Personalized thromboprophylaxis using a risk score for the management of pregnancies with high risk of thrombosis: a prospective clinical study.

Essentials Pregnancy is a risk factor for thrombosis. Management of thrombosis risk in pregnancy remains a challenge. Prophylaxis needs to be personalized. Our score may be a helpful tool for the management of pregnancies at high risk of thrombosis. SUMMARY: Background Patients with thrombophilia and/or a history of venous thromboembolism (VTE) are at risk of thrombosis during pregnancy. A risk score for pregnancies with an increased risk of VTE was previously described by our group (Lyon VTE score). Objectives The aim of this prospective study was to assess the efficacy and safety of our score-based prophylaxis strategy in 542 pregnancies managed between 2005 and 2015 in Lyon University Hospitals. Patients/Methods Of 445 patients included in the study, 36 had several pregnancies during the study period. Among these 445 patients, 279 had a personal history of VTE (62.7%), 299 patients (67.2%) had a thrombophilia marker, and 131 (29.4%) thrombophilic women had a personal history of VTE. During pregnancy, patients were assigned to one of three prophylaxis strategies according to the risk scoring system. Results In the antepartum period, low molecular weight heparin (LMWH) prophylaxis was prescribed to 64.5% of patients at high risk of VTE. Among them, 34.4% were treated in the third trimester only, and 30.1% were treated throughout pregnancy. During the postpartum period, all patients received LMWH for at least 6 weeks. Two antepartum-related VTEs (0.37%; one with a score of < 3 and the other with a score of > 6) and four postpartum-related VTEs (0.73%; three with scores of 3-5 and one with a score of > 6) occurred. No case of pulmonary embolism was observed during the study period. The rate of bleeding was 0.37%. No serious bleeding requiring transfusions or surgery occurred during the study period. Conclusion The use of a risk score may provide a rational decision process to implement safe and effective antepartum thromboprophylaxis in pregnant women at high risk of VTE.

Synthesis of GPIb beta with novel transmembrane and cytoplasmic sequences in a Bernard-Soulier patient resulting in GPIb-defective signaling in CHO cells.

The molecular defect of a new Bernard-Soulier patient, originating from Morocco and presenting thrombocytopenia with large platelets and an absence of ristocetin-induced platelet agglutination, has been identified and reproduced in transfected heterologous cells. Gene sequencing revealed insertion of a guanine in the domain coding for the transmembrane region of the glycoprotein (GP) Ib beta subunit. This mutation causes a translational frame shift, which creates putative novel transmembrane and cytoplasmic 37 and 125 amino acids domains, respectively. A 34 kDa immunoreactive GPIb beta band, instead of the normal 26 kDa subunit, was detected by Western blotting in lysates from the patient's platelets and from transfected cells and in immunoprecipitates of metabolically labeled cells. The abnormal subunit did not associate with GPIb alpha and was mainly intracellular, although a significant fraction could reach the cell surface. Cells expressing the mutant GPIb-IX complex adhered to a von Willebrand factor matrix but were unable to change shape, unlike cells expressing the wild-type receptor. These results strongly suggest a novel role of the GPIb beta subunit and its transmembrane-intracellular region in GPIb-VWF-dependent signaling, in addition to a role in correct assembly and cell surface targeting of the GPIb-V-IX complex.

Thrombospondin binds to the surface of human osteosarcoma cells and mediates platelet-osteosarcoma cell interaction.

