A study of thrombophilia testing and counseling practices of family physicians using the script concordance method in Calgary, Canada.

BACKGROUND: Thrombophilia testing helps to identify populations at risk of venous thromboembolism, but motivations for testing individuals are frequently unclear. OBJECTIVES: Our goals were to assess the motivations for thrombophilia testing among family physicians (FPs) to determine whether testing was congruent with expert opinion, and to study counseling practices. METHODS: The FPs and experts completed a survey involving hypothetical thrombophilia patients. Responses between groups were compared using the script concordance method. RESULTS: The FPs referred 35.9% of cases. Of the five scenarios, two resulted in disagreement regarding appropriateness of testing (P ≤ .037). The FPs were more likely to test male, obese, or pediatric patients, patients with a family history of myocardial infarction or infertility, and patients with a recent event (P ≤ .043). The FPs were more likely to counsel patients after testing (P ≤ .016). CONCLUSION: Disagreement exists between physician groups about the utility of thrombophilia testing. Self-reported lack of pretest counseling among FPs warrants further study.

Low-molecular-weight heparin vs heparin in the treatment of patients with pulmonary embolism. American-Canadian Thrombosis Study Group.

BACKGROUND: Pulmonary embolism (PE) occurs in 50% or more of patients with proximal deep-vein thrombosis. Low-molecular-weight heparin treatment is effective and safe in patients with deep vein thrombosis and may also be so in patients with PE. Recent rigorous clinical trials have established objective criteria for determining a high probability of PE by perfusion lung scanning. OBJECTIVE: To compare low-molecular-weight heparin with intravenous heparin for the treatment of patients with objectively documented PE and underlying proximal deep vein thrombosis. METHODS: In a multicenter, double-blind, randomized trial, we compared fixed-dose subcutaneous low-molecular-weight heparin (tinzaparin sodium) given once daily with dose-adjusted intravenous heparin given by continuous infusion using objective documentation of clinical outcomes. Pulmonary embolism at study entry was documented by the presence of high-probability lung scan findings. RESULTS: Of 200 patients with high-probability lung scan findings at study entry, none of the 97 who received low-molecular-weight heparin had new episodes of venous thromboembolism compared with 7 (6.8%) of 103 patients who received intravenous heparin (95% confidence interval for the difference, 1.9%-11.7%; P = .01). Major bleeding associated with initial therapy occurred in 1 patient (1.0%) who was given low-molecular-weight heparin and in 2 patients (1.9%) given intravenous heparin (95% confidence interval for the difference, -2.4% to 4.3%). CONCLUSIONS: Low-molecular-weight heparin administered once daily subcutaneously was no less effective and probably more effective than use of dose-adjusted intravenous unfractionated heparin for preventing recurrent venous thromboembolism in patients with PE and associated proximal deep vein thrombosis. Our findings extend the use of low-molecular-weight heparin without anticoagulant monitoring to patients with submassive PE.

Treatment and prevention of venous thromboembolic disease in pregnancy.

Pulmonary embolism is a major, but potentially preventable, cause of maternal mortality in North America and Europe. Because venous thromboembolism is an infrequent cause of maternal morbidity, there are few randomized clinical trials to guide clinical decision-making with respect to treatment, prevention, and evaluation of innovative management modalities such as low molecular weight heparin. This article focuses on the evidence supporting the current guidelines for the pharmacologic management of venous thromboembolic disease in pregnancy.

Preoperative vs postoperative initiation of low-molecular-weight heparin prophylaxis against venous thromboembolism in patients undergoing elective hip replacement.

BACKGROUND: Although preoperative and postoperative initiation of prophylaxis for deep vein thrombosis (DVT) with low-molecular-weight heparin (LMWH) are effective, the relative effectiveness and safety of these approaches is unknown. In the absence of a published definitive level 1 trial addressing this question, a meta-analysis is appropriate. OBJECTIVE: To report a meta-analysis comparing preoperative with postoperative initiation of prophylaxis of DVT in patients undergoing elective hip replacement. METHODS: Relevant trials were identified, and potential biases in the meta-analysis were minimized by analyzing all rigorously performed randomized trials that met all of the following criteria for conduct of the trial: (1) double-blind design, (2) objective documentation of the frequencies of DVT by ascending contrast venography, (3) venography performed before or at the time of discharge from the hospital, (4) initiation of the same LMWH preoperatively or postoperatively in dosages shown to be effective, (5) compliance with the criteria for a level 1 trial, and (6) objective documentation of major and minor bleeding according to strict criteria. RESULTS: Treatment with LMWH initiated preoperatively was associated with a DVT frequency of 10.0% compared with a frequency of 15.3% when the LMWH was initiated postoperatively (P = .02, Fisher exact test). Major bleeding was less frequent in patients receiving preoperatively initiated LMWH than in patients receiving postoperatively initiated LMWH (0.9%, vs. 3.5%; P = .01, Fisher exact test). CONCLUSIONS: Our findings support the need for a randomized comparison of preoperative and postoperative initiation of pharmacological prophylaxis of DVT. Such a trial would resolve the divergent practices for DVT prophylaxis between Europe and the North American countries, the United States and Canada, and would affect the treatment for thousands of patients on both continents.

