[Skin necrosis during long-term fluindione treatment revealing protein C deficiency]. / Nécroses cutanées tardives sous fluindione révélant un déficit en protéine C.

BACKGROUND: Cutaneous necrosis is a rare complication of vitamin K antagonist therapy. It presents as cutaneous hemorrhagic necrosis and usually occurs at the start of treatment. We describe an atypical case of recurrent skin necrosis after two years of treatment with fluindione. CASE REPORT: A 70-year old woman with a history of venous thromboembolism and obesity presented with a large haemorrhagic necrosis of the abdominal wall. She had been treated with fluindione for two years. Genetic protein C deficiency was discovered. Resumption of vitamin K antagonist therapy was followed by recurrence of skin necrosis despite concomitant administration of heparin. Treatment with vitamin K antagonists could not be continued. DISCUSSION: This observation is unusual due to the late onset of skin necrosis. The condition usually begins shortly after initiation of vitamin K antagonist therapy, generally between the third and the sixth day of treatment. It is due to a transient hypercoagulable state in patients with protein C deficiency or, in rare cases, protein S deficiency. This late-onset skin necrosis, occurring many years after initiation of anticoagulant therapy, may be explained by a sudden worsening of pre-existing protein C deficiency due to infectious and iatrogenic factors.

[Study of variability in response to aspirin and clopidogrel: clinical and/or biological resistance?]. / Etude de la variabilité de réponse à l'aspirine et au clopidogrel: résistance clinique et/ou biologique?

Millions of people in France are taking long-term treatments with the two main antiplatelet drugs, aspirin and/or clopidogrel. Most of these people are on a secondary preventive regimen after arterial thrombotic events such as myocardial infarction, stroke, or ischemic complications of lower limb arteriopathy. The term resistance is often a source of confusion. When used, its definition should be explicit. It would be probably be wiser to use a term such as "variable response" which is more widely accepted by specialists and researchers. It would be better to use the term variable platelet response since true pharmacological resistance is rare. The distinction may have clinical pertinence in terms of prognosis. An abundant amount of biological and clinical work in the literature has improved our understanding of the topic. Diverse tests for exploring platelet functions can be used to evaluate the biological impact of treatment. They should, in the near future, contribute to the implementation of guidelines or suggestions for optimal therapeutic modalities. Upcoming results of ongoing large-scale prospective studies will be needed before confirming the potential usefulness and clinical pertinence of these tests.

Circulating platelet-leukocyte aggregates: a marker of microvascular injury in diabetic patients.

Diabetes is associated with multiple disorders including metabolic, cellular and blood disturbances leading to vascular complications. Increased circulating levels of platelet-leukocyte aggregates (PLA) have been described in several thrombotic diseases. In this study, we have evaluated circulating PLA in diabetic patients and we have investigated whether they may be a marker of vascular complications. Using flow cytometry assay, we have quantified PLA percentages in 65 diabetics including 20 patients with type I and 45 with type II diabetes, and 25 healthy subjects. Specific labelling identified platelet-polymorphonuclear aggregates (PPA) and platelet-monocyte aggregates (PMA). We have observed a significant increase of PPA and PMA levels in diabetics (22+/-12% and 45+/-18%, respectively) compared to controls (7+/-4% and 19+/-10%, respectively) (p<0.01). However, both PPA and PMA values were similar in the two diabetes types. Circulating PPA and PMA were significantly enhanced in diabetics with vascular lesions (PPA: 24+/-13%; PMA: 50+/-18%) than in diabetics without vascular lesions (PPA: 18+/-8%; PMA: 38+/-15%) (p<0.05 and p<0.01). Patients with PPA>18% and/or PMA>38% showed a more important vascular injury (OR: 6; 95% CI: 1.6-23). Increased PMA circulating rate is particularly correlated to retinopathic injury (OR: 19; 95% CI: 2.3-154). Our findings established a relationship between increased circulating PLA levels, particularly PMA, and the incidence of microvascular complications in diabetes. They reinforce the concept of pro-inflammatory cells involvement in diabetic retinopathy pathogenesis and their link with thrombotic process.