We have previously shown that thrombospondin (TSP) is synthesized and secreted by human MG-63 osteosarcoma cells. In this study, the secretion and cell surface expression of TSP by two different human osteosarcoma cell lines (MG-63 and TE-85) as well as the involvement of TSP in the platelet-aggregating activity of these tumor cells were studied. Using a sandwich enzyme-linked immunosorbent assay, MG-63 cells secreted 3-fold as much TSP as TE-85 cells at 48 h (0.17 +/- 0.01 (SD) versus 0.06 +/- 0.006 micrograms/10(6) cells, P = 0.007). Binding of exogenous 125I-TSP to MG-63 and TE-85 cells in monolayer indicated that binding was time and concentration dependent, saturable, and inhibited by excess cold TSP. However, despite a similar affinity, MG-63 cells had 10-fold more TSP-binding sites than TE-85 cells (402,394 +/- 130,346 versus 36,748 +/- 7,708 TSP-binding sites/cell; P = 0.002). Similar binding differences of 125I-TSP were observed with both osteosarcoma cell lines in suspension. A fluorescence-activated cell-sorting analysis was used in conjunction with an anti-TSP polyclonal antibody, and binding of endogenous TSP to MG-63 and TE-85 cells in suspension was investigated. Addition of an anti-TSP antibody to MG-63 and TE-85 cells in suspension increased the mean fluorescence intensity 50-fold when compared to an irrelevant antibody. Moreover, the fluorescence intensity of MG-63 cells with an anti-TSP polyclonal antibody was increased by 40% when compared to TE-85 cells. Since TSP was expressed on the surface of osteosarcoma cells, the involvement of this glycoprotein in the platelet-aggregating activity of MG-63 and TE-85 cells was therefore investigated using an anti-TSP polyclonal antibody and two monoclonal antibodies (P10 and MA-II), the epitopes of which lie within the Mr 140,000 non-heparin-binding fragment and the Mr 25,000 heparin-binding fragment of TSP, respectively. Preincubation of MG-63 cells (1 x 10(6) cells/ml) with either an anti-TSP polyclonal antibody (100 micrograms/ml) or monoclonal antibody P10 (15 micrograms/ml) inhibited by 80% other platelet-aggregating activity of these tumor cells, while anti-TSP monoclonal antibody MA-II (15 micrograms/ml) had no effect. In sharp contrast, the anti-TSP polyclonal antibody (100 micrograms/ml) only exhibited a slight inhibitory effect on platelet aggregation induced by TE-85 cells when using a low concentration of tumor cells (0.6 x 10(6) cells/ml).(ABSTRACT TRUNCATED AT 400 WORDS)

Management of pregnant women with increased risk of venous thrombosis.

OBJECTIVE: To evaluate the usefulness of score based management of pregnancies with high risk of venous thromboembolism (VTE). METHOD: 116 consecutive pregnancies in 109 women with confirmed thrombophilia and/or history of VTE were studied. Patients were managed in accordance with international recommendations. Recently, a VTE risk prediction score was established. An independent group assessed retrospectively and in a blinded way the usefulness of this score. RESULTS: Of the 116 pregnancies, an antithrombotic prophylaxis by low molecular weight heparin was prescribed in 61 cases (52.6%). All patients with a positive score (n=57, 49.1%) have been treated with an antenatal thromboprophylaxis. In the population where the score was negative (n=55 cases), none of the patients received antenatal prophylaxis. But, despite a negative score, four patients were treated by their general practitioner. During the study period, there was only one episode of VTE. CONCLUSION: Implementing this scoring system has resulted in favorable outcomes and a low risk of recurrent thrombosis in this limited series of women with increased risk of VTE.

Osteonectin is an alpha-granule component involved with thrombospondin in platelet aggregation.

We previously showed that thrombospondin, a major alpha-granule glycoprotein of human platelets, forms a specific complex with osteonectin, a phosphoglycoprotein originally described in bone that is also present in human platelets. The storage organelles and the function of osteonectin in platelets are still unknown. In this study, using electron microscopy in combination with immunogold staining, the major storage organelle for platelet-secreted proteins, the alpha-granules. Furthermore, osteonectin was qualitatively and quantitatively assessed by studying normal platelets and the platelets from a patient with gray platelet syndrome. Gray platelet syndrome is a rare congenital bleeding disorder characterized by a selective deficiency in morphologically recognizable platelet alpha-granules and in the alpha-granule secretory proteins. Binding of an iodinated antiosteonectin monoclonal antibody to gray platelet proteins transferred to nitrocellulose from SDS-polyacrylamide gels showed no band corresponding to osteonectin compared to control platelets. Using a polyclonal antiosteonectin antibody-based radioimmunoassay, gray platelets contained 0.2 +/- 0.03 ng osteonectin per 10(6) platelets, which is only 20% of the normal platelet content of osteonectin (0.93 +/- 0.16 ng per 10(6) platelets). Study of the localization of osteonectin to the surface of human platelets demonstrated that a radioiodinated antiosteonectin polyclonal antibody bound specifically to thrombin-stimulated platelets but not to resting platelets. Binding was concentration-dependent, saturable (1710 +/- 453 binding sites per platelet, Kd = 1 microM), and inhibited by an excess of cold antiosteonectin polyclonal antibody. No binding was observed on the surface of thrombin-stimulated gray platelets. To gain further insights into the role of osteonectin released from activated platelets, the effect of an antiosteonectin polyclonal antibody was tested on the aggregation of washed platelets. F(ab')2 fragments from the antiosteonectin polyclonal antibody inhibited in a dose-dependent manner the aggregation of collagen-stimulated, washed human platelets without affecting collagen-induced platelet serotonin release. To characterize the mechanism through which antiosteonectin F(ab')2 fragments inhibit platelet aggregation, the expression of endogenous thrombospondin (TSP) on the surface of thrombin-activated platelets was studied using 125I-labeled anti-TSP monoclonal antibody P10. The endogenous surface expression of TSP to thrombin-stimulated platelets was significantly inhibited in the presence of antiosteonectin F(ab')2 fragments (6286 +/- 2065 molecules of P10 per platelet) compared to 11,230 +/- 766 molecules of P10 per platelet in the presence of nonimmune F(ab')2 fragments.(ABSTRACT TRUNCATED AT 400 WORDS)

