Recombinant ADAMTS13 for Immune Thrombotic Thrombocytopenic Purpura.

In patients with immune thrombotic thrombocytopenic purpura (iTTP), autoantibodies against the metalloprotease ADAMTS13 lead to catastrophic microvascular thrombosis. However, the potential benefits of recombinant human ADAMTS13 (rADAMTS13) in patients with iTTP remain unknown. Here, we report the clinical use of rADAMTS13, which resulted in the rapid suppression of disease activity and complete recovery in a critically ill patient whose condition had proved to be refractory to all available treatments. We also show that rADAMTS13 causes immune complex formation, which saturates the autoantibody and may promote its clearance. Our data support the role of rADAMTS13 as a novel adjunctive therapy in patients with iTTP.

Comparison of direct oral anticoagulants versus low-molecular-weight heparin in primary and metastatic brain cancers: a meta-analysis and systematic review.

BACKGROUND: The safety and efficacy of direct-acting oral anticoagulants (DOACs) for therapeutic anticoagulation in the setting of primary or metastatic brain cancer is not known. OBJECTIVES: To conduct a meta-analysis and systematic review of studies that compare the risk of intracranial hemorrhage (ICH) in patients with brain cancer treated with DOACs vs low-molecular-weight heparin (LMWH). METHODS: A literature search was conducted using PubMed, EMBASE, and Cochrane databases. Summary statistics were obtained by calculating the risk ratio (RR), and heterogeneity across studies was estimated using the I2 statistic. A total of 10 retrospective studies (n = 1638) met criteria for inclusion. The primary endpoint was the pooled RR for ICH in patients with brain tumors receiving anticoagulation with DOACs compared with those receiving LMWH. Secondary analyses included the risk of fatal ICH in each subgroup. RESULTS: The pooled RR for ICH in patients receiving DOACs vs those receiving LMWH was 0.65 (95% CI, 0.36-1.17; P = .15; I2 = 50%). In studies evaluating primary brain cancer, there was a reduction in risk of ICH with DOACs (RR, 0.35; 95% CI, 0.18-0.69; P = .003; I2 = 0%). In patients with metastatic brain cancer, there was no difference in the risk of ICH with the type of anticoagulation (RR, 1.05; 95% CI, 0.71-1.56; P = .80; I2 = 0%). The overall risk of fatal ICH was not different between anticoagulants. CONCLUSION: The risk of ICH in patients with brain cancer receiving therapeutic anticoagulation varies by anticoagulation agent and diagnosis of primary or metastatic disease.

Anticoagulation management and related outcomes in patients with cancer-associated thrombosis and thrombocytopenia: A systematic review and meta-analysis.

BACKGROUND: Patients with cancer have an increased risk of both venous thromboembolism (VTE) requiring anticoagulation and thrombocytopenia. The optimal management is unclear. We performed a systematic review and meta-analysis to evaluate the outcomes in these patients. METHODS: We searched MEDLINE, Embase, Scopus, and Cochrane Central Register of Controlled Trials from inception to February 5, 2022. Studies assessing adult patients with cancer-associated thrombosis and platelet count <100 × 109/L were included. Three anticoagulation management strategies were reported: full dose, modified dose, or no anticoagulation. The primary efficacy outcome was recurrent VTE, and the primary safety outcome was major bleeding. The incidence rates of thrombotic and bleeding outcomes by anticoagulation management strategies were descriptive, and were pooled using random effects model and expressed as events per 100 patient-months with associated 95 % confidence intervals (CI). RESULTS: We included 19 observational cohort studies (N = 1728 patients) in the systematic review, with 10 included in the meta-analysis (N = 707 patients). Approximately 90 % of patients had hematological malignancies, with low-molecular-weight heparin being the main anticoagulant. The rates of recurrent VTE and bleeding complications were high regardless of management strategies - recurrent VTE on full dose: 2.65/100 patient-months (95 % CI 1.62-4.32), modified dose: 3.51/100 patient-months (95 % CI 1.00-12.39); major bleeding on full dose: 4.45/100 patient-months (95 % CI 2.80-7.06), modified dose: 4.16/100 patient-months (95 % CI 2.24-7.74). There was serious risk of bias in all studies. CONCLUSIONS: Patients with cancer-associated thrombosis and thrombocytopenia have high risks of both recurrent VTE and major bleeding, but current literature is significantly limited to guide the best management.

Anticoagulation in cancer-associated thromboembolism with thrombocytopenia: a prospective, multicenter cohort study.

