Fondaparinux combined with intermittent pneumatic compression vs. intermittent pneumatic compression alone for prevention of venous thromboembolism after abdominal surgery: a randomized, double-blind comparison.

BACKGROUND: The benefit of combined mechanical and pharmacologic methods for venous thromboembolism prevention after abdominal surgery has not been clearly established. OBJECTIVES: To compare the efficacy and safety of fondaparinux in conjunction with intermittent pneumatic compression vs. intermittent pneumatic compression alone in this context. PATIENTS AND METHODS: This was a randomized, double-blind, placebo-controlled superiority trial. Patients aged at least 40 years undergoing abdominal surgery were randomized to receive either fondaparinux 2.5 mg or placebo s.c. for 5-9 days, starting 6-8 h postoperatively. All patients received intermittent pneumatic compression. The primary efficacy outcome was venous thromboembolism up to day 10. The main safety outcomes were major bleeding and all-cause mortality. Follow-up lasted 32 days. RESULTS: Of the 1309 patients randomized, 842 (64.3%) were evaluable for efficacy. The venous thromboembolism rate was 1.7% (7/424) in the fondaparinux-treated patients and 5.3% (22/418) in the placebo-treated patients (odds ratio reduction 69.8%; 95% confidence interval 27.9-87.3; P = 0.004). Fondaparinux significantly reduced the proximal deep vein thrombosis rate from 1.7% (7/417) to 0.2% (1/424; P = 0.037). Major bleeds occurred in 1.6% (10/635) and 0.2% (1/650) of fondaparinux-treated and placebo-treated patients, respectively (P = 0.006), none being fatal or involving a critical organ. By day 32, eight patients (1.3%) receiving fondaparinux and five (0.8%) receiving placebo had died. CONCLUSIONS: In patients undergoing abdominal surgery and receiving intermittent pneumatic compression, fondaparinux 2.5 mg reduced the venous thromboembolism rate by 69.8% as compared to pneumatic compression alone, with a low bleeding risk as compared to placebo.

Traces of factor VIIa modulate thromboplastin sensitivity to factors V, VII, X, and prothrombin.

BACKGROUND: Thromboplastin reagents are used to conduct prothrombin time (PT) clotting tests to monitor oral anticoagulant therapy and screen for clotting factor deficiencies. Thromboplastins made from purified, recombinant tissue factor are generally more sensitive to changes in plasma factor (F) VII levels than are thromboplastins prepared from tissue extracts. This may be problematic as FVII's short plasma half-life can result in day-to-day fluctuation during oral anticoagulant therapy. We hypothesized that trace contamination of tissue-derived thromboplastins with FVII(a) blunts sensitivity to plasma FVII levels. METHODS: Traces of purified FVIIa were added to thromboplastin reagents prepared using recombinant human tissue factor and the effect on sensitivity to individual clotting factors was quantified in PT clotting assays. RESULTS AND CONCLUSIONS: Adding 5-100 pm FVIIa not only decreased thromboplastin sensitivity to plasma FVII, it surprisingly increased sensitivity to plasma levels of FV, FX and prothrombin. In addition, traces of FVIIa interacted with changes in the salt content and phospholipid composition of recombinant thromboplastins to further modulate their sensitivities to individual clotting factors. These results help explain how thromboplastin reagents of differing composition exhibit differing sensitivities to individual clotting factor levels. Implications of our results for monitoring oral anticoagulant therapy and other uses of the PT assay are discussed.

Phospholipid composition controls thromboplastin sensitivity to individual clotting factors.

