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Recent data show that the quality of anticoagulation evaluated in patients receiving vitamin K antagonists (VKA) is not optimal in France. The aim of this retrospective study was to estimate the performances of six French anticoagulant clinics that manage VKA treatments over a 3-year period, from 2009 to 2011.All clinics used the same rule based software. We determined the time spent in the therapeutic range (TTR), a surrogate end-point of quality of treatment with VKA.The overall duration of follow-up was 2755 patient-years concerning 2385 patients. The time spent in the therapeutic range 2 to 3 assigned for 89% of the patients, was 73%. On the other hand the time spent in the therapeutic range for the other two INR ranges (2.5-3.5 and 3-4.5) concerning 11% of patients with prosthetic heart valve was lower (63.7% and 68.8% respectively) with an imbalance in favour of the time below the range. In this study, warfarin (Coumadine(®)) and fluindione (Previscan(®)) allowed an equivalent quality of anticoagulation. The 1728 patients of age ranged from 60 to 100 years spent more time in TTR than the 651 younger patients. The percentage of time spent with an INR greater than 5 was extremely reduced which is a guarantee of safety.These results prove that anticoagulant clinics in France have the same good performances as their counterparts abroad. It can be assumed that a high TTR contributes to a low incidence of both bleedings and thrombosis.

Homozygous or double heterozygous protein-C deficiency can present at birth with purpura fulminans or later in life with venous thrombosis. Two homozygous patients who had previously sustained thrombotic episodes were investigated at a time when they were asymptomatic and not receiving antithrombotic therapy. The plasma levels of protein-C antigen and activity in both individuals were approximately 20% of normal. We administered a highly purified plasma-derived protein C concentrate to these individuals and monitored levels of several markers of in vivo coagulation activation. Assays for protein-C activation (activated protein C and protein C activation peptide) showed a sustained increase from reduced baseline levels, whereas thrombin generation (as measured by prothrombin fragment F1 + 2) gradually decreased over about 24 hours into the normal range. These investigations provide direct evidence that protein C is converted to activated protein C in vivo, and that the protein-C anticoagulant pathway is a tonically active mechanism in the regulation of hemostatic system activation in humans.

We report the case of a 61-year old man in whom a deep venous thrombosis was the presenting feature of disseminated lung carcinoma. A few days later, an arterial thrombosis occurred necessitating amputation. Within a few weeks, the lung cancer progressed dramatically and the patient died. While the association between venous thrombosis and cancer is well known, the relationship between cancer and arterial thrombosis has been less explored. This observation allows discussion of the pathophysiological and clinical aspects of this association, as well as the implications for patient care.

We compared the level of plasma D-dimer in patients with previous venous thromboembolism (VTE), receiving or not oral anticoagulant treatment (OAT) and investigated its predictive value for the risk of VTE recurrence after OAT withdrawal.We have studied 149 patients, 81 receiving oral anticoagulants and 68 after treatment interruption. Patients with known causes of D-dimer increase were excluded. D-dimer measurements were performed by Vidas analyzer (bioMérieux, France).A significantly lower D-dimer plasma level was found in patients under OAT than in untreated patients, 197+/-134 ng/ml versus 399+/-239 ng/ml, respectively (p0.001). This decrease was similar in the different age populations and whether the patient had thrombophilia (n=84) or not. There was no correlation between INR and D-dimer levels. During a mean follow-up of 30 months, no recurrence occurred in patients under OAT versus 7 untreated patients. Among them, 3 had a D-dimer below 500 ng/ml, and 3 others had a level above 500 ng/ml. The last patient was not tested.The physician should be informed of the decrease of D-dimer under OAT, since the usual cut-off of 500 ng/ml used for deep vein thrombosis (DVT) exclusion is probably lower in such treated patients. It has been recently proposed that normal D-dimer level had a high negative predictive value for VTE recurrence when this dosage was performed 3 months after OAT interruption. The small number of recurrences observed in our study with an available result of D-dimer measured more than 3 months after OAT discontinuation does not allow a definite

LMW heparins have recently come into use in North America for treatment of venous thrombosis. Their first line recommendation is a major innovation of the last north american consensus conference on antithrombotics published in Chest at the beginning of 2001. This recommendation is grade 1A regarding its advantageous benefit-risk ratio. An earlier oral vitamine K antagonist treatment and a more regular nomogram use allow to reduce the relay duration and to obtain more often the targeted INR. The more predictable anticoagulant response with weight-based doses induces a simplified anti-Xa activity survey limited to renal dysfunction and obese or less than 50 Kg body weight persons but a regular platelet count remains mandatory. Several questions need to be discussed: once or twice daily subcutaneous injection use and treatment duration which seem related to the persistence of triggering factors, the variety of thrombophilia and comorbidity conditions. Due to a greater evidence-based medicine, the antithrombotic strategy becomes more related to a closer evaluation of the individual thrombotic risk level.

