Coagulation standards in healthy newborns and infants.

BACKGROUND: The range of normal values for coagulation factors in the healthy newborn was described 30 years ago but since then the reagents, automated systems, and dosing techniques have changed considerably. For 30 years, several authors have tried to update the standards and references in children using updated reagents but the newborn and infant population in these studies has been quite small, limiting the findings. The aim of this study was to establish the normal coagulation standards in healthy newborns. METHODS: We included all consecutive healthy newborns with pyloric stenosis presenting to our reference center over a period of 5 years. We calculated the reference ranges defined as mean±2 SD. Normality of distribution was checked graphically and by using the Shapiro-Wilk test. Correlations between two continuous variables were assessed using Spearman's rank coefficient correlation. Statistical testing was done at the two-tailed α-level of 0.05. Data were analyzed using the SAS software package, release 9.4 (SAS Institute, Cary, NC). RESULTS: We included 112 healthy newborns and infants. The median age was 35.5 days (15.0-88.0), median weight was 4062g (2855-6040), and 90.2% were boys. Activated partial thromboplastin time (aPTT) and prothrombin time (PT) were not correlated with age (P=0.92 and P=0.21, respectively) or with weight (P=0.16 and P=0.90, respectively). The reference range was 28.6-46.2 s for aPTT, 0.91-1.49 for aPTT ratio, and 71.3-110.6 s for PT. Regarding fibrinogen (n=24), the median was 2.2g/L (1.2-3.2); the median for factor II was 67.0U/dL (51.0-130.0; n=20), and 101.5U/dL for factor V (68.0-233.0; n=20). Regarding factor VIII, the median was 75.0U/dL (45.0-152.0; n=25), 49.0U/dL for factor IX (32.0-96.0; n=25) and 53.0U/dL (29.0-112.0) for factor XI (n=23). CONCLUSION: This study can help to establish standards for coagulation testing in this very specific population. Indeed, our study represents the largest newborn population in a recent investigation of PT and aPTT using updated reagents.

Intravenous thrombolysis for acute ischaemic stroke in patients on direct oral anticoagulants.

BACKGROUND AND PURPOSE: Whereas intravenous thrombolysis (IVT) is allowed for acute ischaemic stroke in patients on vitamin K antagonists with international normalized ratio ≤1.7, there are no similar recommendations for patients on direct oral anticoagulants (DOACs), notably due to the lack of coagulation tests to assess the therapeutic effects. Although the literature is scarce, consisting of small case series and retrospective studies, considering the frequency of this situation the French Vascular Neurology Society and the French Study Group on Haemostasis and Thrombosis have worked on a joint position paper to provide a practical position regarding the emergency management of ischaemic stroke in patients on DOACs. METHOD: Based on a review of the literature, the authors wrote a first text that was submitted to a broad panel of members from the two societies. The text was then amended by the authors to address experts' comments and to reach a consensus. RESULTS: In patients with normal renal function and who stopped the DOAC for at least 48 h, the management should not differ from that in patients without oral anticoagulant. In patients who are still on DOACs, mechanical thrombectomy is encouraged preferentially when applicable in first line. Otherwise, when specific tests are available, values <50 ng/ml indicate that IVT is allowed. In the absence of specific tests, standard tests (thrombin time, prothrombin time and activated partial thromboplastin time) can be used for dabigatran and rivaroxaban, although interpretation of these tests may be less reliable. In some patients on dabigatran, idarucizumab may be used before IVT. CONCLUSIONS: In this expert opinion paper, it is suggested that IVT can be performed in patients selected according to the time elapsed since the drug was last taken, renal function, type of hospital where the patient is admitted and plasma concentration of DOAC.

French lyophilized plasma versus fresh frozen plasma for the initial management of trauma-induced coagulopathy: a randomized open-label trial.