Effect of the anti-factor Xa and anti-factor IIa activities of low-molecular-weight heparins upon the phases of thrombin generation.

BACKGROUND: Low-molecular-weight heparins (LMWHs), derived from unfractionated heparin (UFH) by different depolymerization procedures, vary in both their relative abilities to enhance the inhibition of FXa (anti-FXa) and thrombin (anti-FIIa), and in their physicochemical properties. OBJECTIVE: We aimed to profile the inhibition of thrombin generation induced by bemiparin, enoxaparin, nadroparin, dalteparin and tinzaparin in platelet-rich plasma (PRP), and to compare them with UFH and fondaparinux (a synthetic pentasaccharide that specifically enhances FXa inhibition). METHODS: Different LMWHs, UFH or fondaparinux were added to normal PRP. Thereafter, tissue factor-triggered thrombin generation was assessed using the Thrombogram-Thrombinoscope assay. RESULTS: At equivalent anti-FIIa activity concentrations, LMWHs and UFH exhibited similar inhibitory effects upon thrombin generation. However, when used at equivalent anti-FXa activity concentrations, tinzaparin was significantly more active than the other LMWHs at inhibiting thrombin generation, and had similar activity to that of UFH. Enoxaparin, nadroparin and dalteparin all showed similar inhibitory activities. In these experiments, bemiparin exhibited the lowest inhibitory effect on thrombin generation of all the LMWHs. At 0.1 microg mL(-1) (0.093 anti-FXa IU mL(-1)), fondaparinux inhibited the rate of thrombin generation by 50%. A 7-fold higher concentration of fondaparinux was required to inhibit the endogenous thrombin potential by 50%. CONCLUSIONS: LMWHs have a variable inhibitory effect on thrombin generation in vitro when compared by anti-FXa activity, but are similar when compared by their anti-FIIa activities. The rate of thrombin generation during the propagation phase, rather than the endogenous thrombin potential, is more sensitive to the anticoagulant activity of fondaparinux and the polysaccharide chains of LMWHs possessing only anti-FXa activity.

[New antitoagulants]. / Les nouveaux anticoagulants.

In contrast to older anticoagulant agents vitamin K antagonists and heparins, the new ones are directed towards a single target in general. The main characteristics of the new agents are: their site of action in the coagulation cascade and their mechanism of action which is indirect, antithrombin dependent, most often such as Fondaparinux and Idraparinux or direct such as Dabigatran, Rivaroxaban; the specificity of the new molecules, since they must not interact with other enzymes: trypsin, kallikrein, t-PA, etc...; their mode of administration parenteral and/or oral; their pharmacokinetics and their clearance frequently by the kidney (Hirudin, fondaparinux) or through hepatic metabolism (argatroban); tolerance including for all compounds the bleeding risk or an unexpected hepatic intolerance for Ximelagatran; the availability of a specific antidote and the cost of the drug; one compound is registered in France Arixtra Fondaparinux in major orthopedic surgery and in the treatment of venous thromboembolism and in prophylactic treatment in medical patients. However, the main indications of interest for these new drugs is atrial fibrillation. There is a real need in this indication and the number of patients to treat is growing with the longer life expectancy.

[Prevention of thrombosis and vascular inflammation: importance of combined cyclooxygenase and 5-lipoxygenase inhibitors]. / Prévention de la thrombose et de l'inflammation vasculaire: place des inhibiteurs mixtes des cyclooxygénases et de la 5-lipoxygénase.