Treatment and prevention of venous thromboembolism.

Where available, low-molecular-weight heparin (LMWH) is the recommended approach for initial management of venous thromboembolism. When unfractionated heparin is administered, one of the cited heparin nomograms should be used to ensure that the heparin dose is sufficient to rapidly produce heparin levels in the therapeutic range for all patients. Because of the varying sensitivities of thromboplastins, each laboratory should correlate the activated partial thromboplastin time results with heparin's therapeutic range, which will correspond to 0.35 to 0.70 U of heparin/ml blood when using the antifactor Xa assay. Constant vigilance and a high level of suspicion are necessary to establish the clinical diagnosis of heparin-induced thrombocytopenia, and to institute appropriate therapy. When administering warfarin therapy, physicians should be aware of the sensitivity of the thromboplastin being used to provide the international normalized ratio (INR). To ensure that the patients are maintained within the target therapeutic range for INR (in most cases 2.0 to 3.0), the INR should be determined frequently, and the warfarin dosage should then be adjusted appropriately. Patients with an acute episode of venous thromboembolism should receive warfarin therapy for at least 3 months. At the present time, it is reasonable to treat the first recurrence with oral anticoagulants for 12 months and to indefinitely treat more than one recurrence. All patients at moderate to high risk for developing venous thromboembolism should receive prophylaxis. The approaches of proven value include low-dose heparin, LMWH, oral anticoagulants, and intermittent pneumatic compression.

The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy. The emerging theme of delayed recurrence.

BACKGROUND: Recent clinical trials of venous thromboembolism treatment suggest inadequate initial heparin therapy predisposes patients to late recurrence of thromboembolism. However, a recent review article was unable to demonstrate a relationship between initial heparin therapy and late recurrence. OBJECTIVE: To evaluate the relationship between initial heparin treatment and long-term clinical outcome in 3 consecutive, randomized, double-blind trials that used similar study designs and patient populations and objective documentation of recurrent venous thromboembolism. METHODS: The trials were performed sequentially and compared the use of continuous intravenous with subcutaneous heparin, continuous intravenous heparin for 10 or 5 days, and continuous intravenous heparin with once-daily subcutaneous low-molecular-weight heparin. All patients were followed up for 3 months to assess the a priori hypothesis that inadequate initial heparin therapy could lead to recurrent venous thromboembolism during long-term therapy with warfarin sodium. RESULTS: The following were the observed rates of recurrent venous thromboembolism: continuous intravenous heparin, 3 (5.2%) of 58 patients vs subcutaneous heparin, 11 (19.3%) of 57 patients; continuous intravenous heparin for 10 days, 7 (7.0%) of 100 patients or for 5 days, 7 (7.1%) of 99 patients; and continuous intravenous heparin, 15 (6.9%) of 219 patients vs low-molecular-weight heparin, 6 (2.8%) of 213 patients. Pooled analysis of the patients treated with continuous intravenous heparin showed that of the total 32 patients with recurrent venous thromboembolism, in 6 patients thromboembolism occurred early (< 10 days) and 26 patients thromboembolism occurred late. Of these patients, the majority (20/32 [62.5%]) had therapeutic prothrombin time or international normalized ratio values before or at the time of the recurrent thromboembolic event. CONCLUSION: Our findings demonstrate that the initial heparin treatment affects the long-term outcome. This conclusion applies when these data are analyzed for each individual study by treatment group, observed difference in outcome, and pooled analysis.

Low-molecular-weight heparin therapy and mortality.

There is ample evidence from clinical trials to justify giving certain low-molecular-weight heparins (LMWHs) subcutaneously rather than administering continuous intravenous unfractionated heparin for the initial treatment of venous thromboembolic disease. The LMWHs given by subcutaneous injection have a predictable anticoagulant response and prolonged duration of action. They can, therefore, be administered once or twice daily to treat venous thrombosis. Furthermore, treatment with these agents does not require laboratory monitoring. Eliminating the need for intravenous therapy and for laboratory monitoring should allow patients to be discharged earlier, and eventually lead to the outpatient treatment of venous thromboembolism. Studies to date indicate that LMWH is safer and as effective as continuous intravenous heparin in the treatment of venous thrombosis. The decreased mortality rates seen in two clinical trials, particularly in patients with metastatic cancer, were an unexpected but intriguing finding. This requires further confirmation, in larger prospective randomized trials.

Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis.

BACKGROUND: Randomized trials have demonstrated the importance of achieving adequate heparinization early in the course of therapy. Recently, some authors reported a pooled analysis of selected studies in the literature that suggested that there is no convincing evidence that the risk of recurrent venous thromboembolism is critically dependent on achieving a therapeutic activated partial thromboplastin time result at 24 to 48 hours. METHODS: We provide the analyses of patient groups entered into our series of 3 consecutive double-blind randomized trials evaluating initial heparin therapy for proximal deep venous thrombosis. RESULTS: Logistic regression analysis of the patient groups receiving the less intense initial intravenous heparin dose of 30,000 U/24 h demonstrated that subtherapy for 24 hours predicted the onset of venous thromboembolic events. Failure to achieve a therapeutic activated partial thromboplastin time by 24 hours was associated with a 23.3% frequency of venous thromboembolism vs 4% to 6% for those whose activated partial thromboplastin time exceeded the therapeutic threshold by 24 hours (P=.02). Time-to-event analysis shows the increased frequency of recurrent venous thromboembolic events during the period of study in patients who were subtherapeutic for 24 hours compared with those who were therapeutic (P=.001). CONCLUSIONS: Our findings reaffirm the clinical importance of rapidly achieving therapeutic levels of heparin. Patients who failed to achieve the therapeutic threshold by 24 hours were at an increased risk of subsequent recurrent venous thromboembolism. These findings are independently supported by the results of a randomized trial comparing different intensities of initial heparin treatment by continuous infusion.

Calcineurin-mediated dephosphorylation of the human placental membrane receptor for epidermal growth factor urogastrone.

The findings of our work were 2-fold: (1) calcineurin (from bovine brain) can catalyze the complete dephosphorylation of the phosphotyrosine and phosphoserine residues in the human placental receptor for epidermal growth factor urogastrone (EGF-URO), and (2) the major calmodulin-binding protein of human placental membranes is a calcineurin-related protein. In terms of its metal ion dependence (Ni2+ greater than Mn2+ greater than Co2+), its calmodulin dependence, and its sensitivity to inhibitors (Zn2+, fluoride, orthovanadate), the phosphotyrosyl protein phosphatase activity of calcineurin, using the EGF-URO receptor as substrate, paralleled the enzyme activity measured with p-nitrophenyl phosphate (PNPP) as a substrate. These characteristics distinguish calcineurin from other classes of protein phosphotyrosyl phosphatases. Calcineurin purified from placental membranes was similar to, if not identical with, bovine brain calcineurin in terms of enzymatic specific activity toward PNPP, subunit electrophoretic mobilities, and immunological cross-reactivity. The enzymatic properties and comparative abundance of calcineurin in the placenta membranes suggest that this enzyme may play an important role in regulating the phosphorylation state of those receptors (e.g., for EGF-URO or insulin) also known to be present in the membranes.

Ca2+-dependent hydrophobic-interaction chromatography. Isolation of a novel Ca2+-binding protein and protein kinase C from bovine brain.

Several bovine brain proteins have been found to interact with a hydrophobic chromatography resin (phenyl-Sepharose CL-4B) in a Ca2+-dependent manner. These include calmodulin, the Ca2+/phospholipid-dependent protein kinase (protein kinase C) and a novel Ca2+-binding protein that has now been purified to electrophoretic homogeneity. This latter protein is acidic (pI 5.1) and, like calmodulin and some other high-affinity Ca2+-binding proteins, exhibits a Ca2+-dependent mobility shift on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, with an apparent Mr of 22 000 in the absence of Ca2+ and Mr 21 000 in the presence of Ca2+. This novel calciprotein is distinct from known Ca2+-binding proteins on the basis of Mr under denaturing conditions, Cleveland peptide mapping and amino acid composition analysis. It may be a member of the calmodulin superfamily of Ca2+-binding proteins. This calciprotein does not activate two calmodulin-dependent enzymes, namely cyclic nucleotide phosphodiesterase and myosin light-chain kinase, nor does it have any effect on protein kinase C. It may be a Ca2+-dependent regulatory protein of an as-yet-undefined enzymic activity. The Ca2+/phospholipid-dependent protein kinase is also readily purified by Ca2+-dependent hydrophobic-interaction chromatography followed by ion-exchange chromatography, during which it is easily separated from calmodulin. A preparation of protein kinase C that lacks contaminating kinase or phosphatase activities is thereby obtained rapidly and simply. Such a preparation is ideal for the study of phosphorylation reactions catalysed in vitro by protein kinase C.