The growth-supportive effect of thrombospondin (TSP1) and the expression of TSP1 by human MG-63 osteoblastic cells are both inhibited by dexamethasone.

Thrombospondin (TSP) is a 450-kDa extracellular matrix glycoprotein which supports the growth of human MG-63 osteoblastic cells [Abbadia et al., FEBS Lett., 329 (1993) 341-346]. In this study, we describe the effect of the glucocorticoid, dexamethasone, on cell proliferation and TSP expression by MG-63 cells. Using a serum-free mitogenesis assay, dexamethasone (25 to 500 nM) caused a dose-dependent decrease in [3H]thymidine incorporation by MG-63 cells in culture, reaching 40% inhibition of cell proliferation at a concentration of 250 nM. Similarly, the stimulatory effect of TSP (500 ng/ml) on proliferation of MG-63 cells was totally abolished in the presence of dexamethasone (250 nM). In situ hybridization indicated that TSP mRNA level in dexamethasone-treated MG-63 cells decreased compared to quiescent cells. As judged by fluorescence-activated cell sorting analysis, dexamethasone treatment of MG-63 cells resulted in a 50 to 70% decrease in TSP cell surface expression compared to quiescent cells. Secretion of TSP in the culture fluid of dexamethasone-treated MG-63 cells also decreased by 40% while, under similar experimental conditions, a 180% increase in alkaline phosphatase activity was observed in dexamethasone-treated cells. Because glucocorticoids induce osteoporosis in vivo and reduce proliferation of osteoblasts in vitro, our results argue for an important role of TSP during bone formation.

Molecular study of Glanzmann thrombasthenia in 3 patients issued from 2 different families.

In an effort to further understand Glanzmann thrombasthenia (GT) 3 patients from 2 different families were studied. After biochemical and immunological analysis these patients were classified as type I. We observed in the first family a new restriction site for Stu I in exon II of the glycoprotein (GP) IIIa gene caused by a homozygous nonsense mutation: 62 Arg to stop codon. The parents were heterozygotes for this mutation. We found in the second family a previously described nonsense mutation: 584 Arg to stop codon in exon 17 of the GPIIb gene. The father and his two affected sons were heterozygous for this genetic defect. This mutation 62 Arg to stop codon is a new description of a genetic defect associated with GT. Furthermore, the discovery of the same mutation in 3 affected families from different ethnic groups raises the possibility of either a hot spot mutation in the CG dinucleotide region of GPIIb gene, or an ancient mutant allele present in diffuse populations at a relatively high frequency.

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.

Aggregation to thrombin and collagen of platelets from a Glanzmann thrombasthenic patient lacking glycoproteins IIb and IIIa.