The usefulness of D-dimers determination for the exclusion of deep vein thrombosis (DVT) has been extensively studied. The persistence of high levels of D-dimers has also been suggested as a marker of hypercoagulability in rare studies and might be used to identify patients at risk for recurrent DVT. We have studied the influence of oral anticoagulant treatment in 149 patients, 17 to 84 year-old, with a history of venous thromboembolism; 81 received oral anticoagulant treatment, 68 did not. Patients with known reasons for high level of D-dimers such as cancer were excluded. Thrombophilia was found in 84 patients. D-dimers measurements were performed by ELFA technique using Vidas (bioMérieux, France) analyzer. A significantly lower level of D-dimers was observed in patients under oral anticoagulant compared to patients without this treatment, 197 +/- 134 mug/L versus 399 +/- 239 mug/L, respectively (p0.001). A level upper the normal value (500 mug/L) was found in only 3 patients out of 81 receiving an oral anticoagulant treatment as compared with 21 of the 68 patients without treatment. This decrease of D-dimers in patients receiving oral anticoagulants was the same in the different age populations. There was no correlation between INR and D-dimers levels in this study. The clinician should be informed of the decrease of D-dimers in patients treated with anticoagulants. The decrease of D-dimers plasma level during oral anticoagulant treatment suggest that D-dimers concentration in plasma is an indirect marker of reduced clotting activity in vivo.

Heparin-induced thrombocytopenia (HIT) is a drug induced immunohematologic adverse reaction which is a rare but potentially very severe accident. Its diagnosis is important for epidemiologic and drug surveillance studies and in order to decide the most appropriate treatment. Its importance is enhanced since there is no gold standard diagnostic criteria. In clinical practice the diagnosis is based on a group of criteria related to clinical events and laboratory tests. We have established a score based on anamnestic criteria which allowed us to evaluate and compare two different laboratory tests: a platelet aggregation test (PAT) and a test for the detection of heparin dependent antibodies (Heparin Platelet Induced Antibodies or HPIA). The functional test PAT which is commonly used in expert laboratories detects antibodies inducing platelet aggregation in the presence of heparin. The HPIA test more recently developed is an ELISA test which detects antibodies directed at heparin-platelet factor 4 complexes. The relative value of theses two methods for the diagnosis of HIT is not well documented. We have analysed the results of these two tests in 273 consecutive patients with a suspicion of HIT. The results were concordant in 70% of patients. In selecting the patients with the lowest and the highest probability of HIT according to the score, PAT was found a more sensitive and HPIA a more specific test than the other. At low probability PAT is more often positive than HPIA 18% and 9% respectively. No test is 100% reliable, the specificity being limited for both tests since in about 20% of cases one or both tests are negative contrasting with a highly probable HIT. In this last group of patients, PAT was more frequently positive (86%) than HPIA (72%). Both tests are negative in 6% of patients suggesting the existence of presently unknown antigenic targets. Considering a group of 19 patients with a high probability of HIT, we have found antibodies against IL-8 or NAP-2 in only 7 patients. The discrepancy between a HPIA positive and a PAT negative encountered in 8% of patients may be explained by the existence of IgA or IgM immunoglobulins since in contrast to IgG they are unable to promote platelet aggregation via the CD32 platelet membrane receptor. This work suggests than neither test is 100% reliable and that they play a complementary role in the diagnosis of HIT. The potential advantage of using both tests should be confirmed in complementary studies

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 (r0.65). 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.

A genetic variation of the prothrombin (factor II) gene, a G to A transition at nucleotide position 20210, was recently found in patients with familial thrombophilia (predisposition to venous thrombosis). It seems to be frequent in patients with the factor V Leiden mutation. We report a family with the factor V Leiden and/or the genetic variation of prothrombin in 3 members.The patient had repeated episodes of deep vein thromboses starting at the age of 30 during the 4th pregnancy. She is a heterozygous carrier of both the factor V Leiden nutation and the prothrombin mutation 20210 A. She has 4 asymptomatic children, aged 28 to 32 and 3 of them have been explored: one son has the prothrombin mutation, one daughter the factor V Leiden and one has none of them.This case report illustrates the polygenic nature of thrombophilia which may explain the heterogeneity of clinical expression observed in isolated congenital abnormalities, especially in factor V Leiden mutation.

