Thrombotic microangiopathy, DIC-syndrome and COVID-19: link with pregnancy prothrombotic state.

For last months, humanity has faced a formidable unknown enemy, which is presented as a new coronavirus infection. Despite the fact that the causative agents of new diseases appear at a certain frequency and that the virus SARS-CoV-2 has certain common properties with its predecessors, at the moment we are dealing with a new unknown pathogenesis of the development of severe complications in patients with risk factors. A final understanding of pathological process mechanisms is the goal of the scientific community. Summarizing research data from different countries, it became obvious that in severe cases of viral infection, we are dealing with a combination of the systemic inflammatory response syndrome, disseminated intravascular coagulation and thrombotic microangiopathy (TMA). Thrombotic microangiopathy is represented by a group of different conditions in which thrombocytopenia, hemolytic anemia, and multiple organ failure occur. The article reflects the main types of TMA, pathogenesis and principles of therapy. The main participants in the process are described in detail, including the von Willebrand factor and ADAMTS-13. Based on the knowledge available, as well as new data obtained from patients with COVID-19, we proposed possible models for the implementation of conditions such as sepsis, TMA, and DIC in patients with severe new coronavirus infection. Through a deeper understanding of pathogenesis, it will be possible to develop more effective diagnosis and therapy.

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.

Reliability of hemostasis biomarkers is affected by time-dependent intra-patient variability.

Essentials Nucleosomes and free DNA are two newly described biomarkers in venous thromboembolism (VTE). Reliability of nucleosomes, plasma free DNA and conventional hemostasis markers were studied. Hemostasis biological parameters vary over a short time-frame in VTE patients. Hemostasis biological parameters also vary over a short time-frame in healthy controls. SUMMARY: Background Previous studies have associated neutrophil-derived circulating nucleosomes and plasma free DNA with venous thromboembolism (VTE). However, there are few data concerning these two biomarkers and no studies have compared the reliability of nucleosomes and plasma free DNA against that of conventional hemostasis markers. Objectives We performed a 3-year prospective study of nucleosomes and plasma free DNA levels in comparison with conventional hemostatic biomarkers and blood cells. Patients/Methods Fifteen healthy controls and 22 randomly selected patients with a history of VTE were followed monthly for 6 months. The reliability of these markers was evaluated by the intraclass correlation coefficient (ICCs). Results and Conclusions In healthy controls and patients, we found a low reliability for nucleosomes and plasma free DNA, with ICCs at 0.538 (95% confidence interval [CI], 0.334-0.764) and 0.091 (95% CI, -0.026-0.328), respectively, in the healthy controls, and at 0.213 (95% CI, 0.042-0.463) and 0.161 (CI 95%, 0.008-0.398) in the patient group. For the conventional hemostasis biomarkers and for blood cells, reliability ranged from poor to good in the healthy volunteers and from poor to acceptable in the patient group. Our study shows for the first time that hemostasis biological parameters spontaneously vary over a short time-frame in VTE patients and, more surprisingly, in normal individuals. The clinical value of such intra-individual variations is currently unknown. This variability might mean reinterpreting diagnostic or prognostic models based on static evaluation of individuals. Studying the intrinsic value of individual patterns of markers' variability is warranted.

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.

Recombinant human FVIIa for reducing the need for invasive second-line therapies in severe refractory postpartum hemorrhage: a multicenter, randomized, open controlled trial.

BACKGROUND: Case reports on recombinant human factor VIIa (rhuFVIIa) use in women with severe postpartum hemorrhage (PPH) showed encouraging results, but no randomized controlled trial (RCT) is available. PATIENTS AND METHODS: Eighty-four women with severe PPH unresponsive to uterotonics were randomized to receive one early single rhuFVIIa infusion (n = 42) or standard care (no rhuFVIIa; n = 42). The primary efficacy outcome measure was the reduction of the need for specific second-line therapies, such as interventional hemostatic procedures, for blood loss and transfusions. The primary safety outcome measure was the number of deaths and thrombotic events during the 5 days following rhuFVIIa infusion. RESULTS: rhuFVIIa was associated with a reduction in the number of patients who needed second-line therapies compared with controls (standard care). Specifically, 39/42 (93%) patients in the standard care arm received second-line therapies and 22/42 (52%) patients in the rhuFVIIa arm (absolute difference, 41%; range, 18-63%; relative risk RR, 0.56 [0.42-0.76]). The delivery mode (vaginal or Cesarean section) did not affect the primary outcome. No death occurred. Two venous thrombotic events were recorded in the rhuFVIIa arm: one ovarian vein thrombosis and one deep vein thrombosis with a non-severe pulmonary embolism. CONCLUSION: This open RCT in women with severe PPH refractory to uterotonics shows that rhuFVIIa reduces the need for specific second-line therapies in about one in three patients, with the occurrence of non-fatal venous thrombotic events in one in 20 patients.

Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients.