The aim of this study was to investigate the platelets of a Glanzmann thrombasthenic patient, which in citrated PRP failed to respond to various agonists, but aggregated and secreted to high concentrations of thrombin (0.36, 0.72 and 1 U/ml) and collagen (4, 10 and 20 micrograms/ml) when washed and resuspended in a Tyrode-albumin solution (containing 2 mM Ca2+). Aggregation of the patient platelets was not affected by anti-IIb/IIIa monoclonal antibody (P18) which strongly inhibits thrombin or collagen induced aggregation of normal platelets. Washed platelets of this patient did not aggregate to ADP (10-100 microM) in the presence of added fibrinogen (2 mg/ml) nor bind 125I-labelled fibrinogen (40 to 320 micrograms/ml) when thrombin-stimulated. Different anti-IIb/IIIa monoclonal antibodies (P2, P18) when used in binding or crossed immunoelectrophoretic studies showed a complete absence of the IIb-IIIa glycoprotein complex on the patient platelets. Moreover, glycoproteins IIb or IIIa were absent on silver-stained two-dimensional (non-reduced/reduced) polyacrylamide gel separations of the patient platelets and were not detected by Western blots used in combination with anti-PLA1 (antigen present on IIIa), anti-Leka (antigen present on IIb). This study shows that platelets lacking glycoproteins IIb or IIIa can aggregate in response to high concentrations of collagen or thrombin when resuspended in the presence of physiological concentrations of calcium. Results obtained in this study could indicate the existence of other mechanisms (other than the IIb-IIIa glycoprotein complex) involving glycolipids, heparans, proteoglycans, and/or unknown membrane glycoproteins to mediate platelet aggregation of stimulated thrombasthenic platelets.

Use of recombinant factor VIIa in 3 patients with inherited type I Glanzmann's thrombasthenia undergoing invasive procedures.

The treatment of bleeds in Glanzmann's thrombasthenia is a challenging issue, especially when repeated platelet transfusions have induced anti-glycoprotein (GP) IIb-IIIa or anti-HLA allo-immunisation. In an attempt to find an alternative treatment regimen, we used recombinant factor VIIa (rFVIIa, NovoSeven, Novo Nordisk, Denmark) as first-line therapy in 3 patients with Glanzmann's thrombasthenia and anti-GPIIb-IIIa iso-antibodies who were scheduled for invasive procedures. The administration of an initial bolus dose of rFVIIa (70-110 microg/kg) was immediately followed by continuous infusion at the rate of 9-30 microg/kg/h for 3-15 days. The treatment resulted in an excellent clinical efficacy and tolerance in 2 cases. In the third patient, whereas efficacy was excellent at the surgical site, pharyngonasal bleeds of traumatic origin persisted for 10 days, and a severe thromboembolic complication occurred 5 days after discontinuation of rFVIIa. Complementary studies are needed for patients with congenital platelet disorders in order to evaluate the safety and the potential therapeutic place of rFVIIa treatment.

Factor IX gene analysis in 70 unrelated patients with haemophilia B: description of 13 new mutations.

Seventy unrelated patients suffering from haemophilia B have been screened for determining the molecular defect and for evaluating the spectrum of factor IX mutations in the Rhône Alpes region in France. Most patients were characterized with respect to factor IX antigen and factor IX coagulant activity. We have used denaturing gradient gel electrophoresis to obtain a full scanning of the whole coding, promoter, and exon flanking sequences of the factor IX gene. This technique enabled us to determine the molecular defect in 68 out of 70 families (97%), and the mutation was further identified in the two last patients with a direct sequencing of the gene. A total of 2 complete gene deletions in patients with antifactor IX inhibitor, 6 small insertions/deletions and 62 point mutations were found. Two of these nucleotide substitutions (Arg145His and Ala233Thr) were detected in 21 patients (30%) suggesting the existence of a local founder effect. Thirteen mutations were previously undescribed, including 7 missense mutations. The detection of mutations in patients affected with haemophilia B may shed some light in the structure-function relationship of factor IX molecule within the coagulation system.

Plasma thrombospondin in patients with chronic renal failure, liver disease and splenectomy.

