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Introduction: Prothrombin G20210A (PT20210) carriers have increased prothrombin levels and increased risk for venous thrombosis. We hypothesized PT20210 carriers would have decreased PT, aPTT, and dRVVT clotting times., Methods: We reviewed 1186 thrombotic risk panels that included PT, aPTT, dRVVT, and PT20210 genotype with potential confounding variables, excluding samples consistent with anticoagulant therapy or lupus anticoagulant presence. We examined relationships of PT20210 with PT, aPTT, and dRVVT correcting for covariates using multivariate regression. We confirmed associations in 1876 separate panel results and a group of homozygotes for PT20210 and used general linear models to determine if associated tests predict PT20210 status., Results: Neither PT, aPTT, nor dRVVT was shorter in PT20210 carriers. Contrary to our hypothesis, PT20210 was significantly associated with higher dRVVT (p=0.001), but not PT or aPTT. dRVVT differences were significant in a replicate sample p=0.035 and an additional sample of PT20210 homozygotes (p=0.02). Of all variables available, only dRVVT predicted PT20210 carrier status (p=0.0008, AUC=0.64)., Conclusions: We observed an association between longer dRVVT and the prothrombin G20210A mutation in a retrospective observational study. These findings merit further study in large well-characterized clinical cohorts and laboratory research experiments., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: In clinical trials, fixed-dose enoxaparin (40 mg once daily) reduces the risk of venous thromboembolism (VTE) in medically-ill patients. However, morbidly obese patients were under-represented in these trials and using fixed-dose enoxaparin in obese patients may be inadequate. We completed a pharmacokinetic study in morbidly obese, medically-ill patients to determine if weight-based dosing of enoxaparin for VTE prophylaxis was feasible, without excessive levels of anticoagulation, as determined by peak anti-Xa levels., Materials and Methods: Twenty eight morbidly obese (BMI>or=35 kg/m(2)) patients were enrolled and completed the study protocol. Enoxaparin 0.5 mg/kg was administered once daily subcutaneously and peak anti-Xa levels were measured approximately 4-6 hours after the enoxaparin dose., Results and Conclusions: Overall, 46% of patients were female, the average age (+/-SD) was 54 (+/-11) years, and the average weight and BMI were 135.6 kg (+/-25.3) and 48.1 kg/m(2) (+/-11.1), respectively. The average daily dose of enoxaparin was 67 mg (+/-12). The average peak anti-Xa level was 0.25 (SD+/-0.11, range 0.08 to 0.59) units/mL. Peak anti-Xa levels did not significantly correlate with weight or BMI. There were no bleeding events, symptomatic VTE, or significant thrombocytopenia. In morbidly obese, medically-ill patients, use of weight-based enoxaparin dosed at 0.5 mg/kg once daily is feasible and results in peak anti-Xa levels within or near recommended range for thromboprophylaxis, without any evidence of excessive anti-Xa activity. These data suggest that this weight-based regimen may be more effective than standard fixed-dose enoxaparin. Clinical outcome studies are warranted to determine the clinical safety and efficacy of this regimen., ((c) 2009 Elsevier Ltd. All rights reserved.)

Anticoagulant therapy for the typical venous thromboembolism patient is straightforward with predictably favorable outcomes. However, for certain patients with venous thromboembolism, there remains uncertainty and controversy about optimal treatment. These controversial areas include venous thromboembolism patients with: heparin resistance, renal insufficiency, morbid obesity, cancer, antiphospholipid antibody syndrome, recurrent thrombosis despite appropriate anticoagulation, and patients with unprovoked VTE who may or may not benefit from thrombophilia testing. This review summarizes the current data for these special patient populations with venous thromboembolism and provides our recommendations for management.

Although unfractionated heparin (UFH) is standard therapy for venous thromboembolism, there is a clinical failure rate of up to 10%. Newer treatment strategies include low-molecular-weight heparins (LMWH). As part of an international study comparing the efficacy and safety of enoxaparin, a LMWH versus UFH in patients with venous thromboembolism, we studied the effects of enoxaparin and UFH on the plasma concentrations of two activation peptides, fragment 1 + 2 (F1 + 2), and thrombin-antithrombin III (TAT) complexes. We hypothesized that enoxaparin would be more effective in suppressing activation of coagulation. Intravenous heparin was given by bolus injection followed by infusion. There were 2 enoxaparin treatment groups (1 mg/kg s.c., bid and 1.5 mg/kg s.c. daily). Plasma samples were obtained from 11 patients in the enoxaparin group and 6 patients in the heparin group prior to and at 6 hour intervals after initiating therapy. Clinical characteristics of the enoxaparin and UFH patient groups were similar. TAT concentrations were not statistically different between groups at any treatment interval. However, plasma F1 + 2 concentrations differed significantly (p < 0.05); concentrations in the enoxaparin group were consistently lower over time than in the UFH group. These results suggest that this LMWH is more effective in suppressing ongoing thrombosis in vivo than UFH in patients with venous thrombosis.