Aspirin, a standard non-steroidal anti-inflammatory drug (NSAID) is currently used in antithrombotic treatment. However, its use is limited by largely recognized gastrotoxicity and recommended doses are low. The major side effect of aspirin is related to its ability to suppress prostaglandin (PG) synthesis by constitutive cyclooxygenase-1 (COX-1). Specific inhibitors of COX-2, the inducible isoform of COX which was more recently described, have potent antiinflammatory effects. They are associated with minor risk of gastric tractus toxicity and reduced inflammatory leukocyte components known for their proatherothrombotic properties. Nevertheless, recent findings attributed a significant cardiovascular risk to some of them. 5-lipoxygenase (5-LOX), an enzyme mainly expressed by leukocytes, is responsible for the generation of leukotrienes, the major lipidic proinflammatory mediators. Development of combined inhibitors of 5-LOX and COX isoforms 1 and 2 inaugurate an interesting new therapeutic pathway. Indeed, such inhibitors suppress not only the activation of platelets, leukocytes and endothelial cells but also prevent their metabolic and functional interactions. In addition to their broad spectrum inhibition, they may be associated with the minor gastrotoxic effect. Thus, platelet-leukocyte interactions which dominate the underlying inflammatory process particularly in atherosclerosis, might reinforce the benefits of such inhibitors.

Primary and secondary prophylaxis of venous thromboembolism with low-molecular-weight heparins: prolonged thromboprophylaxis, an alternative to vitamin K antagonists.

Low-molecular-weight heparins (LMWHs) are used widely in the treatment and prevention of venous thromboembolism (VTE). The LMWHs dalteparin and enoxaparin reduce the rate of VTE by at least 50% if administered for 4-5 weeks following major orthopedic surgery, compared with in-hospital prophylaxis for 7-15 days. Meta-analyses have confirmed that the size of the reduction is similar for both clinical and asymptomatic VTE. Vitamin K antagonists (VKAs) have been shown to be associated with significantly higher bleeding rates compared with LMWH when used as prolonged prophylaxis against VTE following major orthopedic surgery. Patients with cancer are a recognized group at high risk of VTE, and those undergoing major surgery for their malignancy are at particular risk. Evidence from clinical trials is amassing to show that prolonged prophylaxis with LMWH (dalteparin, enoxaparin) in these patients can significantly reduce the rate of postoperative VTE. In cancer patients with acute VTE, the traditional approach is to initiate acute treatment with unfractionated heparin or LMWH followed by long-term treatment with VKA to prevent recurrence. However, clinical trial data have confirmed that the LMWH dalteparin, when administered for 6 months, is significantly more effective than VKA in preventing recurrence, cutting the rate of VTE by 52% without increasing the risk of bleeding. A new and intriguing area of interest is whether LMWH can enhance survival in patients with cancer. Preliminary data suggest that a biological effect of LMWH may act to prolong survival in patients with cancer.

An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study.

BACKGROUND: Little information is available concerning risk factors for venous thromboembolism (VTE) in nonhospitalized patients. PARTICIPANTS AND METHODS: An epidemiologic case-control study of deep vein thrombosis (DVT) risk factors was conducted in 1272 outpatients by general practitioners. The case population (636 patients presenting with DVT) was paired with the control population (636 patients presenting with influenzal or rhinopharyngeal syndrome) according to sex and age. Deep vein thrombosis was to be documented by at least 1 objective test. Risk factors were classified into "intrinsic" ("permanent") and "triggering" ("transient") factors and were evidenced using univariate analysis. RESULTS: In the medical population, defined as patients who had not undergone surgery or application of a plaster cast to the lower extremities within the 3 weeks preceding inclusion (494 cases and 494 controls), intrinsic factors such as history of VTE, venous insufficiency, chronic heart failure, obesity, immobile standing position, history of more than 3 pregnancies, and triggering factors such as pregnancy, violent effort, or muscular trauma, deterioration of general condition, immobilization, long-distance travel, and infectious disease were significantly more frequent in the case patients than in the controls (odds ratio, >1; P<.05). In the overall population, additional risk factors were cancer, blood group A, plaster cast of the lower extremities, and surgery. In both populations, the number of risk factors per patient was greater in the case patients than in the controls. CONCLUSION: Several risk factors for DVT were identified in medical outpatients presenting with DVT, and their comprehension may improve appropriateness and efficiency of the different methods available for thromboprophylaxis. Arch Intern Med. 2000;160:3415-3420.

