Nicola Curry

Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes

Summary.  Background:  Low fibrinogen levels are known to occur in trauma. However, the extent of fibrinogen depletion during trauma hemorrhage, the response to replacement therapy and association with patient outcomes remain unclear.

Hemostatic effects of fresh frozen plasma may be maximal at red cell ratios of 1:2.

BACKGROUND Damage control resuscitation targets acute traumatic coagulopathy with the early administration of high-dose fresh frozen plasma (FFP). FFP is administered empirically and as a ratio with the number of packed red blood cells (PRBC). There is controversy over the optimal FFP:PRBC ratio with respect to outcomes, and their hemostatic effects have not been studied. We report preliminary findings on the effects of different FFP:PRBC ratios on coagulation. METHODS This is a prospective observational cohort study of trauma patients requiring >4 U of PRBCs. Blood was drawn before and after each 4-U PRBC interval for prothrombin time and analysis by rotational thromboelastometry. Interval change in coagulation parameters were compared with the FFP:PRBC ratio received during each interval. RESULTS Sixty 4-U PRBC intervals from 50 patients were available for analysis. All measures of coagulation deteriorated with low FFP:PRBC ratios (<1:2). Maximal hemostatic effect was observed in the 1:2 to 3:4 group: 12% decrease in prothrombin time (p=0.006), 56% decrease in clotting time (p=0.047), and 38% increase in maximum clot firmness (p=0.024). Transfusion with ≥1:1 ratio did not confer any additional improvement. There was a marked variability in response to FFP, and hemostatic function deteriorated in some patients exposed to 1:1 ratios. The beneficial effects of plasma were confined to patients with coagulopathy. CONCLUSIONS Interim results from this prospective study suggest that FFP:PRBC ratios of ≥1:1 do not confer any additional advantage over ratios of 1:2 to 3:4. Hemostatic benefits of plasma therapy are limited to patients with coagulopathy.

The acute management of trauma hemorrhage: a systematic review of randomized controlled trials

IntroductionWorldwide, trauma is a leading cause of death and disability. Haemorrhage is responsible for up to 40% of trauma deaths. Recent strategies to improve mortality rates have focused on optimal methods of early hemorrhage control and correction of coagulopathy. We undertook a systematic review of randomized controlled trials (RCT) which evaluated trauma patients with hemorrhagic shock within the first 24 hours of injury and appraised how the interventions affected three outcomes: bleeding and/or transfusion requirements; correction of trauma induced coagulopathy and mortality.MethodsComprehensive searches were performed of MEDLINE, EMBASE, CENTRAL (The Cochrane Library Issue 7, 2010), Current Controlled Trials, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP) and the National Health Service Blood and Transplant Systematic Review Initiative (NHSBT SRI) RCT Handsearch Database.ResultsA total of 35 RCTs were identified which evaluated a wide range of clinical interventions in trauma hemorrhage. Many of the included studies were of low methodological quality and participant numbers were small. Bleeding outcomes were reported in 32 studies; 7 reported significantly reduced transfusion use following a variety of clinical interventions, but this was not accompanied by improved survival. Minimal information was found on traumatic coagulopathy across the identified RCTs. Overall survival was improved in only three RCTs: two small studies and a large study evaluating the use of tranexamic acid.ConclusionsDespite 35 RCTs there has been little improvement in outcomes over the last few decades. No clear correlation has been demonstrated between transfusion requirements and mortality. The global trauma community should consider a coordinated and strategic approach to conduct well designed studies with pragmatic endpoints.

Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial

BACKGROUND Low fibrinogen (Fg) concentrations in trauma haemorrhage are associated with poorer outcomes. Cryoprecipitate is the standard source for Fg administration in the UK and USA and is often given in the later stages of transfusion therapy. It is not known whether early cryoprecipitate therapy improves clinical outcomes. The primary aim of this feasibility study was to determine whether it was possible to administer cryoprecipitate, within 90 min of admission to hospital. Secondary aims were to evaluate laboratory measures of Fg and clinical outcomes including thrombotic events, organ failure, length of hospital stay and mortality. METHODS This was an unblinded RCT, conducted at two civilian UK major trauma centres of adult trauma patients (age ≥16 yrs), with active bleeding and requiring activation of the major haemorrhage protocol. Participants were randomised to standard major haemorrhage therapy (STANDARD) (n=22), or to standard haemorrhage therapy plus two early pools of cryoprecipitate (CRYO) (n=21). RESULTS 85% (95% CI: 69-100%) CRYO participants received cryoprecipitate within 90 min, median time 60 min (IQR: 57-76) compared with 108 min (67-147), CRYO and STANDARD arms respectively (P=0.002). Fg concentrations were higher in the CRYO arm and were maintained above 1.8 g litre(-1) at all time-points during active haemorrhage. All-cause mortality at 28 days was not significantly different (P=0.14). CONCLUSIONS Early Fg supplementation using cryoprecipitate is feasible in trauma patients. This study supports the need for a definitive RCT to determine the effect of early Fg supplementation on mortality and other clinical outcomes. TRIAL REGISTRY NUMBER ISRCTN55509212.

Mortality from trauma haemorrhage and opportunities for improvement in transfusion practice

The aim of this study was to describe the prevalence, patterns of blood use and outcomes of major haemorrhage in trauma.

Trauma-Induced Coagulopathy—A Review of the Systematic Reviews: Is There Sufficient Evidence to Guide Clinical Transfusion Practice?

Systematic reviews are accepted as a robust and less biased means of appraising and synthesizing results from high-quality studies. This report collated and summarized all the systematic review evidence relating to the diagnosis and management of trauma-related coagulopathy and transfusion, thereby covering the widest possible body of literature. We defined 4 key clinical questions: (1) What are the best methods of predicting and diagnosing trauma-related coagulopathy? (2) Which methods of clinical management correct coagulopathy? (3) Which methods of clinical management correct bleeding? and (4) What are the outcomes of transfusion in trauma? Thirty-seven systematic reviews were identified through searches of MEDLINE (1950-July 2010), EMBASE (1980-July 2010), The Cochrane Library (Issue 7, 2010), National Guidelines Clearing House, National Library for Health Guidelines Finder, and UKBTS SRI Transfusion Evidence Library (www.transfusionevidencelibrary.com). The evidence from the systematic review literature was scanty with many gaps, and we were not able to conclusively answer any of our 4 questions. