Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study.

BACKGROUND: Oral estrogen use and elevated body mass index (BMI) increase the risk of venous thromboembolism (VTE). Recent data suggest that transdermal estrogen might be safe with respect to thrombotic risk. However, the impact of transdermal estrogen on the association between overweight (25 kg m(-2) < BMI < or = 30 kg m(-2)) or obesity (BMI >30 kg m(-2)) and VTE risk has not been investigated. METHODS: We carried a multicenter case-control study of VTE among postmenopausal women aged 45-70 years, between 1999 and 2005, in France. Case population consisted of women with a first documented idiopathic VTE. We recruited 191 hospital cases matched with 416 hospital controls and 62 outpatient cases matched with 181 community controls. RESULTS: The odds ratio (OR) for VTE was 2.5 [95% confidence interval (CI):1.7-3.7] for overweight and 3.9 (95% CI: 2.2-6.9) for obesity. Oral, not transdermal, estrogen was associated with an increased VTE risk (OR = 4.5; 95% CI: 2.6-7.7 and OR = 1.1; 95% CI: 0.7-1.7, respectively). Compared with non-users with normal weight, the combination of oral estrogen use and overweight or obesity further enhanced VTE risk (OR = 10.2; 95% CI: 3.5-30.2 and OR = 20.6; 95% CI: 4.8-88.1, respectively). However, transdermal users with increased BMI had similar risk as non-users with increased BMI (OR = 2.9; 95% CI: 1.5-5.8 and OR = 2.7; 95% CI: 1.7-4.5 respectively for overweight; OR = 5.4; 95% CI: 2.1-14.1 and OR = 4.0; 95% CI: 2.1-7.8 respectively for obesity). CONCLUSIONS: In contrast to oral estrogen, transdermal estrogen does not confer an additional risk of idiopathic VTE in women with increased BMI. The safety of transdermal estrogen on thrombotic risk has to be confirmed.

[Polycythemia vera and pregnancy: difficulties for diagnosis and treatment]. / Maladie de Vaquez: risques et prise en charge au cours de la grossesse.

Polycythemia vera is a myeloproliferative syndrome. This clonal disorder involves a pluripotent stem cell capable of differentiating into red blood cells, granulocytes, and platelets. Polycythemia vera is characterized by the overproduction of mature red blood cells in the bone marrow. Myeloid and megakaryocytic elements are also often increased. Polycythemia vera (PV) is rarely associated with pregnancy. About 20 cases have been reported. Prognosis of PV is not influenced by pregnancy. Conversely, pregnancy outcome is poor, due to the occurrence of gestational hypertension, stillbirth and induced prematurity. During pregnancy, clinical management needs to be close including a collaborative approach between obstetricians, hematologists and anesthesists. The risk of poor outcome may be reduced by the association of antiaggregant and anticoagulant therapy. Phlebotomy can be provided in order to maintain hemoglobin level under 42%.

Use of recombinant factor VIIa (NovoSeven) in patients with Glanzmann thrombasthenia.

Recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) appears effective and relatively safe for the treatment of bleeding and for surgical prophylaxis in patients with Glanzmann thrombasthenia as reported to the International Registry on rFVIIa and Congenital Platelet Disorders. One of the shortcomings of the Registry data is the heterogeneity of treatment protocol, including dosage, number of doses used, duration of treatment before declaration of failure, and mode of rFVIIa administration (bolus v continuous infusion). The data are not yet sufficient to define optimal regimens for various indications such as the type of bleeding or the type of procedures. The place of this drug compared to platelet transfusion in the overall management of patients with Glanzmann thrombasthenia will need to be determined in relationship to a number of challenges and unresolved issues in the clinical care of these patients. These issues include: how to improve local measures for patients with mucosal bleeds, optimal management of young women during menarche, optimal platelet transfusion regimens for various indications, the relationship between antiplatelet antibodies detected by monoclonal antibody-specific immobilization of platelet antigens (MAIPA) and effectiveness of platelet transfusion, whether there are other biological tests that may correlate with effectiveness of platelet transfusion, and management of pregnancy and delivery regarding antiplatelet immunization.

Preclinical phase of polycythemia vera in pregnancy.

BACKGROUND: In some cases, complications of pregnancy are related to thrombophilia. We describe a preclinical phase of polycythemia vera. CASE: A woman, who experienced perinatal deaths in her first two pregnancies, was diagnosed with polycythemia vera during antenatal counseling for a third pregnancy. During this pregnancy, phlebotomies, low molecular weight heparin, and low-dose aspirin treatments resulted in the delivery of a healthy baby. CONCLUSION: Polycythemia vera is a rare condition in women of childbearing age and can exist in a preclinical phase for many years. During pregnancy, it can cause severe but preventable thrombotic complications of placental origin.

Two cases of t(1;16)(p11;p11) in multiple myeloma: confirmation by chromosome painting.