Essentials An immediate supply of plasma in case of trauma-induced coagulopathy is required. The Traucc trial compared French Lyophilised Plasma (FLyP) and Fresh Frozen Plasma (FFP). FLyP achieved higher fibrinogen concentrations compared with FFP. FLyP led to a more rapid coagulopathy improvement than FFP. SUMMARY: Background Guidelines recommend beginning hemostatic resuscitation immediately in trauma patients. We aimed to investigate if French lyophilized plasma (FLyP) was more effective than fresh frozen plasma (FFP) for the initial management of trauma-induced coagulopathy. Methods In an open-label, phase 3, randomized trial (NCT02750150), we enrolled adult trauma patients requiring an emergency pack of 4 plasma units within 6 h of injury. We randomly assigned patients to receive 4-FLyP units or 4-FFP units. The primary endpoint was fibrinogen concentration at 45 min after randomization. Secondary outcomes included time to transfusion, changes in hemostatic parameters at different time-points, blood product requirements and 30-day in-hospital mortality. Results Forty-eight patients were randomized (FLyP, n = 24; FFP, n = 24). FLyP reduced the time from randomization to transfusion of first plasma unit compared with FFP (median[IQR],14[5-30] vs. 77[64-90] min). FLyP achieved a higher fibrinogen concentration 45 min after randomization compared with FFP (baseline-adjusted mean difference, 0.29 g L-1 ; 95% confidence interval [CI], 0.08-0.49) and a greater improvement in prothrombin time ratio, factor V and factor II. The between-group differences in coagulation parameters remained significant at 6 h. FLyP reduced fibrinogen concentrate requirements. Thirty-day in-hospital mortality rate was 22% with FLyP and 29% with FFP. Conclusion FLyP led to a more rapid, pronounced and extended increase in fibrinogen concentrations and coagulopathy improvement compared with FFP in the initial management of trauma patients. FLyP represents an attractive option for trauma management, especially when facing logistical issues such as combat casualties or mass casualties related to terror attacks or disasters.

Compliance with evidence-based clinical management guidelines in bleeding trauma patients.

BACKGROUND: In 2007, the multidisciplinary European Task Force for Advanced Bleeding Care in Trauma published guidelines for the management of the bleeding trauma patient. The present study aimed to assess compliance with the European guidelines during the first 24 h in a level I trauma centre and to determine whether compliance impacts mortality. METHODS: This was a retrospective study of consecutive bleeding trauma patients referred to a university hospital in France between 2010 and 2014. A reference document was developed on the basis of the European guidelines to transform the guidelines pragmatically into 22 objectively measurable criteria. We measured per-patient and per-criterion compliance rates and assessed the impact of guideline compliance on mortality. RESULTS: A total of 121 bleeding trauma patients were included. The median (interquartile range) per-patient compliance rate was 75 (65-82)% and the per-criterion compliance rate 64 (57-81)%. Mortality rates were 18 and 32% at 24 h and 30 days, respectively. After adjusting for injury severity, per-patient compliance rates were associated with decreased mortality at 24 h (odds ratio per 10% increase in patient compliance score, 0.43; 95% confidence interval 0.26-0.71; P = 0.0001) and at 30 days (odds ratio per 10% increase in patient compliance score, 0.47; 95% confidence interval 0.31-0.72; P = 0.0004). CONCLUSIONS: We found that compliance with protocols based on European guidelines impacts trauma outcome, because patient compliance was associated with survival. Further work is needed to improve adherence to these guidelines, with ongoing monitoring to ensure best practice and optimal patient outcome.

[Direct oral anticoagulant associated bleeding]. / Hémorragie survenant chez un patient traité par un anticoagulant oral direct.

Direct oral anticoagulants (DOAC) are recommended for stroke prevention in atrial fibrillation and for the treatment of venous thromboembolism. However, they are associated with hemorrhagic complications. Management of DOAC-induced bleeding remains challenging. Activated or non-activated prothrombin concentrates are proposed, although their efficacy to reverse DOAC is uncertain. Therapeutic options also include antidotes: idarucizumab, antidote for dabigatran, has been approved for use whereas andexanet alpha, antidote for anti-Xa agents, and aripazine, antidote for all DOAC, are under development. Other options include hemodialysis for the treatment of dabigatran-associated bleeding and administration of oral charcoal if recent DOAC ingestion. DOAC plasma concentration measurement is necessary to guide DOAC reversal. We propose an update on DOAC-associated bleeding, integrating the availability of dabigatran antidote and the critical place of DOAC concentration measurements.

Are there any additional mechanisms for haemolysis in HELLP syndrome?