Thrombophilia and venous thromboembolism. International consensus statement. Guidelines according to scientific evidence.

Thrombophilia is the term now used to describe predisposition to increased risk of venous and occasionally arterial thromboembolism due to hematological abnormalities. It can be a multifactorial disorder where congenital defects of anticoagulant or procoagulant factors may be combined with acquired hematological abnormalities. It should be considered in patients with a documented unexplained thrombotic episode or a positive family history. The aim of this document is to provide guidelines for investigation and management of patients with thrombophilia in the presence or absence of venous thromboembolism (VTE).

Assessment of treatment strategy in high-risk surgical patients.

The risk of postoperative venous thromboembolism (VTE) is dependent on the type of surgical procedure and specific characteristics of the patient. Patients with intrinsic factors placing them at higher risk of VTE remain at high risk, even if the procedural risk is low. The identification of factors such as age, obesity, and malignant disease, has made it possible to make a preoperative assessment of risk and ensures that the most appropriate thromboprophylactic regimen is prescribed. Despite the widespread use of prophylaxis, the incidence of VTE is still significant. The investigation and development of new pharmacologic agents, such as hirudins and their recombinant derivatives, may lead to better protection for patients at high or very high risk of VTE.

Thrombolytic therapy: future issues.

A considerable amount of work has been devoted to thrombolytic therapy (about 3000 references from 1991 to 1995 in a Medline search). The most important and well established indication of thrombolytic treatment is acute myocardial infarction (MI). Megatrials have evidenced a significant 30 to 40% reduction in hospital mortality in the treated patients. However, lack of sufficient thrombolysis in approximately 25% of patients, reocclusion in 6 to 16% of patients and intracranial hemorrhage in about 0.5% of patients are the main concerns regarding thrombolysis. Three approaches should improve the results of thrombolytic therapy in acute MI: earlier medical treatment, use of more efficacious thrombolytic agents in combination with more active antithrombotic agents and reduction of severe bleeding with safer combination of drugs. An improved of laboratory monitoring may also reduce the incidence of severe hemorrhagic events. In acute pulmonary embolism (PE), a change of indication for treatment based on echocardiography and high probability ventilation-perfusion lung scan results (without requiring pulmonary angiography) could broaden the use of thrombolysis. However, thus far, there has not been a demonstration of a reduction in mortality in large controlled studies. Thrombolysis in acute ischemic stroke is an attractive treatment but thrombolytic treatment is still at an experimental stage. However, the successful use of rt-PA in acute MI has renewed the interest in thrombolysis for focal cerebro-vascular ischaemia. Large controlled studies with SK, rt-PA or UK locally or intravenously administered have been recently undertaken to evaluate the benefit/risk ratio of treatment which seems surprisingly variable in different subgroups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of a paternal history of premature myocardial infarction on fibrinogen, factor VIIC and PAI-1 in European offspring--the EARS study. European Atherosclerosis Research Study Group.

To assess the role of genetic and environmental factors in the predisposition to atherosclerosis, 682 students whose father had suffered a myocardial infarction before the age of 55 ("cases") and 1312 controls matched for age and sex, were recruited from 14 Universities in Europe. Fibrinogen, factor VIIc and PAI-1 were compared between cases and controls across European regions. Fibrinogen and factor VIIc were positively correlated with BMI, smoking and contraception. PAI-1 was positively and independently correlated with BMI and waist-to-hip ratio, and negatively with contraception. Factor VIIc and PAI-1 were correlated with cholesterol and triglycerides, and fibrinogen was weakly correlated with LDL-cholesterol. After adjustment for covariates and lipids, fibrinogen level was significantly higher in male cases than in controls (2.38 vs 2.29, p < 0.01). No such difference was found in females (2.59 vs 2.57 - NS). There was no significant case/control difference for factor VIIc and PAI-1. These results support the hypothesis that fibrinogen is a transmissible risk factor of coronary artery disease in males. No such evidence was provided for factor VIIc and PAI-1.