Two patients with multiple myeloma and an unbalanced translocation, t(1;16)(p11;p11), are reported. The fluorescence in situ hybridization (FISH) technique was used in one patient to confirm the translocation. To our knowledge, t(1;16)(p36;q13) and t(1;16)(q21;p13), but not t(1;16)(p11;p11), had been reported previously in multiple myeloma. Our results suggest that FISH is useful to characterize structural abnormalities and identify marker chromosomes in multiple myeloma where analysis with conventional cytogenetics is often difficult.

[What vascular events suggest a myeloproliferative disorder?]. / Devant quelles manifestations vasculaires rechercher un syndrome myéloprolifératif?

Patients with polycethemia vera (PV) or essential thrombocythemia (ET) are at increased risk of arterial and venous thromboembolic events. Arterial ischemic complications occur in 24 to 43% of these patients, particularly those with cardiovascular risk factors (especially cigarette smoking). Non-atheromatous arterial thrombosis concerns all large and medium-sized vessels, particularly cerebral, limb, coronary and digestive arteries. Extensive complications have been described in patients with lower limb occlusive arteriopathy, particularly stent or bypass thrombosis, critical ischemia. Juvenile myocardial infarction or rapid postangioplasty coronary thrombosis may reveal certain myeloproliferative disorders, particularly ET. Venous thrombosis is more frequent in PV than in ET; superficial or deep venous thromboses are seen. Thromboembolic events occur in about 25-30% of the patients and account for one-third of the deaths. Mesenteric vein thrombosis, portal thrombosis, or suprahepatic vein thrombosis may occur in all myeloproliferative disorders, but the pathogenesis is not fully understood. Pulmonary hypertension may be the consequence of local thrombosis in the pulmonary vasculature or may be due to the high blood flow in the right heart cavities. Microvascular circulatory disturbance includes erythromelalgia, Raynaud's phenomenon, digital ischemia, acrocyanosis, blue toe syndrome, livedo reticularis, cutaneous ulcers or necrotic purpura. All these manifestations may precede the myeloproliferative disorder by several months.

[Constitutional thrombophilias: indications of the biological profile and therapeutic consequences]. / Thrombophilies constitutionnelles: indications du bilan biologique et conséquences thérapeutiques.

In laboratory screening in patients with clinical thrombophilia (early thromboembolism episode < 50 years, spontaneous thrombosis, recurrent thrombosis, unusual site of thrombosis, thrombotic family history or coumarin-induced skin necrosis complication), an isolated or combined inherited thrombophilia can be observed: antithrombin (0.5 to 4.9 per cent), protein C (1.4 to 8.6 per cent) and protein S (1.4 to 7.5 per cent) deficiencies or factor V Leiden (20 to 30 per cent). Special attention is mandatory in prescribing biological exploration because of the many physiological or pharmacological interferences which can modify the results. Identification of a genetic defect may induce specific management and individuals should receive counselling regarding the implications of this diagnosis. Further prospective studies should help to determine the thrombotic risk in symptomatic and non-symptomatic patients with inherited thrombophilia and the risk/benefit ratio of laboratory screening for hereditary thrombophilia and therapeutic intervention.

[G20210A transition in the prothrombin gene and venous thromboembolic disease]. / La transition G20210A dans le gène de la prothrombine et la maladie thromboembolique veineuse.

INTRODUCTION: Genetic predisposition to venous thrombosis can be due to coagulation inhibitor deficiencies (antithrombin, protein C or protein S) or to activated protein C resistance resulting from factor V Leiden mutation (FV Leiden). Poort et al. recently identified a new polymorphism in the 3'-untranslated region of the prothrombin gene, the G20210A transition (FII G20210A), which was found to be associated with an increased risk of venous thrombosis. EXEGESIS: The prevalence of the A allele is approximately 1 to 4% in the general population, and 5 to 7% in patients with venous thrombosis. Heterozygous carriers have a three to five times increased risk of thrombosis. The diagnosis is based on a polymerase chain reaction technique and restriction enzyme digestion from genomic DNA. Recent studies aim to determine the relative risk of thrombosis and the clinical features which are associated with the mutation (age of first thrombosis, recurrence). The thrombotic risk seems to be higher when FII G20210A transition is associated with the FV Leiden mutation. CONCLUSION: The presence of heterozygous FII G20210A transition does not modify the management of acute thrombotic events but can lead to an increase in the duration of the anticoagulant treatment. When such a genetic abnormality is identified, thorough information of the patient is needed, including on the prophylactic heparin in high-risk situations and caution on the prescription of oral contraceptives containing estrogens.

[Hormone replacement therapy and venous thromboembolism]. / Traitement substitutif de la ménopause et risque thrombotique veineux.

Venous thromboemboembolism is a multigenic and a multifactorial disease. Several genetic risk factors have been identified: antithrombin, protein C and protein S deficiencies, and molecular defects in factor V gene (factor V Leiden) or factor II gene (G 20210A transition). Retrospective and prospective studies have demonstrated that hormone replacement therapy (HRT) in women is associated with a 2-3-fold increase of venous thromboembolism events. To minimize this risk, it seems desirable to carefully evaluate the individual clinical risk factors. Prescribing HRT should clearly be avoided in women with previous thromboembolic events. In case of familial thrombophilia, HRT should probably be prescribed with caution. Recent data suggest that transdermal HRT would induce a lower increase in thrombotic risk, but additional studies are needed to determine whether they can be safely used in women at risk. In each case, the net balance of risk and benefit of HRT use must consider the potential beneficial health effects, the most evident being the relief of climacteric symptoms.

