vc, respectively. Intraindividual (residual) variability (sigma) in plasma concentrations (%CV) was 50.2. Body weight, sex, and age did not account for the variability in either CL or Vc, and the use of alternate pharmacokinetic models did not reduce the value of intraindividual variability. Population parameters for the combined i.v. and oral first-dose data were generally similar to those for the steady-state data. The parameters can be used to design dosing regimens in patients using the Bayesian feedback approach.

Subcutaneous Kaposi's sarcoma. Thallium scan demonstration.

A case of AIDS-related Kaposi's sarcoma involving subcutaneous tissues beyond the visible skin lesions is reported. In this case, the tumor was thallium avid. Thallium scintigraphy was able to demonstrate the true extent of the tumor and may be used to document the presence and extent of cutaneous and extracutaneous AIDS-related Kaposi's sarcoma.

A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer.

BACKGROUND: Cancer patients receiving chemotherapy are at increased risk for thrombosis. Apixaban, a factor Xa inhibitor, is oral and does not require laboratory monitoring. OBJECTIVES: A pilot study was conducted to evaluate whether apixaban would be well tolerated and acceptable in cancer patients receiving chemotherapy. PATIENTS/METHODS: Subjects receiving either first-line or second-line chemotherapy for advanced or metastatic lung, breast, gastrointestinal, bladder, ovarian or prostate cancers, cancer of unknown origin, myeloma or selected lymphomas were randomized to 5 mg, 10 mg or 20 mg once daily of apixaban or placebo in a double-blind manner for 12 weeks. Use of the study drug began within 4 weeks of the start of chemotherapy. The primary outcome was either major bleeding or clinically relevant non-major (CRNM) bleeding. Secondary outcomes included venous thromboembolism (VTE) and grade III or higher adverse events related to the study drug. Thirty-two patients received 5 mg, 30 patients 10 mg, 33 patients 20 mg, and 30 patients placebo. In these groups, there were 0, 0, 2 and 1 major bleeds, respectively. The corresponding data for CRNM bleeds were 1, 1, 2, and 0. The rate of major bleeding in the 93 apixaban patients was 2.2% (95% confidence interval 0.26-7.5%). There were no fatal bleeds. Three placebo patients had symptomatic VTE. CONCLUSIONS: Apixaban was well tolerated in our study population. These results support further study of apixaban in phase III trials to prevent VTE in cancer patients receiving chemotherapy.

Unsuspected pulmonary emboli adversely impact survival in patients with cancer undergoing routine staging multi-row detector computed tomography scanning.

BACKGROUND: While symptomatic venous thromboembolism adversely impacts survival among cancer patients, the outcome of cancer patients with unsuspected pulmonary embolism (UPE) found on routine cancer staging multi-row detector computed tomography (MDCT) scans is unknown. OBJECTIVE: To determine whether UPE detected on routine staging MDCT scans impacts overall survival among cancer patients. PATIENTS AND METHODS: We performed a matched cohort study of cancer patients diagnosed with UPE on routine staging scans between May 2003 and August 2006. Two controls (n = 137) were individually matched by age (± 5 years), cancer type and stage for each UPE patient (n = 70). We used Cox's proportional hazard models to compare the mortality between UPE patients and their matched controls. RESULTS: The hazard ratio (HR) for death among UPE patients was 1.51 (95% CI 1.01-2.27, P = 0.048). Compared with their matched controls, patients with UPE more proximal than the subsegmental arterial branches had a HR for death at 6 months of 2.28 (95% CI 1.20-4.33, P = 0.011) and an overall HR of 1.70 (95% CI 1.06-2.74, P = 0.027). Survival among UPE patients with isolated subsegmental PE (ISSPE) was not significantly different than that of matched controls (HR 1.04 95% CI 0.44-2.39, P = 0.92). CONCLUSIONS: UPE identified more proximal than the subsegmental arterial branches has a significant negative impact on survival among cancer patients.

The metal-dependent conformational changes in factor IX associated with phospholipid binding. Studies using antibodies against a synthetic peptide and chemical modification of factor IX.