Acute ischemic stroke and heparin treatments.

Several case-control studies have reported enhanced platelet activity, hypercoagulation and/or reduced fibrinolytic activity in patients with acute ischemic stroke. However, results of these studies are conflicting and do not allow to make recommendations regarding heparin treatment. The aim of heparin treatment in stroke patients is to prevent venous thromboembolic complications, to improve patient neurologic outcome, to reduce mortality and to prevent early recurrence. Unfortunately, only the first objective has been confirmed. As far as neurologic outcome and mortality are concerned, only trials performed since the CT era should be taken into account because the former ones did not rule out cerebral haemorrhages. The most recent clinical trials using LMWHs gave better results than the previous trials with UFH, but data are still conflicting and firm recommendations cannot be made until the results of ongoing megatriasl (such as IST) become available. As regards prevention of early recurrence, most authors agree that heparin is indicated in cardioembolic stroke.

Changes in haemostatic variables induced by oral contraceptives containing 50 micrograms or 30 micrograms oestrogen: absence of dose-dependent effect on PAI-1 activity.

Several studies have suggested a dose-response relation between the oestrogen content of oral contraceptive (OC) and the risk of both venous thrombosis and arterial disease, when oestrogen doses were higher than 50 micrograms. However, there is no clear epidemiological evidence for a decrease in thrombotic risk with formulations containing less than 50 micrograms oestrogen. Therefore, we investigated haemostatic variables in users of OC containing either 30 micrograms (35 women) or 50 micrograms (29 women) ethinyl estradiol as compared with non users (64 women) matched for age and smoking status. Mean values of antithrombin activity were significantly lower in 30 micrograms or 50 micrograms oestrogen users than in non users (96% and 98% vs 105%, respectively, p < 0.001), but they were not significantly different between the two groups of OC users. There was a significant increase in mean values of factor VII antigen in women taking either 30 micrograms or 50 micrograms oestrogen as compared with non users (96% and 101% vs 85%, respectively, p < 0.005). Although the difference between both groups of OC users was not significant, a positive linear trend in factor VII levels was observed within the 0-50 micrograms oestrogen range (p < 0.001). Mean levels of fibrinogen were slightly higher in 30 micrograms or 50 micrograms oestrogen users than in non users (2.71, 2.66 g/l vs 2.55 g/l, respectively), but there was no significant difference between the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: In Paris, France, clinicians compared data on 64 women aged 19-40 who used combined oral contraceptives (OCs) for 6-200 months with data on 64 healthy women who did not use OCs for the last two months and who were matched for age and smoking status to investigate activity of plasminogen activator inhibitor 1 (PAI-1), factor VII antigen, fibrinogen concentration, and antithrombin activity in users of OCs containing either 30 mcg or 50 mcg estrogen and in nonusers. OC users exhibited lower mean values of PAI-1 activity than nonusers (4.63-4.89 vs. 6.47 AU/ml; p 0.02). There was no dose-dependent effect of estrogen on PAI-1 activity, however. Antithrombin activity values were much lower in OC users than nonusers (96-98% vs. 105%; p 0.001). The difference between the two groups of OC users was not significant, however. The mean values of factor VII antigen in women using either 30 mcg or 50 mcg estrogen were higher than those for nonusers (96% and 101% vs. 85%, respectively; p 0.005). The difference in factor VII antigen values between the two OC groups was not significant, yet there was a positive linear trend in factor VII levels within the 0-50 mcg estrogen range (p 0.001). No significant difference in the mean fibrinogen levels between the three groups (30 mcg estrogen OC group, 50 mcg estrogen OC group, and nonusers) was observed. Hemostatic variables were not significantly different between 30 mcg estrogen OCs containing 100 mcg, 150 mcg, or 200 mcg levonorgestrel. The researchers could not conduct a valid assessment of the progestogen effect in 50 mcg estrogen OCs due to the wide range of different types of progestogens. These findings suggest an alteration of blood coagulation and fibrinolysis in OC users within the 30-50 mcg estrogen range. Estrogen appears to have a dose-dependent effect on factor VII but no significant effect on PAI-1 activity and other markers of thrombogenic risk and arterial disease risk.