BACKGROUND: Tissue factor is the active ingredient in thromboplastin reagents used to perform prothrombin time (PT) clotting tests to monitor oral anticoagulant therapy and to screen for clotting factor deficiencies. Thromboplastins are complex mixtures prepared from extracts of brain or placenta, although newer thromboplastins contain recombinant tissue factor incorporated into phospholipid vesicles. Thromboplastins can vary widely in their sensitivity to reductions in the levels of vitamin K-dependent clotting factors. A system to compensate for this, the International Sensitivity Index (ISI) and International Normalized Ratio (INR), has revolutionized the monitoring of oral anticoagulant therapy. The INR system is also sometimes used to monitor coagulopathies in patients with sepsis or liver failure, applications for which it was not originally designed and for which it has not been rigorously validated. OBJECTIVES: To better understand thromboplastin performance, we systematically investigated which properties of recombinant thromboplastins influence their sensitivities to changes in the levels of specific clotting factors. RESULTS: We now report that relative sensitivities to changes in the plasma levels of factors V, VII, X (FV, FVII, FX) and prothrombin are differentially influenced by a recombinant thromboplastin's content of phospholipid and sodium chloride. Furthermore, thromboplastins of similar ISI values may exhibit quite different sensitivities to each of these clotting factors. CONCLUSIONS: Differing sensitivities of thromboplastin reagents to individual clotting factor levels have implications for monitoring of oral anticoagulant therapy and interpreting results of the PT assay.

Age and stage dependency of estrogen receptor expression by lymphocyte precursors.

Sex steroids negatively regulate B lymphopoiesis in adult mice. Paradoxically, lymphocytes arise during fetal life, when estrogen levels are high and maternal lymphopoiesis is suppressed. Here we demonstrate that embryonic B lymphopoiesis was unaffected by estrogen, but sensitive to glucocorticoids. Both fetal and adult precursors contained glucocorticoid receptor transcripts, but only adult precursors expressed estrogen receptor alpha and beta together with the androgen receptor. Fetal hematopoietic cells did not efficiently acquire functional estrogen receptors after transplantation to irradiated adult mice. Sex steroid receptors were also expressed in a stage- and developmental age-dependent fashion in human precursors. A developmental switch in responsiveness of hematopoietic cells to sex steroids may be essential for formation of the immune system.

Relatively normal human lymphopoiesis but rapid turnover of newly formed B cells in transplanted nonobese diabetic/SCID mice.

Human B lineage lymphocyte precursors in chimeric nonobese diabetic/SCID mice transplanted with umbilical cord blood cells were directly compared with those present in normal bone marrow. All precursor subsets were represented and in nearly normal proportions. Cell cycle activity and population dynamics were investigated by staining for the Ki-67 nuclear Ag as well as by incorporation experiments using 5-bromo-2'-deoxyuridine. Again, this revealed that human B lymphopoiesis in chimeras parallels that in normal marrow with respect to replication and progression through the lineage. Moreover, sequencing of Ig gene rearrangement products showed that a diverse repertoire of V(H) genes was utilized by the newly formed lymphocytes but there was no evidence for somatic hypermutation. The newly formed B cells frequently acquired the CD5 Ag and had a short life span in the periphery. Thus, all molecular requirements for normal B lymphocyte formation are present in nonobese diabetic/SCID mice, but additional factors are needed for recruitment of B cells into a fully mature, long-lived pool. The model can now be exploited to learn about species restricted and conserved environmental cues for human B lymphocyte production.

An association between plasma free protein s concentration and risk of coronary heart disease in middle-aged men.

Protein S is a vitamin K-dependent protein with anticoagulant properties. Case series have reported reduced plasma concentrations in patients with arterial thromboses, while other studies have reported increased levels in patients with coronary heart disease (CHD). The present study sought to clarify the relation between free protein S and risk of CHD. A prospective survey was conducted of 3000 men aged 50 to 61 years, free of clinical CHD at baseline. Free protein S was measured by commercial immunoassay. End-points recorded were sudden coronary death, first nonfatal and fatal myocardial infarction (MI), surgical intervention for symptomatic, angiographically demonstrated CHD, and all-causes mortality. Statistical analysis employed univariate incidence rate ratios followed by Cox proportional hazards regression. There were 168 CHD events recorded during 21,000 person-years of risk. Mean free protein S concentration was 6% higher in those who developed CHD than in the remainder, the crude hazard ratio (HR) for a one standard deviation (S.D.) increase in free protein S being 1.25 (95% CI, 1.08-1.25). Free protein S was associated with cholesterol concentration and other conventional CHD risk factors. In multivariate regression analysis, after adjustment for conventional CHD risk factors a 1 S.D. increase in free protein S was associated with a HR of 1.15 (0.98-1.35) for CHD, of borderline conventional statistical significance. This association of free protein S with risk of CHD may reflect effects of plaque-destabilising inflammatory activity on protein S levels.

Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. Enoxaparin Clinical Trial Group.

BACKGROUND: Patients undergoing hip or knee joint replacement are at risk for venous thromboembolic complications for up to twelve weeks postoperatively. We evaluated the efficacy and safety of a prolonged post-hospital regimen of enoxaparin, a low-molecular-weight heparin, in this patient population. METHODS: Following elective total hip or knee replacement, 968 patients received subcutaneous enoxaparin (30 mg twice daily) for seven to ten days, and 873 were then randomized to receive three weeks of double-blind outpatient treatment with either enoxaparin (40 mg once daily) or a placebo. The primary efficacy end point was the prevalence of objectively confirmed venous thromboembolism or symptomatic pulmonary embolism during the double-blind phase of treatment. RESULTS: Of the 873 randomized patients, 435 underwent elective total hip replacement and 438 underwent elective total knee replacement. Enoxaparin was superior to the placebo in reducing the prevalence of venous thromboembolism in patients treated with hip replacement: 8.0% (eighteen) of the 224 patients treated with enoxaparin had venous thromboembolism compared with 23.2% (forty-nine) of the 211 patients treated with the placebo (p < 0.001; odds ratio, 3.62; 95% confidence interval, 2.00 to 6.55; relative risk reduction, 65.5%). Enoxaparin had no significant benefit in the patients treated with knee replacement: thirty-eight (17.5%) of the 217 patients treated with enoxaparin had venous thromboembolism compared with forty-six (20.8%) of the 221 patients treated with the placebo (p = 0.380; odds ratio, 1.24; 95% confidence interval, 0.76 to 2.02; relative risk reduction, 15.9%). Symptomatic pulmonary embolism developed in three patients, one with a hip replacement and two with a knee replacement; all had received the placebo. There was no significant difference in the prevalence of hemorrhagic episodes or other types of toxicity between the enoxaparin and placebo-treated groups. CONCLUSIONS: Prolonging enoxaparin thromboprophylaxis following hip replacement for a total of four weeks provided therapeutic benefit, by reducing the prevalence of venous thromboembolism, without compromising safety. A similar benefit was not observed in patients treated with knee replacement.

Predictive value of compression ultrasonography for deep vein thrombosis in symptomatic outpatients: clinical implications of the site of vein noncompressibility.

BACKGROUND: Compression ultrasonography has a high negative predictive value for deep vein thrombosis in symptomatic outpatients. Limited data are available on factors influencing positive predictive value. The objective of this study was to evaluate the positive predictive value of compression ultrasonography according to the anatomic site of vein noncompressibility. METHODS: We performed a prospective cohort study of 756 consecutive outpatients with suspected first-episode deep vein thrombosis. Compression ultrasonography was performed at the initial visit: results were abnormal if a noncompressible segment was identified or normal if all segments were fully compressible. Venography was performed in patients with abnormal compression ultrasonography results. Positive predictive value was determined according to the site of noncompressibility: common femoral vein only, popliteal vein only, or both sites. Venography was the reference standard for the presence of deep vein thrombosis. RESULTS: Positive predictive value was 16.7% (95% confidence interval, 0.4%-64.1%) for noncompressibility isolated to the common femoral vein compared with 91.3% (95% confidence interval, 72.0%-98.9%) for the popliteal vein only and 94.4% (95% confidence interval, 72.7%-99.9%) for both sites (P<.001). Of 15 patients with isolated noncompressibility of the common femoral vein, 8 (53%) had pelvic neoplasm or abscess compared with 2 (5%) of 42 with noncompressibility of the popliteal vein only and 6 (13%) of 47 with noncompressibility of both sites (P<.001). CONCLUSIONS: The positive predictive value of noncompressibility isolated to the common femoral vein is too low to be used alone as the diagnostic end point for giving anticoagulant therapy. Noncompressibility isolated to the common femoral vein is a diagnostic marker for pelvic disease.