Factor IX undergoes two sequential metal-ion-dependent conformational transitions [Liebman, H.A. (1987) J. Biol. Chem. 262, 7605-7612]. The first transition is metal ion dependent, but cation nonselective. The second transition is metal ion selective for Ca(II) or Sr(II) and associated with the expression of conformational determinants necessary for phospholipid membrane binding. Using antibodies raised against a synthetic peptide containing Factor IX amino acid residues 28-46, it was demonstrated that the aromatic-amino-acid-stack domain (amino acid residues 41-46) of Factor IX is surface exposed in the metal-free conformer and internalized with the initial metal-ion-dependent conformational transition. The metal-ion-induced internalization of this region of Factor IX protects the tryptophan at position 42 from oxidation by N-bromosuccinimide. The oxidation of Factor IX tryptophan residues is associated with the rapid loss of coagulant activity, but protection of Trp42 allows for the continued expression of the Ca(II)-specific antigenic determinants on Factor IX and the retention of phospholipid binding. These results suggest that the Trp42 residue located in the aromatic amino acid stack domain of human Factor IX is internalized with the metal-ion-dependent conformational transition and is essential for the expression of the phospholipid membrane binding site on Factor IX.

Des-gamma-carboxy (abnormal) prothrombin and hepatocellular carcinoma: a critical review.

Des-gamma-carboxyprothrombin (DCP) appears to be a useful tumor marker for the evaluation of patients with HCC. DCP is produced by the malignant hepatocyte and appears to result from an acquired posttranslational defect in the vitamin K-dependent carboxylase system. DCP production is independent of vitamin K deficiency, although pharmacological doses of vitamin K can transiently suppress DCP production in some tumors. DCP levels greater than 0.1 AU/ml (100 ng/ml) on ELISA are highly suggestive of HCC or tumor recurrence. Normalization of DCP levels correlates well with successful tumor resection and appears to be an excellent marker of tumor activity. Plasma DCP does not correlate with AFP levels. However, when used together, DCP and AFP assays increase the sensitivity to HCC in more than 85% of patients. The specificity of the DCP assay appears to be superior to that of AFP; fewer than 5% of patients with nonmalignant liver disorders have DCP levels in excess of 100 ng/ml. In patients with medium to large HCC, DCP levels do correlate with tumor size. In tumors of less than 3 cm, DCP levels are increased in only 20% of patients. However, the diagnostic threshold for the DCP assay may be improved by newer assays that can detect partially carboxylated DCP species not measured by the monoclonal antibody-based ELISA.

Didanosine in the treatment of AIDS and AIDS-related complex: a critical appraisal of the dose and frequency of administration.

In the summer of 1988, dose-finding phase 1 trials of the efficacy and safety of didanosine were begun by investigators at the National Cancer Institute (NCI), by the AIDS Clinical Trials Group (ACTG) at New York University School of Medicine and the University of Rochester School of Medicine, and by researchers at Boston City Hospital (BCH). The schedules of drug administration studied included once daily (BCH), twice daily (ACTG and NCI), and three times daily (NCI). The total daily dose studied ranged from 0.8 to 66 mg/(kg.d). Significant toxicities developed in more than half of the patients receiving doses of > or = 12 mg/(kg.d). Only 5% of patients given < 10 mg/(kg.d) developed grade 3 or 4 toxicities. Although CD4+ lymphocyte counts increased at doses as low as 1.6 mg/(kg.d), a minimal effective dose could not be determined. An analysis of data on serum levels of p24 antigen suggests that a dose of > or = 5 mg/(kg.d) is superior to lower doses in terms of activity against human immunodeficiency virus. A dose given on a once-daily schedule may exhibit less antiretroviral activity than the same dose given on a twice-daily schedule. Long-term follow-up of the phase 1 trial of the once-daily regimen at BCH has further documented the safety of didanosine given at doses of < 12 mg/(kg.d) for extended periods. A review of these studies suggests that a twice-daily schedule of didanosine administration at a daily dose of 5-10 mg/(kg.d) is safe and is associated with significant antiretroviral activity in vivo.

Treatment of hepatitis C related thrombocytopenia with interferon alpha.