[DVT and combined oral contraceptives: update of the pluridisciplinary CNGOF-FNCGM-GEHT-SFMV group]. / Thrombose et contraception estroprogestative : mise au point du groupe de travail pluridisciplinaire CNGOF-FNCGM-GEHT-SFMV.

Thrombotic risk among combined oral contraceptives (COC) users has recently been debated following a court action initiated by a patient. Recent epidemiological data, as well as accumulating biological data underlying these data, have led French Health authorities to modify COC prescription and reimbursement modalities. A short synthesis is proposed by a multidisciplinary group of experts from four French societies (CGOF, FNCGM, GHT, and SFMV).

[Thrombocytosis in patients treated with low-molecular-weight heparin: more common than imagined?]. / La thrombocytose au cours des traitements par héparine de bas poids moléculaire : une situation plus fréquente qu'on ne le croit ?

BACKGROUND: Use of low-molecular-weight heparin (LMWH) is widespread. Clinicians are well aware of LMWH-related thrombopenia, but reports of thrombocytosis are more exceptional. We evaluated prospectively the incidence of thrombocytosis (>450 G/L) in the general medicine setting among patients needing LMWH treatment. PATIENTS AND METHODS: We followed for the duration of treatment 95 consecutive patients receiving LMWH and managed in a general medicine setting. Thrombotic events, bleeding and platelet counts were noted. RESULTS: Among the 95 patients, 29 developed thrombocytosis during the follow-up (587±102 G/L). In 15 patients, thrombocytosis occurred early after discharge ; in 14 others the counts rose to a pathological level on average 5.4±0.7 days after discharge then returned to normal levels spontaneously in 10.7±7.9 days. Only one clinical event (erysipelas) was reported, potentially associated with this thrombocytosis. There were no thrombotic or hemorrhagic events during the follow-up. DISCUSSION: In our population, the observed cases of thrombocytosis were moderate. Incidence was however not exceptional despite the absence of any notable adverse event, in agreement with the rare data in the literature.

Post-operative use of heparin increases morbidity of pacemaker implantation.

AIMS: The objective of this study is to characterize the incidence of peri-operative severe adverse events (AEs) related to the post-operative use of heparin in patients undergoing pacemaker surgery. METHODS AND RESULTS: We retrospectively compared the outcome of 38 patients with mechanical valves (MVs) and 76 patients with atrial fibrillation (AF) with control cases matched for gender, age, and surgical details. Heparin was systematically used post-operatively in MV patients, but left to clinical judgment in AF patients. The relative risk for severe haemorrhagic AEs was 11 (CI 1.5-81.1, P < 0.01) in the MV group when compared with matched controls and 8 (CI 1.0-62.5, P < 0.05) in the AF group. Overall, the relative risk of heparin use in the post-operative period was 14 (CI 1.88-104, P = 0.0006) and the post-operative stay was prolonged from 7 days in this group when compared with control cases (P < 0.0001).The variables associated with haemorrhage were the delay to restart heparin after surgery and the presence of an MV. CONCLUSION: Post-operative use of heparin increases morbidity of pacemaker implantation. A different approach to management of these patients is possible.

Hemostasis and Thrombosis: Clinical Usefulness of Combined use of Platelet Aggregation Test and Anti PF4-H. Antibodies Elisa test for the Diagnosis of Heparin Induced Thrombocytopenia.

Background. Heparin is the most commonly used drug in patients requiring therapeutic anticoagulation. But the use of heparin has serious side effects such as heparin-induced thrombocytopenia (HIT). The diagnosis of HIT is often difficult. This study was designed to test the diagnosis value of 2 laboratory tests: the platelet aggregation test and the ELISA test (Enzym Linked Immuno-Sorbent Assay). Methods and Results. In order to evaluate the diagnostic value of these 2 tests, we prospectively performed both tests in all patients referred to our laboratory with suspected type II HIT, and compared their results with clinical outcome. Plasmas from 60 patients suspected of HIT, were tested for heparin-dependent platelet-reactive antibodies with a platelet agregation test (PAT) and with an ELISA which detects anti heparin platelet factor 4 antibodies (Anti PF4-H Ab). Among the 60 explored patients, the clinical diagnosis of HIT was confirmed in 27 patients by clinical criteria. In 16 of these 27 patients, PAT and anti PF4-H. Ab were both positive, and in the 11 other patients, one of the 2 tests was negative. In 29 of the 33 patients with no clinical HIT, PAT and anti PF4-H. Ab were both negative, in the 4 remaining patients, one of the 2 tests was positive. Conclusion. For 75% of patients, biological results were concordant with the final clinical diagnosis. The combination of both tests is more reliable than the use of a single test; in the present series, all patients with positive results on both tests had clinically confirmed HIT, and all patients with negative results on both tests had not clinically confirmed HIT.