Venous thromboembolism (VTE) with concurrent thrombocytopenia is frequently encountered in patients with cancer. Therapeutic anticoagulation in the setting of thrombocytopenia is associated with a high risk of hemorrhage. Retrospective analyses suggest the utility of modified-dose anticoagulation in this population. To assess the incidence of hemorrhage or thrombosis according to anticoagulation strategy, we performed a prospective, multicenter, observational study. Patients with active malignancy, acute VTE, and concurrent thrombocytopenia (platelet count <100 000/µL) were enrolled. The cumulative incidences of hemorrhage or recurrent VTE were determined considering death as a competing risk. Primary outcomes were centrally adjudicated and comparisons made according to initial treatment with full-dose or modified-dose anticoagulation. A total of 121 patients were enrolled at 6 hospitals. Seventy-five patients were initially treated with full-dose anticoagulation (62%) and 33 (27%) with modified-dose anticoagulation; 13 (11%) patients received no anticoagulation. Most patients who received modified-dose anticoagulation had a hematologic malignancy (31 of 33 [94%]) and an acute deep vein thrombosis (28 of 33 [85%]). In patients who initially received full-dose anticoagulation, the cumulative incidence of major hemorrhage at 60 days was 12.8% (95% confidence interval [CI], 4.9-20.8) and 6.6% (95% CI, 2.4-15.7) in those who received modified-dose anticoagulation (Fine-Gray hazard ratio, 2.18; 95% CI, 1.21-3.93). The cumulative incidence of recurrent VTE at 60 days in patients who initially received full-dose anticoagulation was 5.6% (95% CI, 0.2-11) and 0% in patients who received modified-dose anticoagulation. In conclusion, modified-dose anticoagulation appears to be a safe alternative to therapeutic anticoagulation in patients with cancer who develop deep vein thrombosis in the setting of thrombocytopenia.

Anticoagulation after intracranial hemorrhage in brain tumors: Risk of recurrent hemorrhage and venous thromboembolism.

BACKGROUND: Intracranial hemorrhage (ICH) is a common and often devastating outcome in patients with brain tumors. Despite this, there is little evidence to guide anticoagulation management following an initial ICH event. OBJECTIVES: To analyze the risk of recurrent hemorrhagic and thrombotic outcomes after an initial ICH event in patients with brain tumors and prior venous thromboembolism (VTE). PATIENTS AND METHODS: A retrospective cohort study was performed. Radiographic images obtained after initial ICH were reviewed for the primary outcomes of recurrent ICH and VTE. RESULTS AND CONCLUSIONS: A total of 79 patients with brain tumors who developed ICH on anticoagulation for VTE were analyzed. Fifty-four patients (68.4%) restarted anticoagulation following ICH. The cumulative incidence of recurrent ICH at 1 year was 6.1% (95% confidence interval [CI], 1.5-15.3) following reinitiation of anticoagulation. Following a major ICH (defined as an ICH >10 mL in size, causing symptoms, or requiring intervention), the rate of recurrent ICH upon reexposure to anticoagulation was 14.5% (95% CI, 2.1-38.35), whereas the rate of recurrent ICH following smaller ICH was 2.6% (95% CI, 0.2%-12.0%). Mortality following a recurrent ICH on anticoagulation was 67% at 30 days. The cumulative incidence of recurrent VTE was significantly lower in the restart cohort compared to patients who did not restart anticoagulation (8.1% vs 35.3%; P = .003). We conclude that resumption of anticoagulation is lowest among patients with metastatic brain tumors with small initial ICH. Following an initial major ICH, resumption of anticoagulation was associated with a high rate of recurrent ICH.

Intracranial hemorrhage with direct oral anticoagulants in patients with brain metastases.

Direct oral anticoagulants (DOACs) are increasingly prescribed in treatment of cancer-associated thrombosis, but limited data exist regarding safety of DOACs in patients with brain metastases. We aimed to determine the incidence of intracranial hemorrhage (ICH) in patients with brain metastases receiving DOACs or low-molecular-weight heparin (LMWH) for venous thromboembolism or atrial fibrillation. An international 2-center retrospective cohort study was designed. Follow-up started on the first day of concomitant anticoagulation and brain tumor diagnosis. At least 2 brain imaging studies were mandated. The primary outcome was the cumulative incidence of any spontaneous ICH at 12-month follow-up with death as a competing risk. Major ICH was defined as spontaneous, ≥10 mL in volume, symptomatic, or requiring surgical intervention. Imaging studies were centrally reviewed by a neuroradiologist blinded for anticoagulant type. PANWARDS (platelets, albumin, no congestive heart failure, warfarin, age, race, diastolic blood pressure, stroke) score for prediction of ICH was calculated. We included 96 patients with brain metastases (41 DOAC, 55 LMWH). The 12-month cumulative incidence of major ICH was 5.1% in DOAC-treated patients and 11.1% in those treated with LMWH (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.09-2.21). When anticoagulation was analyzed as a time-varying covariate, the risk of any ICH did not differ between DOAC- and LMWH-treated patients (HR, 0.98; 95% CI, 0.28-3.40). PANWARDS score was not associated with ICH risk. This international 2-center study suggests comparable safety of LMWH and DOACs in patients with brain metastases.