Management of cancer-related thrombosis in the era of direct oral anticoagulants: A comprehensive review of the 2019 ITAC-CME clinical practice guidelines. On behalf of the Groupe Francophone Thrombose et Cancer (GFTC).

Venous thromboembolism (VTE) is a common disease complication in cancer patients and the second cause of death after cancer progression. VTE management and prophylaxis are critical in cancer patients, but effective therapy can be challenging because these patients are at higher risk of VTE recurrence and bleeding under anticoagulant treatment. Numerous published studies report inconsistent implementation of existing evidence-based clinical practice guidelines (CPG), including underutilization of thromboprophylaxis, and wide variability in clinical practice patterns across different countries and various practitioners. This review aims to summarize the 2019 ITAC-CME evidence-based CPGs for treatment and prophylaxis of cancer-related VTE, which include recommendations on the use of direct oral anticoagulants specifically in cancer patients. The guidelines underscore the gravity of developing VTE in cancer and recommend the best approaches for treating and preventing cancer-associated VTE, while minimizing unnecessary or over-treatment. Greater adherence to the 2019 ITAC guidelines could substantially decrease the burden of VTE and improve survival of cancer patients.

[Acquired autoimmune haemophilia: Where is the place of rituximab in the treatment strategy? Reflection from a monocentric series of 8 patients and literature review]. / Hémophilie acquise auto-immune : quelle est la place du rituximab dans la stratégie thérapeutique ? Réflexion à partir d'une série monocentrique de 8 patients et revue de la littérature.

INTRODUCTION: Autoimmune acquired haemophilia is a rare autoimmune disease. The purpose of immunosuppressive therapy is to stop the production of autoantibodies that inhibit clotting factors VIII or IX. A corticosteroids-cyclophosphamide combination is recommanded as first-line therapy. From our experience at the University Hospital of Nîmes, we discuss the place of rituximab in the therapeutic arsenal. METHODS: We report a monocentric observational retrospective study. Our data are discussed in light of literature data, in particular cohorts EACH2 and SACHA. RESULTS: Eight patients (7 with FVIII anibodies) were consecutively included from 2005. The average age was 68.5 years with a male predominance (62.5%). Bleeding manifestations were usually spontaneous and superficial. A pathology, mostly autoimmune or neoplastic, was associated in 5/8 patients. A "by-pass" haemostatic treatment was prescribed for 3/8 patients. Rituximab was prescribed for 5/8 patients, three times as first-line therapy, and always associated with corticosteroids. Three patients received a cyclophosphamid/cortisone combination, two were treated exclusively with oral corticosteroids. Remission was obtained in all patients, without subsequent relapse. The average time to obtain remission under rituximab (after the first injection) was 32.5 days (10-143). The results observed in our series of patients are consistent with the data from the literature. CONCLUSIONS: Rituximab appears to be an effective and well-tolerated treatment for autoimmune acquired haemophilia. However, its place remains to be specified.

Evaluation of the non-compliance with grouping guidelines which may lead to "wrong blood in tube", an observational study and risk factor analysis.

BACKGROUND: In France, blood group determination requires the completion of two samples collected at two different times to detect identity mistake and "wrong blood in tube". The aims of the present study were: (1) to evaluate the compliance with guidelines and (2) to identify risk factors of non-compliance. MATERIALS AND METHODS: Samples for ABO group determination collected between January 1st and December 15th, 2013 in the University hospital of Nîmes, France were analyzed. An ABO group determination demand was considered non-compliant if more than one tube arrived in the laboratory within ten minutes apart. Between May 1st and June 30th 2014, a self-administered questionnaire was offered to the nurses of the hospital on a random day for each service during this period. The aim was to validate the non-compliance criterion and the identification of risk factors using logistic regression. RESULTS: Among the 16,450 analyzed blood samples, the overall compliance rate was 65.1%. Lower compliance rates were found in the surgical services. Independent risk factors for wrong practice were work overload, surgical service and individual intermediate transfusion frequency. DISCUSSION: More than one third of ABO group determinations did not follow national recommendations, which induces a substantial risk of "wrong blood in tube" and group error. The study revealed major variations among hospital services. Identification of risk factors allows targeted corrective actions.