The diagnostic usefulness of measuring plasma D-dimers using the ELISA method and the latex agglutination test has been prospectively evaluated in 117 patients hospitalized for suspicion of acute venous thrombo-embolism (AVTE): pulmonary embolism was suspected in 80 patients and the remaining 37 had a suspicion of deep vein thrombosis of the lower limbs. The diagnosis of AVTE was confirmed in 50% of the patients, all of whom underwent gold standard invasive investigation i.e. pulmonary angiography and/or contrast venography. The sensitivity, specificity, negative predictive value and positive predictive value of a D-dimers plasma concentration exceeding 500 ng/ml for the diagnosis of AVTE were respectively 98, 58, 97 and 70% when using the ELISA method, and 86, 71, 84 and 75% when using the latex assay. In 47 patients whose lung scans yielded abnormalities of indeterminate probability of pulmonary embolism, the sensitivity of the ELISA method was very high (94%), but that of latex assay was low (67%). Our results demonstrate that measuring the plasma D-dimers by the latex assay should not be used in the diagnosis of AVTE. On the other hand, the ELISA method might be of great interest in the diagnostic strategy of AVTE, as a normal concentration of D-dimers rules out almost definitely the diagnosis of AVTE, and hence, spares from performing invasive investigations.

We report the case of a 57-year old woman whose severe protein C deficiency was revealed soon after oral anticoagulants were introduced into her treatment. Two previous episodes of deep leg vein thrombosis followed by a third episode with suspicion of embolus migration had led to treatment with heparin later replaced by oral anticoagulants. On the 4th day of anticoagulant therapy, she developed skin necrosis of the left calf. A protein C assay showed severe deficiency (19% level as compared with the 70-120% normal levels). The main causes of acquired protein C deficiency were excluded. The first results of a family study demonstrated moderate protein C deficiency in a 30-year old, asymptomatic daughter.

Platelet aggregation induced by platelet activating factor (PAF) was studied in 95 subjects: 39 controls, 23 patients receiving aspirin and 33 receiving ticlopidine. Potentiation of aggregation by concentrations of adrenaline unable to induce aggregation when used alone was also assessed. The 33 patients treated with ticlopidine showed a highly significant fall of platelet aggregation (p less than 0.001) at the three concentrations of PAF used. The 23 subjects receiving aspirin showed a diminution of platelet aggregation induced by PAF due to inhibition of ADP release. In these last two groups, adrenaline often potentiated platelet aggregation. However, this phenomenon was absent in subjects having taken aspirin in the hours before blood was drawn. This study demonstrates ticlopidine's inhibitory action on PAF-induced aggregation and confirms ticlopidine's role in reducing platelet aggregation by ADP, which has previously been demonstrated.

Plasma beta-thromboglobulin (BTG) was measured in 132 patients with valvular heart disease: 43 were studied before, 89 after surgery (78 mechanical valves and 11 bioprostheses). In this group of 89 selected patients, a history of thromboembolism was present in 53 (5 of them had bioprosthesis). Some abnormalities have been observed in patients with valvular heart disease as compared with controls: decreased platelet count and retention on glass column, and increased BTG. There is no statistically significant difference in BTG level between patients with (m +/- SD: 62.4 +/- 42.0 ng ml-1), or without (59.5 +/- 41.0 ng ml-1) a prosthesis; in the small series of 11 patients with a bioprosthesis, BTG was slightly lower than in other patients (44.5 +/- 14.1 ng ml-1), but still higher than in controls (26.8 +/- 13.3 ng ml-1). In the patients with a history of thromboembolism, BTG was significantly higher (66.7 +/- 47.9 ng ml-1 than in patients without this complication (49.9 +/- 21.0 ng ml-1). Thus, BTG evaluation may have some value in valvular heart disease but, at present, it should be confined to systematic research including prospective studies.