OBJECTIVES: To assess the prevalence of the main causes of morbi-mortality in the antiphospholipid syndrome (APS) during a 10-year-follow-up period and to compare the frequency of early manifestations with those that appeared later. METHODS: In 1999, we started an observational study of 1000 APS patients from 13 European countries. All had medical histories documented when entered into the study and were followed prospectively during the ensuing 10 years. RESULTS: 53.1% of the patients had primary APS, 36.2% had APS associated with systemic lupus erythematosus and 10.7% APS associated with other diseases. Thrombotic events appeared in 166 (16.6%) patients during the first 5-year period and in 115 (14.4%) during the second 5-year period. The most common events were strokes, transient ischaemic attacks, deep vein thromboses and pulmonary embolism. 127 (15.5%) women became pregnant (188 pregnancies) and 72.9% of pregnancies succeeded in having one or more live births. The most common obstetric complication was early pregnancy loss (16.5% of the pregnancies). Intrauterine growth restriction (26.3% of the total live births) and prematurity (48.2%) were the most frequent fetal morbidities. 93 (9.3%) patients died and the most frequent causes of death were severe thrombosis (36.5%) and infections (26.9%). Nine (0.9%) cases of catastrophic APS occurred and 5 (55.6%) of them died. The survival probability at 10 years was 90.7%. CONCLUSIONS: Patients with APS still develop significant morbidity and mortality despite current treatment. It is imperative to increase the efforts in determining optimal prognostic markers and therapeutic measures to prevent these complications.

[Anesthetic management of severe or worsening postpartum hemorrhage]. / Prise en charge anesthésique d'une hémorragie du post-partum sévère ou résistant au traitement médical.

INTRODUCTION: Risk factors of maternal morbidity and mortality during postpartum hemorrhage (PPH) include non-optimal anesthetic management. As the anesthetic management of the initial phase is addressed elsewhere, the current chapter is dedicated to the management of severe PPH. METHODS: A literature search was performed using PubMed and Medline databases, and the Cochrane Library, for articles published from 2003 up to and including 2013. Several keywords related to anesthetic and critical care practice, and obstetrical management were used, in various combinations. Guidelines from several societies and organisations were also read. RESULTS: When PPH worsens, one should ask for additional team personnel (professional consensus). Patients should be monitored for heart rate, blood pressure, skin and mucosal pallor, bleeding at skin puncture sites, diuresis and the volume of genital bleeding (grade B). Because of the possible rapid worsening of coagulapathy, patients should undergo regular evaluation of coagulation status (professional consensus). Prevention and management of hypothermia should be considered (professional consensus), by warming intravenous fluids and blood products, and by active body warming (grade C). Antibiotics should be given, if not already administered at the initial phase (professional consensus). Vascular fluids must be given (grade B), the choice being left at the physician discretion. Blood products transfusion should be decided based on the clinical severity of PPH (professional consensus). Priority is given to red blood cells (RBC) transfusion, with the aim to maintain Hb concentration>8g/dL. The first round of products could include 3 units of RBC (professional consensus), and the following round 3 units of RBC, and 3 units of fresh frozen plasma (FFP). The FFP:RBC ratio should be kept between 1:2 and 1:1 (professional consensus). Depending on the etiology of PPH, the early administration of FFP is left at the discretion of the physician (professional consensus). Platelet count should be maintained at>50 G/L (professional consensus). During massive PPH, fibrinogen concentration should be maintained at>2g/L (professional consensus). Fibrinogen can be given without prior fibrinogen measurement in case of massive bleeding (professional consensus). General anesthesia should be considered in case of hemodynamic instability, even when an epidural catheter is in place (professional consensus). CONCLUSION: The anesthetic management aims to restore and maintain optimal respiratory state and circulation, to treat coagulation disorders, and to allow invasive obstetrical and radiologic procedures. Clinical and instrumental monitoring are needed to evaluate the severity of PPH, to guide the choice of therapeutic options, and to assess treatments efficacy.

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.

[Latest developments on risk factors and prophylaxis of thromboembolic disease in obstetrics]. / Actualités sur les facteurs de risque et la prévention des complications thrombotiques de la grossesse.

Venous thromboembolic disease and placental vascular pathology are responsible for an important maternal and foetal morbi-mortality with a modification of the hemostasis parameters. As these biological factors combined with particular clinical features can increase or reduce the risk of occurrence of these diseases, knowing the risk factors would help to prevent problems during the pregnancy. Several antithrombotic therapies exist, including very recent ones. Furthermore, a lot of recommendations are available in the literature. A lot of data are thus at our disposal but their synthesis is necessary to be really useful. We review here the risk factors, therapies and recommendations to help improve the management of these women.

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.

Clinical implications of clopidogrel non-response in cardiovascular patients: a systematic review and meta-analysis.