Antiphospholipid antibodies and the risk of severe and non-severe pre-eclampsia: the NOHA case-control study.

BACKGROUND: pre-eclampsia (PEecl) can be defined as non-severe (NS-PEecl) or severe (S-PEecl). Our study aimed to determine the incidence of antiphospholipid antibodies (aPLs) in women with a past history of NS-PEecl or S-PEecl. PATIENTS AND METHODS: This case-control study includes 195 control women, 199 NS-PEecl patients and 143 S-PEecl patients whose plasma samples were collected 6 months after their first delivery. Each plasma was tested for lupus anticoagulant (LA), anticardiolipin (aCL) and antiß2GP1 antibodies, as well as antibodies against phosphatidylserine/prothrombin complex (aPS/PT) and domain I of the ß2GP1. RESULTS: When compared with the control group no significant associations were found for the NS-PEecl group after adjustment of confounding variables. For the S-PEecl group, there was an association with antiß2GP1 immunoglobulin G (IgG) (OR 16.91, 95% CI 3.71-77.06), as well as age, obesity, smoking and multiparity. Antiß2GP1-domain I IgG was associated with aCL, antiß2GP1 and aPS/PT IgG in the three groups. aPS/PT IgG was associated with aCL IgG, and aPS/PT IgM was associated with aCL and antiß2GP1 IgM in the three groups. CONCLUSION: S-PEecl is a distinct entity from NS-PEecl and is mainly associated with the presence of antiß2GP1 IgG. Antiß2GP1 domain I correlates with other aPL IgG tests, and aPS/PT may be promising in patients for whom LA tests cannot be interpreted.

Does the type of fluid affect rapidity of shock reversal in an anaesthetized-piglet model of near-fatal controlled haemorrhage? A randomized study.

BACKGROUND: The optimal resuscitation fluid for the early treatment of severe bleeding patients remains highly debated. The objective of this experimental study was to compare the rapidity of shock reversal with lactated Ringer (LR) or hydroxyethyl starch (HES) 130/0.4 at the early phase of controlled haemorrhagic shock. To assess the influence of vascular permeability in this model, we measured plasma vascular endothelial growth factor (VEGF) levels during the experiment. METHODS: Thirty-six anaesthetized and mechanically ventilated piglets were bled (<30 ml kg(-1)) to hold mean arterial pressure (MAP) at 40 mm Hg for more than 30 min and were resuscitated in two randomized groups: LR (n=14) or HES (n=14) at 1 ml kg(-1) min(-1) until MAP reached its baseline value of ±10%. MAP was maintained at its baseline value for 1 h. The time and fluid volume necessary to restore the baseline MAP value were measured. RESULTS: The time to restore the baseline MAP value of ±10% was significantly lower in the HES group (P<0.001). During the initial resuscitation phase, the infused volume was 279 (119) ml in the HES group and 1011 (561) ml in the LR group (P<0.0001). During the stabilization phase, the infused volume was 119 (124) ml in the HES group and 541 (506) ml in the LR group. Biological data and plasma VEGF levels were similar between the groups. CONCLUSIONS: Restoration of MAP was four times faster with HES than with LR in the early phase of controlled haemorrhagic shock. However, there was no evidence of increased vascular permeability.

Paternal endothelial protein C receptor 219Gly variant as a mild and limited risk factor for deep vein thrombosis during pregnancy.