beta-thromboglobulin (beta TG), a platelet-specific protein, was measured in the plasma of 53 healthy subjects (20 men and 33 women), 53 women using estrogen-progestogen contraceptives, 31 patients with cardiac valve disease (including 19 with prosthesis) and 71 patients about to undergo scintigraphy for suspected pulmonary embolism. Compared with levels in healthy subjects, beta TG levels were significantly increased in oral contraceptive users and in cardiac patients with or without prosthesis. High beta TG levels were also found in 20 out of 28 patients with pulmonary embolism confirmed by scintigraphy, but also in some of the .9 lung patients with chronic bronchopulmonary disease. Cardiac patients treated with heparin had higher beta TG levels than non heparin-treated patients, which raises queries about a possible influence of heparin on this particular blood protein.Beta-thromboglobulin (BTG), a platelet-specific protein, was measured in the plasma of 53 healthy subjects (20 men and 33 women), 53 women using estrogen progrestogen contraceptives, 31 patients with cardiac valve disease (including 19 with prosthesis) and 71 patients about to undergo scintigraphy for suspected pulmonary embolism. Compared with levels in healthy subjects, BTG levels were significantly increased in oral contraceptive users and in cardiac patients with or without prosthesis. High BTG levels were also found in 20 out of 28 patients with pulmonary embolism confirmed by scintigraphy, but also in some of the .9 lung patients treated with heparin had higher BTG levels than non heparin-treated patients, with chronic bronchopulmonary disease. Cardiac patients treated with heparin had higher BTG levels than non heparin-treated patients, which raises queries about a possible influence of heparin on this particular blood protein. (Author's modified)

Approximately 100 families with congenital dysfibrinogenemia have already been reported in the literature. We have had the opportunity to study 13 affected families in France. The study of these dysfibrinogenemias has two purposes: 1) analysis of the relationships between the structural and functional abnormalities of the fibrinogen defect, since it appears that, in a significant percentage of dysfibrinogenemias, recurrent thrombosis has been observed. The diagnosis of dysfibrinogenemia is easily presumed in hemostasis laboratories since it rests upon prolonged thrombin and/or reptilase clotting times and the discrepancy between the fibrinogen levels obtained by an immunological method and a coagulation method. Many studies have been carried out during the last few years, and in at least seven cases the fibrinogen molecular defect has been elucidated.

Acquired von Willebrand syndrome is reported in four patients with monoclonal IgG: benign gammapathy in three cases, multiple myeloma in one case; to our knowledge, this last association has not been previously reported. Coagulation abnormalities included a borderline bleeding time, a low platelet retention on glass beads, decreased levels of factor VIII coagulant activity (VIII: C), factor VIII related-antigen (VIII R: Ag) and ristocetin induced agglutination cofactor (VIII R: RC). The late clinical onset, the negative family history and the immunological abnormality suggest an acquired von Willebrand syndrome. After cryoprecipitate infusion the patients did not show the expected rise and there was no secondary increment in factor VIII: C. Time-dependent inhibition of factor VIII R: RC and factor VIII: C was found in one case only and was associated with qualitative abnormality of factor VIII R: Ag demonstrated by crossed-immunoelectrophoresis. It was not possible to interpret this last test in the other cases, due to the very low level of factor VIII R: Ag. The factor VIII abnormalities might be related to the binding and/or destruction of factor VIII by a circulating antibody, or to the adsorption of this factor on the malignant lymphocytes.

Five type I protein C deficient male patients received 5 mg stanozolol b.i.d. during 4 weeks. After four weeks of treatment plasma protein C activity increased from 0.42 to 0.74 U/ml and protein C antigen from 0.49 to 0.75 U/ml. This approximately 1.6 fold increase in plasma protein C was accompanied by an increase in factor II antigen (1.5 fold), factor V activity (1.6 fold), factor X antigen (1.1 fold), antithrombin III antigen (1.3 fold) and heparin cofactor II antigen (1.5 fold), while the concentration of factor VII, factor VIII, and factor IX activity, and of protein S antigen remained unchanged. Prothrombin fragment F1+2, measured in two patients, increased 1.3 fold. In addition to its effect on procoagulant and anticoagulant factors stanozolol had profibrinolytic effects, reflected in an increase in tPA activity and in the concentration of plasminogen. These data indicate that in type I protein C deficient patients stanozolol increases the concentrations of both procoagulant and anticoagulant factors and favours fibrinolysis. The efficacy of stanozolol in preventing thrombotic disease in type I protein C deficient patients, however, remains to be established. During the four weeks of stanozolol treatment no thrombotic manifestations were observed in the protein C deficient patients.

A lupus or lupus-like inhibitor was detected in 57 patients: 24 systemic lupus erythematosus, 9 autoimmune diseases, 10 lymphoproliferative disease, 11 miscellaneous diseases and 3 asymptomatic patients. No hemorrhagic diathesis was observed in spite of major surgery. Thromboembolism occurred in 19 patients. Among them, 5 patients had recurrent abortions. An extensive study of coagulation profile compared different assays to investigate lupus-like inhibitor: the most sensitive assay was the partial thromboplastin time performed without activator. When performed with kaolin, it was the only assay detecting the lupus cofactor. Prothrombin time was prolonged in only 53% of the patients. Factors VIII, IX, XI and XII were in the normal range in 40% of the patients. When decreased, apparent deficiencies were usually not detectable on further dilutions of the test samples. In 7 patients factor XII antigen and activity were both decreased, suggesting an apparent factor XII deficiency. No relationship was observed between thromboembolic events, underlying disease or biological pattern.

Haemorrhage is the most frequent complication of oral anticoagulant therapy (OAT) and a resistance to these drugs is rarely reported. The following classification of OAT resistance is proposed: primary or secondary resistance according to the delay of onset (at the initiation of therapy or later); selective or generalized according to the number of drugs involved (only one or several); absolute or relative as judged by the prolongation of the prothrombin time (absent or moderate). Six cases are reported and the mechanisms of resistance are discussed: no intake, variations in the vitamin K availability (diet, intestinal absorption and synthesis of vitamin K), variations in the pharmacokinetics of oral anticoagulants (drug interactions, abnormal hepatic metabolism) and variations in the receptor affinity (hereditary resistance). Resistance is often overcome by progressive increase of the doses of oral coagulant, or by changing drugs, to warfarin or coumadin (long acting drugs).

In seven patients with acquired von Willebrand's disease (AvWD) associated with lymphoproliferative disorders or benign monoclonal gammopathies, the platelet contents of von Willebrand factor antigen and ristocetin cofactor (vWF:Ag and vWF:RiCof, respectively) were normal. All the multimers of vWF:Ag could be seen in the 1.6% SDS-agarose gel electrophoresis patterns of plasma and platelet lysates. Infusion of 1-deamino-8-D-arginine vasopressin (DDAVP) augmented plasma levels of vWF:Ag and vWF:RiCof of all patients and corrected prolonged bleeding times (BT). However, compared with patients with congenital vWD type I and comparable degrees of baseline abnormalities treated in the same way, vWF:Ag and vWF:RiCof were increased less and cleared more rapidly from plasma and the BT remained normal for a shorter period of time. These studies provide evidence that these AvWD patients have qualitatively normal vWF in plasma, but at lower concentrations, that vWF in platelets is normal both qualitatively and quantitatively, and that cellular vWF can be rapidly released into plasma by DDAVP to correct the hemostatic abnormalities. However, vWF is removed rapidly from plasma, making the correction more transient than in congenital vWD type I.

A diagnosis of heparin induced thrombocytopenia (HIT) in the 26 patients was based on: 1. normal platelet count prior to heparin administration; 2. its fall to less than 100 Giga/l (m = 46 +/- 23) at time of first sample collection for test to detect a platelet aggregation factor (PAF); 3. restoration of normal values after discontinuation of heparin treatment during which the thrombocytopenia had appeared. The result of the first PAF test in these 26 patients was positive in 22 cases, negative in 2; twice the plasma provoked platelet control aggregation without in vitro addition of heparin. The origin, dose and mode of administration of the heparin did not appear determinant in the production of the thrombocytopenia: 16 of the patients were later treated with a low molecular weight heparin (LMWH). An in vitro "compatibility" test was able to be performed 8 times previously and was negative in 7 cases in the 16 patients. Samples were collected during LMWH treatment and were negative in 13 cases, and this in agreement with the increased platelet count after 7 +/- 3 days and the clinical improvement. In 3 patients the test was positive: in one case the count did not return to normal, in the second case this did occur, but slowly (21 days); the PAF test in the last patient was positive prior to LMWH treatment and remained so while the count became normal. Concordance exists therefore between negativity of the test practiced with LMWH and the increase in count when this heparin is administered; inversely, the positivity of the test does not exclude normalization of the platelet count.

