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.

ETFAD/EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients.

Atopic dermatitis (AD) is a clinically defined, highly pruritic, chronic inflammatory skin disease of children and adults. The diagnosis is made using evaluated clinical criteria. Disease activity is best measured with a composite score assessing both objective signs and subjective symptoms, such as SCORAD. The management of AD must consider the clinical and pathogenic variabilities of the disease and also target flare prevention. Basic therapy includes hydrating topical treatment, as well as avoidance of specific and unspecific provocation factors. Anti-inflammatory treatment of visible skin lesions is based on topical glucocorticosteroids and the topical calcineurin inhibitors tacrolimus and pimecrolimus. Topical calcineurin inhibitors are preferred in sensitive locations. Tacrolimus and mid-potent steroids are proven for proactive therapy, which is long-term intermittent anti-inflammatory therapy of the frequently relapsing skin areas. Systemic anti-inflammatory or immunosuppressive treatment is indicated for severe refractory cases. Biologicals targeting key mechanisms of the atopic immune response are promising emerging treatment options. Microbial colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial treatment. Systemic antihistamines (H1R-blockers) may diminish pruritus, but do not have sufficient effect on lesions. Adjuvant therapy includes UV irradiation, preferably UVA1 or narrow-band UVB 311 nm. Dietary recommendations should be patient specific and elimination diets should only be advised in case of proven food allergy. Allergen-specific immunotherapy to aeroallergens may be useful in selected cases. Psychosomatic counselling is recommended to address stress-induced exacerbations. 'Eczema school' educational programmes have been proven to be helpful for children and adults.

Diffuse cutaneous mastocytosis: analysis of 10 cases and a brief review of the literature.

BACKGROUND: Diffuse cutaneous mastocytosis (DCM) is an extremely rare disease characterized by mast cell (MCs) infiltration of the entire skin. Little is known about the natural course of DCM. OBJECTIVES: We decided to characterize clinical manifestations, the frequency of MCs mediator-related symptoms and anaphylaxis, risk of systemic mastocytosis (SM) and prognosis, based on 10 cases of DCM, the largest series published to date. METHODS: Diffuse cutaneous mastocytosis, DCM was confirmed by histopathological examination of skin samples in all cases. SCORing Mastocytosis (SCORMA) Index was used to assess the intensity of DCM. The analysis of clinical symptoms and laboratory tests, including serum tryptase levels was performed. Bone marrow biopsy was done only in selected cases. RESULTS: Large haemorrhagic bullous variant of DCM (five cases) and infiltrative small vesicular variant (five cases) were identified. The skin symptoms appeared in age-dependent manner; blistering predominated in infancy, whereas grain-leather appearance of the skin and pseudoxanthomatous presentation developed with time. SM was not recognized in any of the patients. Mast cell mediator-related symptoms were present in all cases. Anaphylactic shock occurred in three patients. Follow-up performed in seven cases revealed slight improvement of skin symptoms, reflected by decrease of SCORMA Index in all of them. Serum tryptase levels declined with time in six cases. CONCLUSIONS: Diffuse cutaneous mastocytosis, DCM is a heterogeneous, severe, cutaneous disease, associated with mediator-related symptoms and risk of anaphylactic shock. Although our results suggest generally favourable prognosis, the review of the literature indicate that SM may occur. Therefore, more guarded prognosis should be given in DCM patients.

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).

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.

[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.

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)

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)

[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.