BACKGROUND: Half of all venous thromboembolism (VTE) cases during pregnancy are associated with a maternal thrombophilia. The influence of paternal genotype on the placenta and in the genesis of VTE has not been described. OBJECTIVES: To determine if the maternal and paternal Ser219Gly dimorphism of the endothelial protein C receptor (EPCR), evaluated through detection of the PROCR 6936G allele, is a risk factor for VTE during pregnancy. METHODS: Using a case-control study nested in the NOHA first cohort of primigravidae, 66 patient couples with a first episode of gestational VTE and randomly selected non-thrombotic control couples were investigated. For each couple, factor V gene (F5) G1691A, factor II gene (F2) G20210A, factor XII gene (F12) C46T and PROCR A6936G polymorphisms were determined. RESULTS: Only maternal F5 1691A, F2 20210A and F12 46T alleles were independently associated with iliac and infra-iliac deep vein thromboses (DVT). The maternal PROCR 6936G allele was a mild risk factor for iliac DVT (OR = 5.5 [2.3-13.0]). The paternal PROCR 6936G allele was also a mild independent risk factor for iliac DVT (OR = 2.6 [1.1-6.2]) and only during pregnancy (rather than postpartum) among maternal carriers of the F5 1691A allele (OR = 77.6 [4.2 to > 999.9]). CONCLUSIONS: The paternal PROCR 6936G allele could be a risk factor for maternal iliac DVT. Its impact was milder than the F5 1691A and F2 20210A polymorphisms in mothers. We hypothesize that the prothrombotic effect of the paternal PROCR 6936G allele is localized. Therefore, DVT during pregnancy may be influenced by trophoblastic cell-surface proteins inherited from both maternal and paternal alleles.

Associations between tumor necrosis factor-alpha and lymphotoxin-alpha polymorphisms and idiopathic recurrent miscarriage.

Heightened expression of tumor necrosis factor (TNF)-alpha and lymphotoxin-alpha (LT-alpha) was associated with pregnancy complications, including idiopathic recurrent miscarriage (RM). Whereas TNF-alpha and LT-alpha gene polymorphisms affect serum cytokine concentrations, their contribution to RM is controversial. The single nucleotide polymorphisms (SNPs) TNF-alpha (-238G/A, -308G/A) and LT-alpha (+252A/G) were investigated in 350 RM women and 200 control women. Higher frequency of the TNF-alpha -238A, but not the TNF-alpha -308A or the LT-alpha+252G, allele was seen in patients, with comparable frequencies of TNF-alpha -238G/A, TNF-alpha -308G/A, and LT-alpha+252A/G genotypes seen between both groups, except for TNF-alpha -238G/G, which was lower in patients. Regression analysis confirmed the association of the TNF-alpha -238G/A SNP with idiopathic RM, and both TNF-alpha -308A/TNF -238G/LT-alpha+252G and TNF-alpha -308G/TNF-alpha -238A/LT-alpha+252G haplotypes played a susceptible role in idiopathic RM. TNF-alpha -238G/A and -238A/A, and LT-alpha+252G/G genotypes were positively associated only with exclusively early RM. This supports the concept of the association of TNF-alpha (-238G/A) and LT-alpha (+252A/G) polymorphic variants in idiopathic RM.

Role of allelic variants Gly972Arg of IRS-1 and Gly1057Asp of IRS-2 in moderate-to-severe insulin resistance of women with polycystic ovary syndrome.

To assess the role of insulin receptor, insulin receptor substrate (IRS)-1, and IRS-2 genes in insulin resistance, we explored the genomic DNA in women with polycystic ovary syndrome (PCOS) and a variable degree (mean +/- SE) of insulin resistance (homeostasis model assessment index for insulin resistance [HOMA(IR)] 3.2 +/- 0.6, n = 53; control subjects 1.56 +/- 0.34, n = 102) using direct sequencing. Whereas no novel mutations were found in these genes, gene-dosage effects were found on fasting insulin for the Gly972Arg IRS-1 variant and on 2-h plasma glucose for the Gly1057Asp IRS-2 variant. The Gly972Arg IRS-1 variant was more prevalent in insulin-resistant patients compared with non-insulin-resistant individuals or control subjects (39.3 vs. 4.0 and 16.6%, P < 0.0031, respectively). A multivariate model that included BMI as a variable revealed significant effects of the Gly1057Asp IRS-2 variant on insulin resistance (P < 0.016, odds ratio [OR] 7.2, 95% CI 1.29-43.3). HOMA(IR) was higher in carriers of both IRS variants than in those with IRS-2 mutations only or those with wild-type variants (6.2 +/- 2.3, 2.8 +/- 0.5, and 1.8 +/- 0.2, respectively; P < 0.01), and it was significantly associated with this genotype (P < 0.0085, OR 1.7, 95% CI 1.09-2.99). We conclude that polymorphic alleles of both IRS-1 and IRS-2, alone or in combination, may have a functional impact on the insulin-resistant component of PCOS.