Antibodies to thrombomodulin are found in patients with lupus anticoagulant and unexplained thrombosis.

OBJECTIVE: To test the hypothesis that thrombomodulin (TM) may be a target for lupus anticoagulant (LAC) antibodies. METHODS: A recombinant soluble form of TM was produced and used as an antigen for an ELISA to detect antibodies to TM (TMAB). Sixty-one samples from 58 patients identified by the coagulation laboratory as having a LAC and 200 patients with unexplained thrombosis were evaluated along with 201 healthy controls. RESULTS: Eighteen (30%) of the 58 patients with a LAC and 20 (10%) of 200 patients with unexplained thrombosis had antibodies to TM. Similar antibodies were found in only 4 (2%) of 201 normal controls. TMAB show selectivity for TM lacking chondroitin sulfate, but do not otherwise have an immunodominant region. The IgG from 6 patients with TMAB was purified, and it bound TM in our ELISA. Three of the 6 IgG fractions inhibited protein C activation 40% to 70% compared to no inhibition in 7 healthy controls. CONCLUSION: Some patients with LAC and unexplained thrombosis have antibodies to TM that may arise in response to TM that has been altered and lost its chondroitin sulfate attachment. Antibodies to TM may be an important risk factor for inflammation and thrombosis in these patients.

Hyperhomocysteinemia, aortic thrombus, and peripheral arterial emboli--a case report.

A young Native American woman presented with ischemia of the left lower limb resulting from embolic occlusion of the left common iliac artery and left femoral artery. The source of her emboli was aortic thrombus. The only underlying abnormality responsible for her hypercoagulability appeared to be hyperhomocysteinemia.

A comparison of danaparoid and warfarin for prophylaxis against deep vein thrombosis after total hip replacement: The Danaparoid Hip Arthroplasty Investigators Group.

Orgaran (danaparoid sodium injection) is a novel antithrombotic agent. Early studies suggest that this compound may be beneficial in preventing deep vein thrombosis in predisposed patients. This multicenter, randomized, assessor blinded, clinical trial compared subcutaneous danaparoid with warfarin for the prevention of deep vein thrombosis in patients undergoing hip replacement surgery. Bilateral venography was used to detect thrombi. Patients also underwent follow-up examinations 1, 2, and 3 months after discontinuation of the study to determine the after effects of treatment. Nearly 27% of patients who received warfarin and 14.6% of patients who received danaparoid developed deep vein thrombosis, a risk reduction of 46%. The absolute difference in the incidence of deep vein thrombosis was 12.3% in favor of danaparoid. The incidence of venographically documented proximal deep vein thrombosis was 1.5% for danaparoid and 4.1% for warfarin. These results demonstrate that danaparoid is more effective than warfarin in preventing deep vein thrombosis following hip replacement surgery. The preoperative administration of danaparoid does not increase surgical blood loss compared with warfarin.

PFA-100 system: a new method for assessment of platelet dysfunction.