Thrombocytopenia is a common extrahepatic manifestation of hepatitis C (HCV) infection. Treatment with steroids may be effective, but can exacerbate the viral infection. Interferon alpha (INF) has documented efficacy in the treatment of HCV, but its use in the treatment of HCV thrombocytopenia is controversial. We treated eight patients with HCV-related thrombocytopenia, who had platelet counts of fewer than 50 x 10(9)/l (range: 16 to 46 x 10(9)/L) with INF 3 MU SQ three times a week. Planned duration of treatment was 24 weeks. Five patients had no evidence of hepatic cirrhosis, three had cirrhosis, and two had palpable splenomegaly. Only three patients tolerated the full course of treatment, and all three had improvement in their platelet counts to greater than 50 x 10(9)/l. Two other patients had improvement in platelet counts to more than 50 x 10(9)/l with shorter duration of treatment (six and 16 weeks, respectively). The mean increase in platelet count in the five responders was 44 x 10(9)/lL (range: 28 to 90 x 10(9)/l). The average peak platelet count in the responders was 81 x 10(9)/l (range: 62 to 136 x 10(9)/l). Duration of response ranged from four to 18+ months, with the shortest responses observed in the two patients treated with a shorter course of INF. Response was independent of the presence of cirrhosis. Responding patients had improvement in hepatic transaminases, reduction in cryoglobulin and anticardiolipin antibodies, and HCV plasma RNA when tested. Relapse was associated with an increase in these laboratory markers of HCV infection. We conclude that INF can be an effective treatment in patients with HCV-related thrombocytopenia.

Bone marrow response in treated patients with Gaucher disease: evaluation by T1-weighted magnetic resonance images and correlation with reduction in liver and spleen volume.

PURPOSE: To determine whether T1-weighted magnetic resonance (MR) images can demonstrate response in the marrow of patients with type 1 Gaucher disease treated with enzyme replacement therapy (ERT) and to determine whether a relationship exists between liver and spleen volume reductions and visible marrow changes. PATIENTS: Forty-two patients with type 1 Gaucher disease were evaluated on at least two occasions. Thirty-two patients received ERT. Of these patients, 15 had a baseline examination prior to the initiation of ERT. The remaining 10 patients did not receive ERT. DESIGN: T1-weighted and gradient recalled echo (GRE) coronal images of the femurs and hips were obtained. Concurrently, liver and spleen volumes were determined using contiguous breath-hold axial gradient-echo images. T -weighted images of the hips and femurs were evaluated to determine change or lack of change in the yellow marrow. RESULTS: Of the 32 patients receiving ERT, 14 (44%) demonstrated increased signal on T1-weighted images suggesting an increase in the amount of yellow marrow. If only the 15 patients with a baseline examination were considered, the response rate to ERT was 67%. Using Student's t-test a highly significant correlation (P<0.005) was found between marrow response and reduction in liver and spleen volume. CONCLUSIONS: Marrow changes in patients receiving ERT can be detected by T -weighted images. This response correlated with reductions in visceral volumes (P<0.0005).

Treatment of refractory antibody mediated autoimmune disorders with an anti-CD20 monoclonal antibody (rituximab).

BACKGROUND: Rituximab, a chimeric monoclonal anti-CD20 antibody, has recently been used for the treatment of refractory antibody mediated autoimmune diseases such as immune mediated thrombocytopenia and haemolytic anaemia. PATIENTS: Because of its novel mechanism of action, rituximab was used to treat three patients with refractory systemic antibody mediated autoimmune disorders. The first patient, a 71 year old woman with idiopathic type II mixed essential cryoglobulinaemia, had both dermatological and neurological manifestations with marked renal disease attributed to her cryoglobulinaemia. Patient 2, a 73 year old woman with Goodpasture's syndrome, was refractory to conventional treatment (cyclophosphamide, prednisone, plasmapheresis). She had persistent haemoptysis and haematuria and positive antiglomerular basement membrane antibodies. The third patient, a 75 year old man with primary biliary cirrhosis, myelodysplasia, and systemic immune complex vasculitis, had progressive renal insufficiency, a macular erythematous rash, and severe thrombocytopenia. RESULTS: Treatment with rituximab resolved all clinical and laboratory manifestations in the three patients. CONCLUSIONS: Rituximab may be an important therapeutic agent for the treatment of patients refractory or intolerant to corticosteroid or cytotoxic treatment, or both.