Primary sinusoidal lymphoma of the liver revealed by autoimmune hemolytic anemia.

Primary liver lymphomas usually present with the clinical picture of a liver tumor, and are characterized by a predominantly portal invasion by lymphoid cells of the B-cell phenotype. We report a case of primary sinusoidal lymphoma of the liver, in a 36 year-old male patient, revealed by homogeneous hepatosplenomegaly and infiltration of liver sinusoids by morphologically normal lymphocytes, without destruction of the parenchyma. Immunohistochemistry in paraffin-embedded tissue sections was positive for the pan T-cell marker MTI, weakly positive for UCHLI, and negative for CD3, and B-cell markers were negative; these findings were consistent with the diagnosis of T-cell lymphoma. The clinical, histological and immunological presentation of this lymphoma was similar to that of hepatosplenic gamma delta T-cell lymphoma. Autoimmune hemolytic anaemia preceded the lymphoma. Despite chemotherapy, the patient died 24 months after the initial presentation in the leukemic phase. A better understanding of this exceptional but characteristic entity is required for an accurate and early diagnosis.

Factor IX gene mutations causing haemophilia B: comparison of SSC screening versus systematic DNA sequencing and diagnostic applications.

The search for mutations of the factor IX gene responsible for haemophilia B should nowadays be used routinely for the molecular diagnosis of this inherited disorder, i.e. carrier detection and prenatal diagnosis. A number of methodologies have been proposed, most of them being delicate or expensive. We have used a simple strategy based on a preliminary screening of eight factor IX gene fragments by single-strand conformation analysis (SSCA), followed by direct sequencing of fragments displaying an abnormal migration pattern. Carrier testing is then performed by use of an enzyme restriction site altered by the mutation or by the SSCA itself. By using this strategy we were able readily to identify the factor IX molecular defect of nine unrelated haemophilia B patients from southern France. We validated the efficiency and reliability of the SSC-based detection of mutations by sequencing all the polymerase chain reaction (PCR) fragments studied in the haemophilic patients. No other sequence alteration could be found except the one detected by SSC analysis. We conclude that this method can be advantageously used for diagnosis purposes in a routine laboratory involved in haemophilia B diagnosis and report nine previously undescribed haemophilia B families with their factor IX mutation.

Immunohistochemical study of tumor cell-associated plasminogen activators and plasminogen activator inhibitors in lung carcinomas.

STUDY OBJECTIVE: To compare the expression of plasminogen activators (PA) and plasminogen activator inhibitors (PAI) in normal lung mucosa and lung carcinomas. DESIGN: Immunohistochemical localization of urokinase-type PA (uPA), tissue-type PA (tPA), type 1 PAI (PAI-1), and type 2 PAI (PAI-2) in four normal lung biopsy specimens and in four adenocarcinomas (AC), four squamous carcinomas (SC), two large-cell carcinomas (LCC), and ten small-cell carcinomas (SCC) biopsy specimens. Qualitative immunostaining scoring system. RESULTS: tPA and uPA immunostaining scores from all specimens were statistically similar. The cellular staining for uPA and tPA was generally constant (normal epithelial layers, AC cells, SC cells) except for LCC cells (inconstant uPA staining, p < 10(-3). Both PAIs were detected in cells of the normal epithelial layer. The four carcinoma cell types stained for PAI in a statistically different pattern (p < 10(-3)). Cells of the peripheral cords of SCC were inconstantly PAI-1 and PAI-2 positive (p < 10(-3)). LCC were PAI-2 negative and inconstantly stained for PAI-1. SCC cells were PAI-1 and PAI-2 negative. CONCLUSION: Lung carcinomas of worst clinical prognosis no longer express PAI reactivity. The imbalance of the plasminogen activation pathway may favor the spreading of the more invasive histologic types of bronchogenic carcinomas.

[Epstein-Barr virus infection and syndrome of inappropriate macrophage activation]. / Infection à virus Epstein-Barr et syndrome d'activation macrophagique inappropriée.