HELLP syndrome is a microangiopathy that leads to severe maternal complications. The objective of this study was to identify any additional mechanisms that could have contributed to HELLP syndrome-induced haemolysis. This is a pilot, prospective and observational study that lasted 9months. All patients with HELLP syndrome treated at academic tertiary care women hospital accepted to participate. Sixteen patients were included. In ten patients (63%), schizocytes were detected following a blood smear test. Six patients (38%) were diagnosed with a partial expression deficiency of proteins regulating the complement system (CD 55 or CD 59). In nine patients (56%), an activation of the complement classical pathway was detected. In two patients (13%), an ADAMTS 13 activity below 30% was detected. Three patients (19%) were diagnosed with a folate deficiency and one (6%) with an antiphospholipid syndrome. All patients developed maternal or fetal morbidity including nine (56%) an acute kidney injury. All patients but one had at least one additional mechanism that could contribute to haemolysis, besides a simple physical injury. Larger studies should be promoted to understand haemolysis in HELLP syndrome.

Postpartum haemorrhage related early increase in D-dimers is inhibited by tranexamic acid: haemostasis parameters of a randomized controlled open labelled trial.

BACKGROUND: Beneficial effects of tranexamic acid (TA) have been established in surgery and trauma. In ongoing postpartum haemorrhage (PPH), a moderate reduction of blood loss was observed in a previously published randomized controlled trial. Analysis of haemostasis parameters obtained from samples collected as part of this study are presented. METHODS: Women with PPH >800 ml after vaginal delivery were assigned to receive either TA (4 g over 1 h, then 1 g per h over six h) (TA) or not (H). A non-haemorrhagic group (NH), <800 ml blood loss, was included as postpartum reference. At four time-points (enrolment, +30 min, +2 h, +6 h), haemostasis was assessed. Haemostasis assays were performed blinded to group allocation. Data were expressed as median [interquartiles] and compared with non-parametric tests. RESULTS: In H compared with NH group, D-dimers increase (3730 ng ml(-1) [2468-8493] vs 2649 [2667-4375]; P=0.0001) and fibrinogen and factor II decrease were observed at enrolment and became maximal 2 h later. When comparing TA to H patients, the increase in Plasmin-Antiplasmin-complexes at +30 min (486 ng ml(-1) [340-1116] vs 674 [548-1640]; P=0.03) and D-dimers at +2 h (3888 ng ml(-1) [2688-6172] vs 7495 [4400-15772]; P=0.0001) was blunted. TA had no effect on fibrinogen decrease. CONCLUSIONS: This study provides biological evidence of an early increase in D-dimers and plasmin-antiplasmin complexes associated with active post-partum haemorrhage and its attenuation by the early use of a clinically effective high dose of TA, opening the perspective of dose ranging studies to determinate the optimal dose and timing in this setting. CLINICAL TRIAL REGISTRATION: ISRCTN09968140.

Circulatory support devices: fundamental aspects and clinical management of bleeding and thrombosis.

Circulatory support devices are increasingly being used to overcome cardiac or respiratory failure. Long-term devices are used either as a 'bridge to transplant' to support patients who are unable to wait any longer for a heart transplant, or, more recently, as 'destination therapy' for older patients suffering from end-stage heart failure and who have contraindications to heart transplantation. Short-term support devices for high-risk percutaneous coronary intervention, or as a 'bridge for decision' for patients suffering from refractory cardiogenic shock, have also been developed. The clinical benefit of such assist devices has been demonstrated in several important studies, but, unfortunately, thrombotic and bleeding complications are two major clinical issues in patients requiring these devices. Overcoming these issues is of major importance to allow the safe and broad use of these devices, and to consider them as true alternatives to heart transplantation. The present review focuses on thrombotic and bleeding complications, and describes how the risk of thrombosis and bleeding may vary according to the clinical indication, but also according to the type of device. We describe the current knowledge of the mechanisms underlying the occurrence of these complications, provide some guidance for choosing the most appropriate anticoagulation regimen to prevent their occurrence for each type of device and indication, and provide some recommendations for the management of patients when the complication occurs.

[Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors. Proposals of the Working Group on Perioperative Haemostasis (GIHP) - March 2013]. / Prise en charge des complications hémorragiques graves et de la chirurgie en urgence chez les patients recevant un anticoagulant oral anti-IIa ou anti-Xa direct. Propositions du Groupe d'intérêt en Hémostase Périopératoire (GIHP) - mars 2013.