Procoagulant albumin (Pro-Alb) is an anionic form of albumin isolated from normal human plasma that regulates vascular endothelial cell hemostatic properties, including induction of tissue factor activity. We investigated the biochemical modification of Pro-Alb that was associated with procoagulant-inducing activity. Tryptic digestion of Pro-Alb identified greatest bioactivity in the carboxy-terminus of the molecule, a region associated with lipid binding sites. Activated charcoal treatment and phopholipase C digestion reduced the procoagulant-inducing activity of Pro-Alb, and Pro-Alb contained 2.3-fold more phosphorus than inactive albumin. We conclude that modification of albumin by phospholipid imparts tissue factor-inducing activity to Pro-Alb.

Previous studies have indicated that the skin bleeding time test does not accurately reflect visceral bleeding time (BT). The present study examines the predictive value of the skin bleeding time for brain bleeding tendency. Sixteen Sprague-Dawley rats were divided into equal groups. The first group (controls) underwent standardized skin and brain bleeding time tests under general anesthesia. Mean skin BT was found to be 168.8 sec with a standard deviation of +/- 20.8 sec. Mean brain BT was found to be 172.5 sec with a standard deviation of +/- 19.6 sec. The second group was given 23.2 mg/kg of aspirin per day for five days prior to skin and brain BT testing. Mean skin BT in this group was 315 seconds with a standard deviation of +/- 72.2 sec which proved to be significantly different from the control skin BT (P = 0.0005). Brain BT in the aspirin treated group was 155.6 sec with a standard deviation of +/- 22.6 sec. Brain BT in both control and aspirin treated groups was not significantly different (P = 0.13). All animals were euthanized 30 minutes after brain BT and their brains harvested. One animal in the control group showed evidence of a small subcortical hemorrhage upon brain sectioning. Sectioned brains in the aspirin-treated group showed no evidence of subcortical hematoma. The results indicate that skin BT is prolonged by aspirin administration, but brain bleeding time is unaffected. Brain hemostasis is likely more dependent on intrinsic procoagulant than platelet function. The skin BT test may therefore be of little utility as a preoperative screening test for neurosurgical patients.

Procoagulant albumin (P-Al) is present in normal human plasma and increases monocyte and endothelial cell expression of tissue factor activity. To develop a bioassay for P-Al, we partially purified plasma from healthy volunteers and several patient groups using BaCl2 and (NH4)2SO4 precipitation. The samples were assayed for tissue factor (TF) inducing activity, expressed as a percentage increase compared to a serum-free media control. Over six months, the assay was reproducible in stored samples and in serial samples from normal volunteers. The plasma P-Al activities of 35 volunteers averaged 141 +/- 8.2% (SEM). There was no diurnal variation. There was no difference in the P-Al activity after a 12 hour fast and 2 hours after a large meal in 4 healthy volunteers. There was no increase in activity (r = 0.16) with the subject's age. The average activity from 16 poorly-controlled diabetics was 131 +/- 11% (SEM). No alteration in activity was seen with samples from patients with uremia, liver dysfunction, hemophilia, thrombotic events, or adenocarcinoma. These results indicate that P-Al activity can be bioassayed in individual patient samples; however, pathologic states associated with abnormal P-Al-induced tissue factor activity presently remain unidentified.

Endothelial cell regulation of protein C activation and fibrinolysis are important components of the hemostatic response to vascular injury or perturbation. Procoagulant albumin (P-A1), a constituent of normal human plasma has been purified and identified as an inducer of endothelial cell tissue factor activity. The purpose of the studies reported herein was to investigate the effects of P-A1 on human endothelial cell protein C activation and fibrinolysis. P-A1 suppressed protein C activation, enhanced release of plasminogen activator inhibitor-1, but had no effect on tissue-plasminogen activator release. Plasminogen activator inhibitor-1 released by P-A1 was functional as evidenced by the capacity to form a covalent complex with 125I-urokinase. Inactive albumin (isolated during the same purification procedure as P-A1, but without tissue factor-inducing activity) did not suppress protein C activation or increase plasminogen activator inhibitor-1 release. These results indicate that P-A1, a component of human plasma, can modulate multiple vascular hemostatic properties, and support the hypothesis that P-A1 is involved in normal or pathologic hemostasis.

Factor Xa-catalyzed prothrombin activation occurs on cellular surfaces, including those of vascular endothelial cells. In a reconstituted model, endothelial cells and platelets acted synergistically to maximally activate prothrombin in the presence of Factor Xa. Synergism was observed at platelet concentrations less than 1 X 10(8)/ml. Thrombin formation was required for optimal prothrombin activation by endothelial cells and Factor Xa, with thrombin serving as an activator of Factor V. These data provide additional support for the hypothesis that vascular endothelium is a physiologic surface for hemostasis.

The clinical course of a patient with a well-differentiated monocytic leukemia which later underwent blastic transformation is described. Cytochemical, ultrastructural and cell surface analysis data were obtained at periods throughout her illness and correlated with the blastic transformation. Although surface markers characteristic of monocytic leukemia persisted, a deficiency of peroxidase in the granules of this patient's monocytes was observed as well as loss of alpha-naphthyl butyrate esterase staining during transformation.