UNLABELLED: BSUMMARY BACKGROUND: Previous studies have shown an important risk of cardiovascular events in patients with clopidogrel biological non-response, and data have shown considerable, unexplored heterogeneity. OBJECTIVES: To evaluate the magnitude of cardiovascular risk associated with clopidogrel non-response and to explore heterogeneity. METHODS: This was a systematic review and meta-analysis of prospective studies of patients treated with clopidogrel for symptomatic atherothrombosis, evaluated by light transmission aggregometry with ADP and monitored prospectively for clinical ischemic events. RESULTS: Fifteen studies were included, totaling 3960 patients, of whom 25% were considered to be clopidogrel non-responders. The global relative risk (RR) for recurrent ischemic events in clopidogrel non-responders was 3.5 [95% confidence interval (CI) 2.4-5.2, P < 0.0001]. The results of the different studies were heterogeneous (Cochran P = 0.01 and I(2) = 52%). The most recent studies yielded lower RRs [global RR = 2.9 (95% CI 2.3-3.8) after 2007, and global RR = 6.6 (95% CI 3.7-11.9) before 2007, P = 0.01]. Heterogeneity was present in the group of studies in which more than 10% of patients took glycoprotein (GP)IIb-IIIa inhibitors [Cochran P = 0.003 and I(2) = 70%; RR = 3.8 (95% CI 2.9-5.1)] and was absent in the other studies [Cochran P = 0.88 and I(2) = 0; RR = 2.5 (95% CI 1.7-3.6)]. The RR was significantly higher in studies using higher ADP maximal aggregation cut-offs (> 65%) for clopidogrel non-response than in studies using lower cut-offs [RR = 5.8 (95% CI 3.2-10.3) and RR = 2.9 (95% CI 2.2-3.7), respectively, P = 0.03]. CONCLUSIONS: The risk of ischemic events associated with clopidogrel non-response is now more precisely defined. The risk is heterogeneous across studies, possibly because of an interaction with GPIIb-IIIa inhibitors and the use of different cut-offs to identify non-responders.

Observational study of pregnant women with a previous spontaneous abortion before the 10th gestation week with and without antiphospholipid antibodies.

BACKGROUND: A clinical subtype of purely obstetrical antiphospholipid antibody (aPL-Ab) syndrome (APS) requires three or more unexplained consecutive embryonic losses before the 10th week of gestation associated with persistently positive lupus anticoagulant (LAC), and/or anticardiolipin IgG or IgM, and/or anti-beta2-glycoprotein I (abeta2GpI) IgG or IgM. Although this diagnostic classification of APS appeared to be the most sensitive, the APS-associated serological criteria are still debated. PATIENTS/METHODS: We prospectively observed the second pregnancy of 284 women with a previous embryonic loss, both with and without aPL-Ab. RESULTS: aPL-Ab-positive women were more prone to pregnancy loss, embryonic loss, pre-eclampsia, placental abruption and intrauterine fetal growth restriction. Type IIa aPL-Ab positivity (LAC present alone) was associated with the highest risk of recurrent embryonic loss and intrauterine growth restriction. Type I aPL-Ab positivity (combinations of aPL-Ab type positivity) was associated with the strongest risks of late complications, pre-eclampsia and placental abruption. Finally, abeta2GpI-M positivities were not clinically relevant in these women. CONCLUSION: Patients with a first unexplained pregnancy loss before the 10th week of gestation who are also positive for aPL-Abs have a higher risk of various complications in their second pregnancy. In this study, measurement of abeta2GpI-M had a questionable prognostic value.

Prothrombin G20210A carriers the genetic mutation and a history of venous thrombosis contributes to thrombin generation independently of factor II plasma levels.

SUMMARY BACKGROUND: The prothrombin (PT) G20210A gene mutation is a common risk factor for venous thrombosis (VT), which is mainly mediated through an increase in factor II (FII) plasma levels. High FII plasma levels may act through an increase in endogenous thrombin potential (ETP) a key step in hemostasis and thrombosis. While FII may be the main contributor to ETP in PT G20210A carriers, the knowledge of other environmental or genetic factors influencing ETP may help to better identify those at risk of VT. AIMS: ETP was determined in 472 non-carriers of PT G20210A (PT-) and in 325 unrelated carriers of PT G20210A (PT+) with (symptomatic n = 158) or without (asymptomatic, n = 167) a history of VT. All PT+ were heterozygous and free of other thrombophilic defects. RESULTS: ETP was higher in asymptomatic PT+ than in PT- (2038 +/- 371 vs. 1616 +/- 267 nmol L(-1) min; P < 0.0001). ETP was significantly higher in symptomatic PT+ than in controls PT+ (2129 +/- 430 vs. 2038 +/- 371 nmol L(-1) min; P = 0.01). Multivariate analyses evidenced the importance of FII and fibrinogen plasma levels in determining ETP. DISCUSSION: After taking these variables into account, a personal history of VT remained associated with ETP in PT+ carriers. Moreover, PTG20210A still contributes to ETP after consideration of FII levels. CONCLUSION: In conclusion, the increase in ETP observed in carriers is not entirely explained by higher FII or fibrinogen plasma levels but also by the history of VT.