New direct oral anticoagulants (NOAC), inhibitors of factor IIa or Xa, are expected to be widely used for the treatment of venous thromboembolic disease, or in case of atrial fibrillation. Such anticoagulant treatments are known to be associated with haemorrhagic complications. Moreover, it is likely that such patients on long-term treatment with NOAC will be exposed to emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose management for optimal safety as regards the risk of bleeding in such emergency conditions. In this article, only dabigatran and rivaroxaban were discussed. For emergency surgery at risk of bleeding, we propose to dose the plasmatic concentration of drug. Levels inferior or equal to 30ng/mL for both dabigatran and rivaroxaban, should enable the realization of a high bleeding risk surgery. For higher concentration, it was proposed to postpone surgery by monitoring the evolution of the drug concentration. Action is then defined by the kind of NOAC and its concentration. If the dosage of the drug is not immediately available, proposals only based on the usual tests, PT and aPTT, also are presented. However, these tests do not really assess drug concentration or bleeding risk. In case of severe haemorrhage in a critical organ, it is proposed to reduce the effect of anticoagulant therapy using a nonspecific procoagulant drug (activated prothrombin concentrate, FEIBA, 30-50U/kg, or non-activated 4-factors prothrombin concentrates 50U/kg). For any other type of severe haemorrhage, the administration of such a procoagulant drug, potentially thrombogenic in these patients, will be discussed regarding concentration of NACO and possibilities for mechanical haemostasis.

Trauma-induced coagulopathy.

Hemorrhage is the leading cause of death in trauma patients who arrive alive at hospital. This type of hemorrhage has a "coagulopathic" component, specific to major trauma and associated with poor outcomes. Over the last decade, a better understanding of this trauma-induced coagulopathy lead to a new therapeutic approach requiring earlier and more aggressive management. This hemostatic resuscitation includes early activation of massive transfusion protocols with: 1) immediate delivery of blood packs with high ratios for RBC units: fresh frozen plasma: platelet-concentrates; 2) antifibrinolytics; 3) substitution of coagulation factors. However, early identification of coagulopathic patients requiring aggressive hemostatic resuscitation remains challenging, with an increasing role of point of care devices for hemostatic diagnosis and monitoring. Efforts have to be focused on the early diagnosis of coagulopathy for immediate delivery of blood products and coagulation factors to the right, accurately screened patients through pre-established protocols within the golden hour.

[Management of massive bleeding in 2013: seven questions and answers]. / Prise en charge en 2013 de l'hémorragie aiguë massive: réponses à sept questions.

The management of massive bleeding has improved, thanks to high-quality blood components and new transfusion strategies. However, it remains controversial and, despite a huge body of literature, randomised control trials are still lacking. However, the therapeutic approach has also evolved, requiring earlier and more active management. If a 'no delay' management is well recognized, its modes are still discussed. Immediate delivery of blood products with ratios close to 1:1:1 for RBC units/fresh frozen plasma/platelet concentrates, through massive transfusion protocol using blood packs, has been advocated, but yet this approach is not evidence-based. Secondly, a targeted strategy to provide fibrinogen concentrates is under evaluation. Tranexamic acid is effective in trauma patients. Recombinant factor VIIa should only be used on a compassionate basis.

[1/1 plasma to red blood cell ratio: an evidence-based practice?]. / Le ratio transfusionnel PFC/CGR 1/1: un phénomène de mode basé sur des preuves?

Coagulopathy during massive haemorrhage increases morbidity and mortality rates. The modalities of treatment by transfusion of fresh frozen plasma (FFP) are a matter of debate. According to most clinical practice guidelines, FFP administration is driven by coagulation tests but, in cases of massive transfusion, patient management may be delayed whilst awaiting results and thawing FFP. Several retrospective cohort studies of military or civilian multiple trauma casualties requiring massive transfusion (>10 red blood cells (RBC) within 24h) have suggested that early use of FFP and high FFP:RBC ratios (approaching 1) might improve survival and lessen morbidity. However, the methodology of these studies is suboptimal. They are subject, in particular, to survival bias. Massive FFP transfusions can also lead to an enhanced incidence of transfusion-related acute lung injury (TRALI), acute respiratory distress syndrome (ARDS), and multi-organ failure. At the present time, it is clear that FFP transfusion should be initiated early with a high FFP:RBC ratio in massive bleeding associated with haemostatic abnormalities such as multiple trauma. This does not imply that such a recommendation can be extended to the correction of high blood loss in other situations such as scheduled surgery. Actually, very few patients are likely to derive benefit from a 1/1 FFP:RBC transfusion strategy. They are chiefly multiple trauma victims with haemorrhagic shock and cases of ruptured abdominal aortic aneurysm. In other patients, in order to minimize risks and costs, a more parsimonious FFP use policy remains the best option until evidence for the benefit of 1/1 FFP:RBC is demonstrated.