Thrombospondin (TSP), is a major constituent of human blood platelet alpha-granules. Stimulation of platelets causes the release of TSP in parallel with other alpha-granule constituents such as beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) but the thrombospondin plasma in vivo half life is significantly greater than beta-TG and PF4. The aim of this study was to assay TSP levels in plasma of patients with chronic renal failure (CRF), liver disease (LD) and following splenectomy. The TSP values were then compared to the patients plasma levels of two traditional markers of platelet activation, beta-TG and PF4, and to fibronectin (FN) and von Willebrand factor (VIII:vWF). Plasma TSP levels (67.6 +/- 16.9 ng/ml) assayed in 14 CRF patients were significantly higher (p less than 0.05) than those measured in 28 donors (55.5 +/- 11.7 ng/ml). No correlation was observed, in CRF patients, between the TSP level and PF4 (2.5 +/- 1.5 ng/ml), beta-TG (131.1 +/- 21 ng/ml), FVIII:vWF (252 +/- 85%), or FN (102 +/- 33%) plasma levels. The TSP plasma level in CRF patients was significantly correlated (p less than 0.02) with that of fibrinopeptide A (4.1 +/- 1.9 ng/ml). Although the beta-TG (23.5 +/- 6.9 ng/ml) and PF4 (2.9 +/- 2 ng/ml) plasma levels in six LD patients were normal, the TSP levels (82.5 +/- 39.1 ng/ml) were significantly increased (p less than 0.01). Thrombospondin plasma levels (77.1 +/- 20.1 ng/ml) in 14 patients having undergone splenectomy were significantly increased (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Human plasma fibrinogen measurement derived from activated partial thromboplastin time clot formation.

Prothrombin time-derived measurement of fibrinogen (PTd) has already been described. Activated partial thromboplastin time-derived measurement of fibrinogen (aPTTd) has not yet been clearly defined. Using an MDA II coagulometer (Organon Teknika, Durham, North Carolina, USA), we have therefore compared fibrinogen levels determined with Clauss, PTd, and aPTTd assays and an enzyme immunoassay (EIA) in 172 samples. Of these, 47 were from pre-operative controls, 18 from patients with liver disease, 28 from patients with hyperfibrinogenaemia, 33 from patients treated with vitamin K antagonists, 22 from patients treated with unfractionated heparin and 24 from haemophilic patients. Within the normal range, interassay and intra-assay variations were comparable. For control samples, PTd, aPTTd and Clauss assays were well correlated, without any systematic error. EIA was also correlated but values were slightly higher (mean of difference = 0.24). Pathological samples showed an overestimation of fibrinogen when using PTd measurements in patients treated with vitamin K antagonists, as well as when using aPTTd measurements in patients presenting with factor VIII and factor IX deficiencies. These results indicate that, despite expected financial savings, aPTTd fibrinogen measurements should not be used without restriction. PTd and aPTTd fibrinogen determinations are provided without any additional cost. Their comparison with Clauss fibrinogen results may constitute a validation tool or have additional diagnostic utility (e.g. identifying polymerization abnormalities in case of dissimilar results).

Comparison of hemostasis with two high-flux hemocompatible dialysis membranes.

Eight adults with chronic renal failure were dialyzed using polyacrylonitrile (AN 69) or polysulfone (PS) membranes with a high (HHR) or low (LHR) continuous non-fractionated heparin regimen--a total of either 90 or 50 IU/kg body weight. With the HHR, for a mean anti-Xa (aXa) activity of around 0.40 IU/ml, no plasma activation of coagulation was observed; fibrinopeptide A (FPA) was in agreement with the residual blood volume (RBV) and the state of the bubble trap, especially with the PS membrane. With the LHR, for a mean aXa below 0.21 IU/ml, there was only moderate activation of coagulation. The PS membrane gave different results from the AN 69 membrane, RBV values on the HHR and aXa being lower on both the HHR and LHR, with FPA values being regularly lower on the LHR. The decrease in plasma beta-TG on the LHR was more marked with the PS than with the AN 69 membrane due to loss on dialysis or adsorption, as shown by the arterio-venous difference. The increase in plasma PF4 was related to the effect of heparin. However, there was no platelet activation. On the LHR, platelet count and intraplatelet beta-TG and PF4 levels remained very stable. The two high-flux membranes were very hemocompatible and require only low doses of heparin, but the dialyzer with AN 69 membrane need its geometry improving.

[Diagnosis of venous thrombosis and/or pulmonary embolism by determination of d-dimers using ELISA. Review based on a study of 80 consecutive patients hospitalized in an emergency unit]. / Le diagnostic de la thrombose veineuse et/ou de l'embolie pulmonaire par le dosage des D-Dimères ELISA. Mise au point à partir d'une étude portant sur 80 patients consécutifs hospitalisés dans un service d'urgence médicale.