An 11-year-old girl presented with a typical serologically proven infectious mononucleosis with persistent fever, jaundice and hepatosplenomegaly in spite of steroid therapy. Laboratory tests showed pancytopenia, fibrinopenia and hypertriglyceridemia. The liver biopsy revealed an infiltration with hyperbasophilic cells. One month later, a slight improvement was noted and fever disappeared after 4 days on acyclovir therapy. The authors recall the spectrum of the macrophagic activation syndrome.

Procoagulant activity of endotoxin or tumor necrosis factor activated monocytes is enhanced by IgG from patients with lupus anticoagulant.

The effect of lupus anticoagulant (LA) positive plasma on the expression of human monocyte procoagulant activity (PCA) was studied. LA positive plasma were able to enhance the endotoxin or TNF alpha induced monocyte associated PCA. The monocyte PCA had the characteristic of tissue factor activity (factor VII, factor X dependence). The enhancement of monocyte PCA could be confirmed using purified LA positive IgG. The stimulating effect was supported by the F(ab')2 fragments.

Venous occlusion and chronic cigarette smoking: dose-dependent decrease in the measurable release of tissue-type plasminogen activator and von Willebrand factor.

This study was aimed at examining the effect of chronic cigarette smoking on a venous occlusion test. Two groups of young healthy men, a control group of 20 non-smoking subjects and a group of 21 smoking subjects having an average consumption of 17.6 packages.day-1.years (SD 8.6) were studied. Venous occlusion performed in smokers did not induce a significant measurable release of von Willebrand factor (vWF). The release of tissue-type plasminogen activator (t-PA) was significantly weaker for the smokers than for the control group (P less than 0.02). An inverse correlation was found between the cumulative parameter of tobacco consumption and the measurable amount of t-PA Ag or vWF Ag released during venous occlusion (r' = -0.994 and r' = -0.889). Cigarette smoking is thus associated with disturbances of the biological response to this venous occlusion test.

[Recurrent venous thromboembolism caused by heparin cofactor II deficiency. A case]. / Maladie thrombo-embolique veineuse récidivante liée à un déficit en second cofacteur de l'héparine. Une observation.

We report the case of a 28-year-old man who was admitted in an emergency because of severe abdominal pain with gastrointestinal haemorrhage and shock. Laparotomy showed infarction of the small intestine with mesenteric veins thrombosis. Severe thromboembolic complications occurred during the post-operative period: bilateral femoral deep vein thrombosis with pulmonary embolism, axillary and subclavian vein thrombosis associated with an intravenous catheter, portal hypertension related to portal vein thrombosis and cavernoma, thrombosis of the superior longitudinal sinus. Laboratory investigations performed after thrombotic episodes and repeated 5 years later evidenced a type 1 Heparin Cofactor II deficiency (HCII Ag by EID: 40 percent; functional Tollefsen's method: 60 percent). This heterozygous deficiency was also found in one of the patient's sons. This is the first reported case of HCII deficiency associated with mesenteric infarction and cerebral thrombophlebitis. The relationship between these severe venous thrombotic episodes and the HCII deficiency is discussed in relation to the dermatan sulphate-HCII couple physiology. Vascular injury may act as a triggering factor in patients with HCII deficiency.

[Impaired fibrinolytic response to the venous occlusion test in patients with cryptogenic colitis]. / Réponse anormale au test d'occlusion veineuse chez les patients atteints de colite cryptogénique.

The fibrinolytic response to venous occlusion was studied in 17 patients with inflammatory bowel disease: 7 with Crohn's disease, 10 with ulcerative colitis and compared with those obtained in 20 controls. Patients with inflammatory bowel disease showed decreased tissue-type plasminogen activator antigen release (t-PA Ag), no significant Von Willebrand antigen release (vWF Ag), and a residual plasminogen activator inhibitor activity (PAI activity) after venous occlusion. These modifications were more important in the evolutive colitis group compared with the remission group. Hypofibrinolysis, as defined by a defective t-PA release, and a residual PAI activity after venous occlusion might contribute to digestive and/or extra digestive thrombotic manifestations observed during the course of inflammatory bowel diseases.