Human anti-streptokinase antibodies induce platelet aggregation in an Fc receptor (CD32) dependent manner.

Exposure to streptokinase (SK) elicits anti-SK antibodies (Abs), which inhibit fibrinolysis and induce platelet aggregation. The mechanism of the latter is not fully understood, although it seems to involve platelet binding by a plasminogen streptokinase and anti-SK ternary complex. Anti-SK Abs were purified by affinity chromatography from serum of patients having received SK for acute myocardial infarction (AMI), and were shown to be of the IgG type. Their effects were studied with (i) human platelets in citrated plasma in the presence of SK or acetylated plasminogen-SK activator complex (APSAC), and (ii) in washed platelets, resuspended in Tyrode buffer after lowering the ionic strength, in the presence of APSAC (which provides both SK and plasminogen). An antibody concentration-response curve was obtained, showing a plateau in the presence of 0.1 mg/ml IgG. By increasing the concentration of APSAC, we obtained a unimodal response curve, the optimal concentration of APSAC being 0.05 U/ml. Aggregation was suppressed by chelating calcium with EDTA, blocking fibrinogen binding by the synthetic peptide Arg-Gly-Asp-Ser (RGDS), and raising intraplatelet cAMP with Iloprost (a prostacyclin analogue). Aggregation required the interaction of the anti-SK Ab Fc domain with the platelet Fc-gamma receptor type II, also known as CD32, since: (i) it was blocked by the monoclonal antibody IV-3 directed against CD32, (ii) it did not occur with F(ab)'2 fragments, which block the response to the intact IgG. The clinical relevance of these platelet-activating anti-SK antibodies remains to be determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative effects of recombinant staphylokinase and streptokinase on platelet aggregation.

Recombinant staphylokinase (RSTA) has been shown to offer promise as a thrombolytic agent. In contrast to streptokinase (SK), few studies have been devoted to possible effects of RSTA on platelets. We have compared the capacity of RSTA and SK to trigger platelet aggregation and to modify ADP (2.5 microM) response in platelet-rich plasma (PRP) of 125 healthy subjects. Thus, exposure of PRP to SK (40 to 50 micrograms/ml) induced platelet aggregation in 6 out of 25 subjects. However, under the same conditions, RSTA failed to induce platelet aggregation in all cases (25 out of 25 subjects). In contrast to RSTA, SK (0.4 to 50 micrograms/ml) greatly reduced ADP-induced platelet aggregation in 12 out of 25 subjects. Preincubation of plasma with SK is associated with a decrease in the fibrinogen concentration. Furthermore, there was a good correlation between SK-induced fibrinogenolysis and SK-induced platelet aggregation defect (r2 = 0.9; p = 0.001). No fibrinogenolysis was observed when different amounts of RSTA (0.4 to 50 micrograms/ml) were incubated in plasma for one min. However, there was a marked decrease in fibrinogen level (about 50%) when the plasma was incubated for five min with a very high concentration of RSTA. SK markedly enhanced the platelet response to ADP in 13 out of 25 subjects. In PRP of 6 out of 25 subjects, SK induces platelet aggregation and potentiates platelet response to ADP, however in PRP of 7 out of 25 subjects, SK caused only the increase of platelet response to ADP. The monoclonal antibody anti-Fc gamma RIIa1, I-3 (2 micrograms/ml), abolished SK-induced platelet aggregation and SK-enhanced ADP-induced platelet aggregation. In all cases (25 out of 25 subjects), RSTA failed to potentiate platelet response to ADP. These findings confirm that RSTA has a lesser fibrinogenolytic ability than SK and suggest its negligible effect on platelet function.