[Transfusion and postpartum haemorrhage]. / Transfusion et hémorragie du post-partum.

Postpartum haemorrhage is the leading cause of maternal death in France and worldwide. Guidelines help to conduct a timed management and to reduce maternal morbidity and mortality. Rescue and surgical care, transfusion and monitoring have to be previously organized.

Drug-eluting stents: trading restenosis for thrombosis?

Within the last 6 years, it has been demonstrated that drug-eluting stents (DES) reduce significantly angiographic and clinical restenosis after percutaneous coronary interventions. These results are consistent across several clinical randomized controlled trials comparing these new devices with bare metallic stents (BMS), which themselves have already markedly improved the results obtained with balloon angioplasty in the early days of this method of myocardial revascularization. Nevertheless, some concerns have been raised regarding a delayed endothelialization of the coated prostheses leading to late stent thrombosis occurring mainly when antiplatelet therapy is discontinued in the follow-up. The most recent data show that, in comparison with BMS, there is a small excess of late (> 1 year) stent thrombosis but this is not associated with an increased risk of death or myocardial infarction or all cause mortality. These concerns do not outweigh the strong benefits of DES in preventing restenosis but require a number of measures concerning a longer dual antiplatelet treatment (than initially expected), to control patient treatment compliance and to provide a complete education of patients and physicians. Future devices dealing with the two issues (antiproliferative properties with rapid controlled endothelialization preventing thrombosis) would be the next major advance in this rapidly evolving field.

Relevance of tissue factor in cardiovascular disease.

Overexpression and exposition of tissue factor (TF) in atherosclerotic plaques and/or arterial thrombi are critical events in atherothrombosis. TF, the receptor for factor VII (FVII) and activated factor VII (FVIIa), is the principal initiator of blood coagulation and induces thrombin generation leading to fibrin formation and platelet activation. TF also plays a major role in cell migration and angiogenesis. TF activity is downregulated by Tissue Factor Pathway Inhibitor (TFPI), a Kunitz-type inhibitor, which forms a neutralizing complex with TF, FVIIa and activated factor X. In physiological conditions, TF is absent from vascular cells which come into contact with flowing blood and is present as an inactive pool in fibroblasts and smooth muscle cells (SMC). In contrast, TF is widely expressed in atherosclerotic plaques and is found in macrophages, SMCs, and foam-cells and also in extracellular matrix and acellular lipid-rich core. TF expression is up-regulated by inflammatory cytokines and oxidized lipids. Plaque thrombogenicity is directly correlated to their TF content. After fibrous cap disruption, TF is exposed on plaque surface and triggers thrombus formation leading to arterial lumen occlusion and/or downstream embolization. In coronary and carotid plaques, TF content was found to be higher in plaques from symptomatic than asymptomatic patients. Soluble forms of TF and microparticles of monocyte and platelet origin, and bearing TF, constitute "blood-born TF". The contribution of this TF pool to arterial thrombosis is still under discussion. TF pathway is a target for new therapeutic agents that can decrease TF activity, such as active site-inactivated factor VIIa, recombinant TFPI and antibodies against TF or peptides interfering with TF-FVIIa complex activity.

[Prophylaxis of thromboembolic events during urologic surgery]. / Prévention de la maladie thromboembolique en chirurgie urologique.

Few scientific evidences are available in the literature, and the methodologic quality of the studies is often under average. Nevertheless, the conclusions are the following. Nephrectomy, renal transplantation, open surgery of the lower urinary tract and lumbar or pelvic lymph nodes dissection are at high risk for thromboembolic events. Other open or endoscopic urological procedures are at low risk. The laparoscopic approach doesn't change the risk associated with the procedure itself. Thromboprophylaxis is recommended in high-risk procedures. There was no evidence to recommend starting the prophylaxis before more than after the procedure. The use of low molecular weight heparin is recommended for prophylaxis. It can be associated with compressive stockings. It is recommended to treat for around seven days after the procedure. In case of cancer surgery, prophylaxis could be needed for four to six weeks.