The sensitivity and specificity of an ELISA method (Fibrinostika Fbdp Organon Teknika) for assay of D-dimers in the diagnosis of deep vein thrombosis and/or pulmonary embolism was studied in 80 consecutive patients seen at an emergency unit. Fifty-six of the patients presented clinical signs of deep vein thrombosis. Diagnosis was confirmed in 26 of the 56 patients with a D-dimer level above 370 ng/ml (sensitivity 92.3%) and 370 ng/ml for 13 of 30 patients with a negative venous ultrasound Doppler examination (specificity 43.3%). The positive predictive value was 58.5% and the negative predictive value was 87%. There was a significant difference in the level of D-dimers between distal and proximal deep vein thrombosis. In 40 cases with suspected pulmonary embolis, either alone or with suspected deep vein thrombosis, diagnosis was made in only 4 of 9 with a highly or intermediately probable ventilation/perfusion scan. D-dimer level was always above 3,000 ng/ml. Coupling the ELISA dimer test with noninvasive explorations improves negative predictive value but can also avoid invasive explorations (venography, pulmonary angiography) in certain patients. A D-dimer test as sensitive as the ELISA test and as rapid as the latex test remains to be described.

[Protein C deficiency and pregnancy. Apropos of 2 case reports]. / Déficit en protéine C et grossesse. A propos de deux observations.

Protein C is a protein found in the serum, dependent on vitamin K. It is a strong protection against venous thrombosis. Deficiency in protein C, whether constitutional or acquired, can give rise to thrombo-embolic accidents in young patients without any obvious triggering factor. The authors start by describing the physiological features of protein C. Deficiencies of this protein are transferred through a dominant autosome. Two cases are described where protein C deficiency occurred in pregnancy. This association has not been previously described. They then discuss the kinetics of protein C in pregnancy, at delivery and in the newborn. They then point out how important it is to treat with anticoagulants in prophylactic doses during the pregnancy. They use repeated doses of Heparin as an anticoagulant and for its antivitamin K action following the delivery. They give a list of precautions that have to be observed in this relay system which should be slow and carefully worked out later. Obstetrical observation has to look for the onset of pre-eclampsia and intra-uterine growth retardation due to placental microthrombi. The authors conclude, after pointing out the frequency and the seriousness of this condition, by proposing that it should systematically be looked for in families where there have been cases of thrombo-embolic accidents.

[Isolated increase in the bleeding time: the hemorrhagic risk and therapeutic problems]. / Allongement isolé du temps de saignement: risque hémorragique et problème thérapeutique.

An isolated increase of the bleeding time is rare. In the young, there may exist a history of bleeding disorders such as epistaxis. In middle age, the increased risk of bleeding during surgery is low but real, and depending on the type of surgery. There are many drugs responsible for increased bleeding time; these must be avoided: the principle that one haemostatic defect is often well tolerated whereas two are not is very real. So the management of such patients during surgery must be meticulous and the use of some drugs must be avoided. Careful surgical management with regard to haemostasis undoubtedly allows many patients with this sort of defect to undergo surgery without excessive bleeding. Some treatments are possible (e.g. steroids, DDAVP), but their routine use is not warranted.

[The Budd-Chiari syndrome (hepatic vein obstruction). The diagnostic and therapeutic management of acute and subacute forms]. / Syndrome de Budd-Chiari (obstruction des veines hépatiques). Prise en charge diagnostique et thérapeutique des formes aiguës et subaiguës.

EARLY DIAGNOSIS: The Budd-Chiari syndrome results from an obstruction of the suprahepatic venous drainage. The condition spontaneously evolves towards liver fibrosis and death. Early diagnosis is thus of prime importance to initiate adapted treatment promptly. EXPLORATIONS: Color-coded and pulsed Doppler coupled with ultrasonography is the key to positive diagnosis. Magnetic resonance imaging may provide further precision. DECONGESTION OF THE LIVER: As the hepatic lesions are reversible, satisfactory drainage must be achieved as rapidly as possible, either by percutaneous puncture or surgery. The problem is to control the underlying hematology disease to prevent recurrent venous thrombosis, generally the cause of treatment failure. PREVENTIVE ANTICOAGULATION: Effective anticoagulation using low-molecular-weight heparin, which appears to be more adapted than standard heparin, must be achieved prior to any decongestion procedure. Long-term management requires anti-vitamin K therapy if the risk of thrombosis persists.