Monitoring heparin therapy using activated partial thromboplastin time--results of a multicenter trial establishing the therapeutic range for SILIMAT, a reagent with high sensitivity to heparin.

APTT is widely used for laboratory monitoring of treatment with unfractionated heparin (UFH). However, since its sensitivity to heparin varies significantly from one reagent to another, the therapeutic range had to be defined for each brand of APTT reagent. As an example, SILIMAT (bio-Mérieux) is a new APTT reagent containing rabbit brain phospholipids and micronized silica as an activator. Since its high sensitivity to heparin has been previously reported, a multicenter trial was carried out in an attempt to define the therapeutic range of APTT performed using this new reagent. For that purpose, 170 blood samples drawn for routine coagulation testing from 170 different patients treated with UFH were analyzed. A single batch of two different APTT reagents were used on KC10 coagulometers: SILIMAT and Automated APTT (Organon-Teknika) whereas the anti-Xa activity was evaluated by a chromogenic substrate-based assay. The same methodology was used in all the centers. In order to obtain a plasma anti-Xa activity within the therapeutic range i.e. between 0.30 and 0.70 IU/ml, the APTT ratios were found between 1.90 and 5.40 for SILIMAT, which corresponded to clotting times of the patients plasma between 63 and 178 s. The APTT ratios were significantly lower when evaluated using Automated APTT (between 1.70 and 4.10), with clotting times between 53 and 127 s. In addition, a good correlation was found between the Anti-Xa activity and APTT for both reagents (r > 0.65). However, it is not possible to make recommendations regarding the therapeutic ranges without restrictions. Although about 70% of the patients with an anti-Xa activity between 0.30 and 0.70 IU/ml had an APTT in the above defined ranges, the degree of concordance between the two assays is not absolute. Actually more than 30% of the patients had discordant anti-Xa activity and APTT and more than a quarter of the patients included in the above defined therapeutic range for APTT had an anti-Xa activity outside the 0.30-0.70 IU/ml range, whatever the reagent used. In conclusion, to define the therapeutic ranges of APTT using the recommended method is practicable but some critical points could be raised, suggesting that a better method is awaited in order to improve the standardization.

Haemostatic variables and menopausal status: influence of hormone replacement therapy.

Large cohort studies have shown that postmenopausal estrogen use was associated with a reduction in the risk of coronary heart disease. This putative beneficial effect of hormone replacement therapy (HRT) may be partly mediated through changes in clotting factors and fibrinolytic system. We have measured haemostatic variables in 293 consecutive healthy women aged 45-54 years who attended a health check-up centre in Paris (IPC). Premenopausal women taking hormonal therapy were excluded (n = 34). Most women using HRT were given 17-beta estradiol in combination with progestin. Mean levels (m +/- sd) of plasma fibrinogen, factor VII coagulant activity and plasminogen activator inhibitor (PAI) were significantly higher in postmenopausal women not taking HRT (n = 99) than in premenopausal women (n = 139) within the same decade (319 +/- 52 mg/dl vs 304 +/- 60 mg/dl, 107 +/- 17% vs 96 +/- 16%, 9.73 +/- 5.71 U/ml vs 7.61 +/- 4.36 U/ml respectively). Allowance for main cardiovascular risk factors made no substantial differences to the results, although the effect of the menopause on fibrinogen was no longer significant. HRT (n = 21) significantly reversed the menopause-related changes in factor VII (94 +/- 15%), even after adjustment for confounding factors. The same trend in both fibrinogen (294 +/- 46 mg/dl) and PAI (8.22 +/- 5.51 U/ml) was observed. Similar results were found in women using oral or percutaneous estrogen. Our findings suggest that 17-beta estradiol in combination with progestins may protect against an increased thrombotic tendency in postmenopausal women. Randomized clinical trials are urgently needed for a better understanding of HRT effect on atherothrombotic process.