The PFA-100 system is a platelet function analyzer designed to measure platelet-related primary hemostasis. The instrument uses two disposable cartridges: a collagen/epinephrine (CEPI) and a collagen/ADP (CADP) cartridge. Previous experience has shown that CEPI cartridges detect qualitative platelet defects, including acetylsalicylic acid (ASA)-induced abnormalities, while CADP cartridges detect only thrombocytopathies and not ASA use. In this seven-center trial, 206 healthy subjects and 176 persons with various platelet-related defects, including 127 ASA users, were studied. The platelet function status was determined by a platelet function test panel. Comparisons were made as to how well the defects were identified by the PFA-100 system and by platelet aggregometry. The reference intervals for both cartridges, testing the 206 healthy subjects, were similar to values described in smaller studies in the literature [mean closure time (CT) 132 s for CEPI and 93 s for CADP]. The use of different lot numbers of cartridges or duplicate versus singleton testing revealed no differences. Compared with the platelet function status, the PFA-100 system had a clinical sensitivity of 94.9% and a specificity of 88.8%. For aggregometry, a sensitivity of 94.3% and a specificity of 88.3% were obtained. These values are based on all 382 specimens. A separate analysis of sensitivity by type of platelet defect, ASA use versus congenital thrombocytopathies, revealed for the PFA-100 system a 94.5% sensitivity in identifying ASA users and a 95.9% sensitivity in identifying the other defects. For aggregometry, the values were 100% for ASA users and 79.6% for congenital defects. Analysis of concordance between the PFA-100 system and aggregometry revealed no difference in clinical sensitivity and specificity between the systems (p > 0.9999). The overall agreement was 87.5%, with a Kappa index of 0.751. The two tests are thus equivalent in their ability to identify normal and abnormal platelet defects. Testing 126 subjects who took 325 mg ASA revealed that the PFA-100 system (CEPI) was able to detect 71.7% of ASA-induced defects with a positive predictive value of 97.8%. The overall clinical accuracy of the system, calculated from the area under the ROC curve, was 0.977. The data suggest that the PFA-100 system is highly accurate in discriminating normal from abnormal platelet function. The ease of operation of the instrument makes it a useful tool to use in screening patients for platelet-related hemostasis defects.

The clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis.

BACKGROUND: Ultrasonography using vein compression accurately detects proximal deep venous thrombosis in symptomatic outpatients. Repeated testing is required for patients with normal results at presentation, but the optimal management of such patients is uncertain. OBJECTIVE: To test the safety of withholding anticoagulation in outpatients suspected of having first-episode deep venous thrombosis who have normal results on simplified compression ultrasonography at presentation and on a single repeated test done 5 to 7 days later. DESIGN: Prospective cohort study. SETTING: Noninvasive vascular laboratories at a university teaching hospital and a Veterans Administration medical center. PATIENTS: 405 consecutive outpatients suspected of having first-episode deep venous thrombosis. INTERVENTION: Ultrasonography was performed at presentation. The common femoral and popliteal veins were assessed for compressibility. If the result was normal, anti-coagulation was withheld and testing was repeated 5 to 7 days later. Anticoagulation was withheld from all patients whose results remained normal according to compression ultrasonography, regardless of their symptoms. The safety of this approach was tested by follow-up lasting 3 months. MEASUREMENTS: Objective testing was done during follow-up in all patients with symptoms or signs of venous thromboembolism. The outcome measure was symptomatic venous thrombosis or pulmonary embolism during follow-up, confirmed by objective testing. RESULTS: Ultrasonography had normal results in 335 patients (83%) and abnormal results in 70 (17%). None of the patients with normal results died of pulmonary embolism. Venous thromboembolism occurred during follow-up in 2 patients with normal ultrasonographic results (0.6% [95% CI, 0.07% to 2.14%]) and in 4 patients with abnormal results (5.7% [CI, 1.58% to 13.99%]) (P = 0.009). CONCLUSIONS: It is safe to withhold anticoagulation in outpatients suspected of having first-episode deep venous thrombosis if results of simplified compression ultrasonography are normal at presentation and on a single repeated test done 5 to 7 days later.

Activated factor VII levels in patients with angiographically confirmed coronary artery disease.

We have examined factor VIIa levels in consecutive consenting patients undergoing coronary angiography (n = 702) to determine if levels are related to the presence of coronary arterial narrowing and to the degree and extent of that narrowing. Both men and women with clinically defined coronary artery disease (> or = 50% stenosis in at least 1 vessel) had factor VIIa levels that were similar to men and women with less stenosis or normal coronary arteries.

Thrombophilic mechanisms of OCs.