Forty-two patients with total occlusion of a coronary vessel were treated with intracoronary fibrinolytic agents. Four therapeutic protocols were compared: group I received streptokinase (SK) as a continuous infusion; group II and III received SK as a bolus at different doses and group IV received lysplasminogen (Pg) plus urokinase (UK); maximal doses were 350,000 IU of SK and 250,000 IU of UK plus 75 microK of Pg. Thrombolysis was assessed by coronary angiography. Coagulation studies were performed prior to, 15 min and 6 hr after the end of the thrombolytic treatment. Recanalization was achieved in 27 of the 31 SK-treated patients (87%) and in 7 of the 11 Pg-UK-treated patients (63.6%). The recanalization frequency was the same in the three SK-treated groups, even though when SK was administered as a bolus, the dose was significantly less than when administered on a continuous infusion. Although systemic fibrinolysis occurred in all 4 groups of patients, this effect was less pronounced in the UK-treated patients than in the three SK-treated groups. This study also shows that recanalization can be achieved with a dose of SK lower than the anti-SK antibody level. Haemorrhagic side effects were minimal in all patients studied. Severe defibrination is usually considered a risk of haemorrhage. These preliminary results suggest that bolus injection of SK or the use of UK plus lys-Pg can reduce the level of defibrination and thus the haemorrhagic risk.

The aim of this retrospective study was to evaluate the efficacy and tolerance of a moderate dose of urokinase (UK : 2000 IU/kg/h) for at least 24 h in a series of 23 patients with massive pulmonary emboli (PE) (mean pulmonary vascular obstruction = 70 +/- 7%). All patients received heparin in conjunction with UK. A control pulmonary angiography, performed at the end of UK therapy, revealed an important decrease in pulmonary obstruction (-50%). One patient died before the end of UK therapy from shock due to PE (early mortality = 4.3%). Severe hemorrhagic complications occurred in 3 patients (13%) and dictated the stoppage of UK administration, but bleeding was never the cause of death or sequelae. Thus, moderate doses of UK associated with heparin appear to effectively induce clot lysis in patients with massive pulmonary emboli. The incidence of hemorrhagic complications should be decreased by strictly respecting all contraindications to the use of thrombolytic agents and by avoiding excessive heparinization.

To evaluate the influence of heparin on spontaneous platelet aggregation (SPA) two groups of patients, one treated with heparin and the other without heparin, were compared. The frequency of SPA is highly increased in patients with prosthetic heart valves treated with heparin as compared to patients not treated with heparin. Thus, the high frequency of SPA in prosthetic heart valve carriers treated with heparin might be due either to the prosthesis itself or to heparin. In contrast, in patients with thromboembolic disease, SPA does not seem to be more frequent in heparin-treated than in untreated patients.

The study concerns 131 patients with a history of recurrent deep vein thrombosis. The predisposing and triggering factors of thrombosis have been carefully recorded and a study of hemostasis parameters has been performed, including AT III determination, fibrinolytic activity before and after venous occlusion, plasminogen, alpha 2-antiplasmin and histidine-rich glycoprotein determination. A congenital AT III deficiency was detected in six patients (4.4%). The most frequent finding was a decrease in fibrinolytic activity after venous occlusion. If one accounts for patients with a disease predisposing to thrombosis: Behçet's disease, cancer, hiatus hernia, Cockett's syndrome (14 patients), or a biological anomaly such as: deficiency in AT III, decrease in fibrinolytic activity. circulating anticoagulant, increase in lipids or uric acid, decrease in plasminogen or increase in alpha 2-antiplasmin (57 patients), there are still 60 patients (45% of the cases) in whom thromboses remain unexplained.

A case of intravascular coagulation in a patient with a very large ventricular aneurysm is reported. Biological signs of defibrination with a low serum fibrin of 0,80 g/1, thrombocytopaenia of 80,000/mm3 and the presence of soluble complexes and FDPs were detected after recurrent haematuria. Low dose heparin (0,15 to 0,20 ml x 2/day by subcutaneous injection) led to normalisation of the fibrinogen levels, increased the platelet count and reversed the consumptive coagulopathy. Each withdrawal of heparin (5 attempts over 16 months) led to a biological relapse. At the final withdrawal of therapy, the biological abnormalities remained minor; the consumption of fibrinogen and platelets was well compensated. Similar cases have been published in aortic aneurysms with and without dissection, but the association with a cardiac aneurysm has not been reported previously. The physiopathological mechanism of the coagulopathy is discussed and the authors suggest routine study of the coagulation system in all patients with cardiac aneurysms. This case illustrates the efficacity of moderate doses of heparin in a patient with "biological hypercoagulability" well documented by laboratory investigations.