Efficacy of a synthetic pentasaccharide, a pure factor Xa inhibitor, as an antithrombotic agent--a pilot study in the setting of coronary angioplasty.

AIM OF THE STUDY: To assess the antithrombotic properties of SR90107/ORG31540. a sulfated pentasaccharide, which enhances specifically antithrombin III mediated inactivation of factor-Xa, in a clinical setting known to promote arterial thrombosis, i.e. coronary angioplasty. METHODS AND RESULTS: Percutaneous transluminal coronary angioplasty (PTCA) was carried out with conventional balloons with a single 5 min intravenous infusion of 12 mg pentasaccharide, and 500 mg intravenous aspirin. Heparin was not allowed before, during PTCA, and within 24 h after PTCA. The primary end point was the rate of abrupt vessel closure during and within 24 h after the procedure. The sample size was set at 60 evaluable patients, in order to be able to conclude with a good level of confidence (>95%) that the abrupt vessel closure rate was less than 10%, if less than 3 abrupt vessel closures were observed. Seventy-one patients were included in the study, of whom 10 needed elective stenting, and were not considered as evaluable for efficacy. Two out of the 61 remaining evaluable patients experienced acute vessel closure during the study period [3.28%, 95% confidence interval (0.4%; 11.4%)]. No major bleeding occurred. The drug plasma concentrations reached 1.91+/-0.39 mg/], 10 min after pentasaccharide injection, and decreased on average to 1. 18+/-0.27 mg/l at 2 h, and to 0.36+/-0.11 mg/l at 23 h after administration of pentasaccharide. Activated clotting time (ACT) and activated partial thromboplastin (aPTT) time remained within normal range. Thrombin-antithrombin complex levels fell from 22+/-17.1 to 4.5+/-3.4 microg/ml, prothrombin fragment 1+2 levels decreased from 2.15+/-1.01 to 1.73+/-0.87, and activated factor VII levels decreased from 43.4+/-16.8 mU/ml to 18.9+/-7.3 mU/ml respectively from baseline to 2 h following injection of the tested drug. CONCLUSIONS: Administration of pentasaccharide led to the inhibition of thrombin generation without modification of aPTT and ACT. The rate of abrupt vessel closure was within range of rates reported in historical series. Thus we conclude that the anti-thrombotic activity of pentasaccharide, as shown in this pilot trial in the setting of coronary angioplasty, deserves further investigation.

Prevention of deep vein thrombosis after hip replacement--comparison between two low-molecular heparins, tinzaparin and enoxaparin.

Consecutive patients undergoing total hip replacement in 43 centres were randomly assigned to receive blindly either enoxaparin (40 mg) or tinzaparin (4,500 anti-Factor IU Xa), as once daily subcutaneous injections. The first injection was administered 12 h preoperatively. Efficacy was assessed by bilateral venography performed 12-14 days postoperatively. Efficacy and safety were blindly and centrally adjudicated. Among the 499 patients included, 440 had a venogram. The total incidence of DVTs was 44 (20.1%) of the 219 patients of the enoxaparin group and 48 (21.7%) of the 221 patients of the tinzaparin group. The upper limit of the 80% confidence interval of the difference between the two treatment groups was less than 5.0%. Therefore according to the protocol's specifications equivalence was shown. Proximal DVTs occurred in 10.5% of the enoxaparin group (23 patients) and in 9.5% (21 patients) of the tinzaparin group. No overt major bleeding was observed. One patient in the enoxaparin group developed severe thrombocytopenia and died. The LMWH tinzaparin appears clinically to be as effective and safe as enoxaparin in the prophylaxis of deep vein thrombosis after total hip replacement, at the doses used and under the conditions of this study.