Oral contraceptives (OCs) have minor effects on procoagulant and anticoagulant factors. Clotting factor changes that are associated with the use of low-androgenic OCs include a 10% to 20% increase in fibrinogen, variable effects on factor VII, an increase in fibrinopeptide A, and a 10% to 20% decrease in protein S (in comparison, levels of protein S decrease approximately 70% during pregnancy). Although these acquired changes can be statistically significant between OC users and nonusers, there is no evidence that they are clinically significant. In contrast, increased risk of venous thrombosis has been associated with inherited deficiencies in protein S and protein C, which are both natural anticoagulant proteins. In addition, activated protein C (APC) resistance can occur via a mutation of factor V, known as factor V Leiden, which is present in 5% of the general population and 20-40% of patients with venous thrombosis. In one study, the combination of OC use and factor V Leiden positivity was associated with a 35-fold increased risk of venous thrombosis compared with controls. However, the absolute risk of venous thrombosis in this group was low; the incidence of venous thrombosis was 28.5 events per 10,000 women-years in women with both factors (in comparison, pregnancy was associated with an incidence of 5.9 per 10,000 women-years). Even if venous thrombosis could be totally prevented in OC users with the Leiden mutation, there would be little impact on the total number of cases of venous thrombosis; therefore, routine screening for factor V Leiden or APC resistance prior to starting women on OCs does not seem to be warranted.

Monitoring low-dose warfarin therapy by a central laboratory and implications for clinical trials and patient care. The Coumadin Aspirin Reinfarction (CARS) Pilot Study Group.

The central laboratory provides International Normalized Ratio results in close agreement with the local laboratory for monitoring the anticoagulant effect of low-dose warfarin. A central laboratory may have practical advantages for patients in rural areas that lack laboratory facilities for anticoagulant monitoring.

Coagulation and thrombosis with OC use: physiology and clinical relevance.

PIP: Recent studies suggesting that oral contraceptives (OCs) containing the progestins desogestrel and gestodene are associated with a two-fold increased risk of nonfatal venous thromboembolism (VTE) compared to earlier formulations have raised new issues for clinicians. The increased risk of 20-30 cases of VTE per 100,000 women annually compares with 60 VTE cases associated with pregnancy. Women with a documented history of unexplained VTE should not use OCs, and when there is a family history, physicians should weigh factors such as age of onset of thrombosis in the affected relative, the clinical setting (e.g., after surgery or trauma), and severity of the episode. The effects of OCs on procoagulants and anticoagulants are minor, except in the 5% of women with factor V Leiden mutation. A clotting assay can determine activated protein C resistance and a polymerase chain reaction test can identify the presence of this mutation; however, widespread screening of OC users is not recommended due to the low incidence of factor V Leiden and the low likelihood these women will develop clots. The present state of knowledge about OCs and VTE risk supports the application of informed clinical judgment.^ieng

Fibrinogen levels in women having coronary angiography.

Fibrinogen has emerged as a risk factor for coronary artery disease in men that equals cholesterol in importance. It is known to play an important role in reparative processes, and evidence is accumulating that fibrinogen/fibrin accumulates at the site of minimal vascular injury. Fibrinogen contributes significantly to blood viscosity and its adherence to endothelium may mediate progression of atheromatous lesions. This study was designed to examine a number of markers of risk in a consecutive series of cardiology patients undergoing coronary catheterizations over a 15-month period. This article examines the level of fibrinogen in relation to the number of reported coronary stenoses and disease severity in a series of Caucasian female patients (n = 101). Women were classified as diseased if they had at least 1 lesion > or = 25% in the coronary anatomy and nondiseased if they had no lesions > or = 25%. The number of reported lesions correlates significantly with fibrinogen levels (r = 0.36, p = 0.0002). Women with fibrinogen levels > or = 283 mg/dl had a 3.2-fold increased risk (95% confidence interval 1.2 to 9.1) of having at least 1 stenosis > or = 25% after adjusting for age and diabetic status. Smoking and body mass index did not differ by disease status and thus did not confound the finding. Mean fibrinogen levels showed a progressive positive association with increasing clinically defined vessel involvement (stenosis > or = 50%).