Ristocetin-induced platelet aggregation for monitoring of bleeding tendency in CLL treated with ibrutinib.

Bleeding because of impaired platelet function is a major side effect of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. We quantitatively assessed ristocetin-induced platelet aggregation (RIPA) in 64 patients with chronic lymphocytic leukemia (CLL) under ibrutinib at 287 time points. Eighty-seven bleeding episodes in 39 patients were registered (85 Common Toxicity Criteria (CTC) grade 1 or 2, 2 CTC grade 3) during a median observation period of 10.9 months. At times of bleeding, RIPA values were significantly lower (14 vs 28 U; P<0.0001). RIPA was impaired in patients receiving concomitant antiplatelet therapy or anticoagulation (14 vs 25 U, P=0.005). A gradual decline of median RIPA values was observed with increasing bleeding severity. Importantly, no CTC grade 2 or 3 bleeding were observed with RIPA values of >36 U. Sequential monitoring indicated a decrease of RIPA values from a median of 17 to 9 U within 2 weeks after initiation of treatment as well as an increase above the critical threshold of 36 U within 7 days when ibrutinib was paused. Low RIPA values were similar during treatment with another BTK inhibitor, CC292. Quantitative assessment of platelet function is a practical tool to monitor bleeding tendency under BTK-inhibitor therapy.

Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium.

BACKGROUND: Venous thromboembolism is a leading cause of morbidity and mortality during pregnancy and the puerperium. However, the role of mutations in the prothrombin and factor V genes and other thrombophilic abnormalities as risk factors for thromboembolism in women during pregnancy and the pueperium is not known. METHODS: In a study of 119 women with a history of venous thromboembolism during pregnancy and the puerperium and 233 age-matched normal women, we measured the activity of antithrombin, protein C, protein S, and lupus anticoagulant. We also performed genetic analyses to detect the G1691A mutation in the factor V gene (factor V Leiden), the G20210A mutation in the prothrombin gene, and the C677T mutation in the methylenetetrahydrofolate reductase gene. Blood samples were obtained at least three months post partum or after the cessation of lactation. RESULTS: Among the women with a history of venous thromboembolism, the prevalence of factor V Leiden was 43.7 percent, as compared with 7.7 percent among the normal women (relative risk of venous thromboembolism, 9.3; 95 percent confidence interval, 5.1 to 16.9); that of the G20210A prothrombin-gene mutation, 16.9 percent as compared with 1.3 percent (relative risk, 15.2; 95 percent confidence interval, 4.2 to 52.6); and that of both factor V Leiden and the G20210A prothrombin-gene mutation 9.3 percent as compared with 0 (estimated odds ratio, 107). Assuming an overall risk of 1 in 1500 pregnancies, the risk of thrombosis among carriers of factor V Leiden was 0.2 percent, among carriers of the G20210A prothrombin-gene mutation, 0.5 percent, and among carriers of both defects, 4.6 percent, as calculated in a multivariate analysis. CONCLUSIONS: The G20210A prothrombin-gene mutation and factor V Leiden individually are associated with an increased risk of venous thromboembolism during pregnancy and the puerperium, and the risk among women with both mutations is disproportionately higher than that among women with only one mutation.

FAN, a novel WD-repeat protein, couples the p55 TNF-receptor to neutral sphingomyelinase.

The initiation of intracellular signaling events through the 55 kDa tumor necrosis factor-receptor (TNF-R55) appears to depend on protein intermediates that interact with specific cytoplasmic domains of TNF-R55. By combined use of the yeast interaction trap system and a peptide scanning library, the novel WD-repeat protein FAN has been identified, which specifically binds to a cytoplasmic nine amino acid binding motif of TNF-R55. This region has been previously recognized as a distinct functional domain that is both required and sufficient for the activation of neutral sphingomyelinase (N-SMase). Overexpression of full-length FAN enhanced N-SMase activity in TNF-treated cells, while truncated mutants of FAN produced dominant negative effects. The data suggest that FAN regulates ceramide production by N-SMase, which is a crucial step in TNF signaling.

Effect of interferon gamma on infection-related death in patients with severe injuries. A randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the efficacy of interferon gamma in reducing infection and death in patients sustaining severe injury. DESIGN: Multicenter, randomized, double-blind, placebo-controlled trial with observation for 60 days and until discharge for patients with major infection on day 60. SETTING: Nine university-affiliated level 1 trauma centers. PATIENTS: Four hundred sixteen patients with severe injuries, assessed by Injury Severity Score and degree of contamination. INTERVENTION: Recombinant human interferon gamma, 100 micrograms, was administered subcutaneously once daily for 21 days (or until patient discharge if prior to 21 days) as an adjunct to standard antibiotic and supportive therapy. MAIN OUTCOME MEASURES: Incidence of major infection, death related to infection, and death. RESULTS: Infection rates were similar in both treatment groups; however, patients treated with interferon gamma experienced fewer deaths related to infection (seven [3%] vs 18 [9%]; P = .008) and fewer overall deaths (21 [10%] vs 30 [14%]; P = .17). While 12 early deaths (days 1 through 7) occurred in each treatment group, late death occurred in 18 placebo-treated patients and nine in interferon gamma-treated patients. The results were dominated by findings at one center, which had the highest enrollment and higher infection and death rates. Statistical analysis did not eliminate the possibility of an unidentified imbalance between arms as an explanation for the results. CONCLUSION: Further evaluation is required to determine the validity of the observed reduction in infection-related deaths in patients treated with interferon gamma.

Improved recognition of cor pulmonale in patients with severe chronic obstructive pulmonary disease.

To compare sensitivity of clinical methods (physical examination, electrocardiogram, and chest radiograph) to echocardiography in the detection of cor pulmonale, and to determine the role of nocturnal oxygen desaturation in its development, 33 non-hypoxemic patients who had severe chronic obstructive pulmonary disease (COPD) were evaluated by clinical methods, echocardiography, and overnight ear oximetry. Compared to 25 age-matched control subjects, COPD patients had higher peak pulmonary systolic pressures by contrast-enhanced Doppler (40 +/- 13 versus 22 +/- 5 mm Hg, or 5.3 +/- 1.7 versus 2.9 +/- 0.7 kPa) and ratios of right to left ventricular volume (1.1 +/- 0.6 versus 0.6 +/- 0.1, both p less than 0.05). Defining cor pulmonale as pulmonary hypertension, right ventricular enlargement, or right ventricular hypertrophy, 25 COPD patients (75 percent) had cor pulmonale by echocardiography and 13 (39 percent) by clinical methods (p less than 0.05). Nocturnal desaturation was present in only 21 percent of patients. Echocardiographic measurements were similar between patients with emphysema and patients with bronchitis, and between patients with and without sleep desaturation. In patients who have severe COPD without waking hypoxemia, cor pulmonale is detected nearly twice as often by echocardiography as by clinical methods, but is usually not associated with sleep desaturation.