Nattokinase atherothrombotic prevention study: A randomized controlled trial.

BACKGROUND: Described to be antithrombotic and antihypertensive, nattokinase is consumed for putative cardiovascular benefit. However, no large-scale, long-term cardiovascular study has been conducted with nattokinase supplementation. OBJECTIVE: To determine the effect of nattokinase on subclinical atherosclerosis progression and atherothrombotic biomarkers. METHODS: In this double-blinded trial, 265 individuals of median age 65.3 years, without clinical evidence of cardiovascular disease (CVD) were randomized to oral nattokinase 2,000 fibrinolytic units or matching placebo. Primary outcome was rate of change in subclinical atherosclerosis measured by serial carotid ultrasound every 6 months as carotid artery intima-media thickness (CIMT) and carotid arterial stiffness (CAS). Additional outcomes determined at least every 6 months were clinical parameters including blood pressure and laboratory measures including metabolic factors, blood rheology parameters, blood coagulation and fibrinolysis factors, inflammatory markers and monocyte/macrophage cellular activation markers. RESULTS: After median 3 years of randomized treatment, annualized rate of change in CIMT and CAS did not significantly differ between nattokinase supplementation and placebo. Additionally, there was no significant effect of nattokinase supplementation on blood pressure or any laboratory determination. CONCLUSIONS: Results of this trial show that nattokinase supplementation has a null effect on subclinical atherosclerosis progression in healthy individuals at low risk for CVD.

Eculizumab therapy results in rapid and sustained decreases in markers of thrombin generation and inflammation in patients with PNH independent of its effects on hemolysis and microparticle formation.

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a clonal bone marrow disorder which results in the loss of glycosylphosphatidyl inositol (GPI) anchors from cell membranes. As a consequence, membrane inhibitors of complement are lost rendering the cells more susceptible to complement mediated destruction. This results in hemolysis, leukopenia, thrombocytopenia and thrombophilia. Eculizumab, a monoclonal antibody to complement protein 5, has been approved for the treatment of PNH and is associated with a significant reduction in hemolysis, thromboembolic events and fatigue. We prospectively studied the effect of Eculizumab therapy on plasma markers of thrombin generation (D-Dimers, TAT), inflammation (IL-6), soluble P-selectin (sP-selectin), antigenic (TFMP) and functional (fTFMP) tissue factor bearing microparticles and total plasma microparticle ex vivo factor Xa generation (MPFXa) in eleven Eculizumab naive PNH patients. Blood sampling occurred day 1, prior to Eculizumab treatment, then on days 8,15,22,29, 43, 90. Our results demonstrate a statistically significant reduction in D-Dimer, TAT, IL-6, sP-selectin, and TFMP during the induction phase of treatment (day 1-29) which was sustained during the maintenance treatment (day 29-90). Although the serum LDH levels decreased rapidly, there was no correlation between the change in LDH and the markers of thrombin generation and inflammation. Although there was a statistically significant decrease in TFMP, this decrease did not correlate with changes in markers of thrombin generation or inflammation. Ex vivo MPFXa generation did not decrease with Eculizumab treatment suggesting continued microparticle formation despite inhibition of hemolysis. Ex vivo total microparticle FXa generation was found to have an inverse correlation with markers of thrombin generation, suggesting that in PNH patients in vivo thrombin generation occurs by a pathway independent of hemolysis and microparticle generation.

Subclinical haemostatic activation and current surgeon volume predict bleeding with open radical retropubic prostatectomy.

OBJECTIVE: To assess subclinical haemostatic activation and clinical variables to predict bleeding during radical retropubic prostatectomy (RP), as haemostatic activation is common in cancer and might be useful for predicting outcomes, but routine coagulation screening does not correlate with bleeding. PATIENTS AND METHODS: Clinical data and blood samples were collected from 153 patients (median age 63 years; prostate-specific antigen, PSA, level 5.92 ng/mL) before RP and lymph node dissection. Plasma was assayed for d-dimer and thrombin-antithrombin complex (TAT). Univariable then multivariable analyses were used to identify associations between plasma markers and clinical variables for bleeding and thrombosis. RESULTS: Most patients (77%) were stage T1c and most (76.5%) had organ-confined cancer (< or =pT2). Pathological Gleason scores were < or =6 in 68 (44.4%) and > or =8 in 14 (9%) of the patients. The median (range) estimated blood loss (EBL) was 400 (50-3000) mL, the median decrease in haemoglobin level 3.5 (-0.1, 6.6) g/dL, and eight men (5.2%) required a transfusion. In the univariable analysis, a lower TAT before RP (P < 0.001) and d-dimer level (P = 0.023) correlated with a greater decline in haemoglobin level. The platelet count, international normalised ratio, and activated partial thromboplastin time (aPTT) did not predict the EBL nor change in haemoglobin level; the eight transfused patients had lower platelet counts before RP (P = 0.004). Higher surgical volume predicted a lower EBL (P < 0.001) and lower decrease in haemoglobin (P < 0.05). Multivariable linear regression showed that TAT remained significant for the decrease in haemoglobin, and surgical volume for EBL and decrease in haemoglobin. CONCLUSIONS: Haemostatic activation before RP was associated with significantly less bleeding when assessed by objective measures, predicting the decrease in haemoglobin level better than prothrombin time, aPTT or platelet counts. Current surgeon volume might also predict both subjective and objective bleeding variables.

Chemotherapy-induced activation of hemostasis: effect of a low molecular weight heparin (dalteparin sodium) on plasma markers of hemostatic activation.

PURPOSE: To evaluate the effect of standard chemotherapeutic regimens on the hemostatic profile of patients with breast and lung carcinoma; and to evaluate the effect of a single dose of a low molecular weight (LMW) heparin, dalteparin sodium, administered prior to the chemotherapy on markers of hemostatic activation. PATIENTS AND METHODS: 11 patients with breast cancer and 10 patients with lung cancer receiving systemic chemotherapy were studied. 10 breast cancer patients and 9 lung cancer patients completed at least 1 cycle of treatment and had all hemostatic studies. Patients had a complete hemostatic and prothrombotic profile performed at study initiation. Markers of hemostatic activation consisting of immunoassays for thrombin-antithrombin (TAT) complex and D-dimer were measured in plasma samples obtained prior to chemotherapy and at 1, 24 and 48 h after treatment. A 2500 U dose of dalteparin was given prior to the 2nd cycle of chemotherapy; 5000 U of dalteparin was given prior to the 4th treatment cycle. RESULTS: Chemotherapy resulted in statistically significant increases in TAT and D-dimer for the 1, 24 and 48 h plasma samples in both the breast and lung cancer patients for all cycles of chemotherapy given without LMW heparin. There were statistically significant increases in basal thrombin generation over the 4 cycles of treatment which was unrelated to active cancer. Both pretreatment doses of dalteparin effectively prevented increases in the markers of hemostatic activation. However, in the lung cancer patients, who had significantly increased basal thrombin generation, the 5000 U dose dalteparin was more effective. CONCLUSION: Chemotherapy results in significant hemostatic activation in patients with breast and lung cancer. The effect of treatment appears to be cumulative. A single dose of LMW heparin administered prior to therapy can suppress hemostatic activation.