A 62 year old man presented a diffuse hemorrhagic syndrome related to the presence of an acquired factor VII inhibitor (proconvertin). Autoantibodies were of the IgG class and no subjacent disease was detected during a 7-month follow up. Treatment with high-dose polyvalent immunoglobulins was ineffective, and the onset of an intracerebral hemorrhage required therapy by a series of plasma exchanges combined with immunosuppressive treatment. The plasma inhibitor was no longer present after the first exchange and clinical and biological remission was rapid.

A 45 years old woman with AL amyloidosis presented with a hypofibrinogenemia (fibrinogen 100 mg/dl) without severe bleeding. There was laboratory evidence of fibrinolysis with shortened euglobulin lysis time, decreased alpha-2 plasmin inhibitor and decreased plasminogen. The mechanism of this primary fibrinolysis remains unclear, since there is no enhancement of the tissue-type plasminogen activator. Analysis of the 8 cases related in the literature of excessive fibrinolysis associated with amyloidosis demonstrated improvement of bleeding manifestations and abnormal fibrinolysis following the administration of antifibrinolytic agents.

Streptokinase was administered to 98 patients, 75 of them with arterial occlusion of the limbs, in accordance with the classical protocol of high and continuous doses (150,000 international units per hour for 48 to 78 hours after an initial standard dose of 500,000 units). There were a total of 15 haemorrhagic complications: --related to a non-respected contraindication (1 case) --traumatic (4 cases) --spontaneous (10 cases), responsible for or contributing to a fatal outcome in 4 instances. In addition, there were 13 spontaneous or provoked haemorrhagic side effects. Retrospective analysis of laboratory results shows that it is difficult to predict haemorrhage: the degree of fibrinopaenia and fibrin breackdown product levels are not closely related to the onset of bleeding. Nevertheless, the combination of a residual fibrin level of less than 1.50 g/l approximately with an amount of fibrinogen broken down (difference between fibrinogen levels before treatment and during treatment) of more than 3 grams was present in the great majority of patients in whom complications developed. The absence of bleeding seen when plasma thrombolytic activity, assessed by the Blix test, is inadequate, suggests the existence of a relationship between biological effectiveness and the risk of haemorrhage. In practice, apart from strict observation of contraindications, the risk of haemorrhage must be born in mind when the therapeutic decision is made. Careful clinical surveillance is today more important than laboratory studies in the prevention of haemorrhagic complications, the price which must be paid for the thrombolytic activity of streptokinase. The latter is capable of acting not only upon the vascular obstruction but also upon haemostatic clots.

Investigation of 118 patients for protein C deficiency using an immunological and a functional assay, and subsequent investigation of those (nine) found to be deficient, identified 22 patients (14 women, eight men) with protein C deficiency, of whom six were asymptomatic, 15 had histories of venous thromboembolism, and one had a history of arterial thromboembolism. Protein C deficiency was associated in the nine probands with young age at first episode of thromboembolic disease (mean 24.1 (SD 11.9) years), absence of a precipitating condition (five (56%], and a family history of thromboembolic disease (six (66%]. Investigation of the nine families suggested autosomal dominant transmission of the defect. Thromboembolic episodes were seen in patients with protein C antigen concentrations below 0.6 U/ml. Mean (SD) protein C antigen concentrations were 0.48 (0.12) U/ml in 18 patients not receiving oral anticoagulant treatment and 0.28 (0.05) U/ml in four receiving such treatment. One patient with severe protein C deficiency (0.16 U/ml) developed skin necrosis soon after starting oral anticoagulant treatment.

The frequency of thrombotic episodes in patients with Behçet's disease prompted us to study their hemostasis. Seventy patients were investigated and 27 of them (38%) had history of venous thrombosis; they were compared to 27 healthy subjects and to 16 hospitalized patients in whom the diagnosis of Behçet disease was ruled out. Fibrinolytic activity after a 10 minute venous occlusion was significantly decreased while fibrinogen, factor VIII and von Willebrand factor was increased as well as the tPA inhibitor (PAI-I): the last 3 proteins are synthetized by the endothelial cell. No significant difference was observed between patients with or without history of thrombosis. Coagulation and fibrinolysis changes observed are not specific of Behçet disease since they were also found in a population of patients without Behçet disease and without history of thrombosis.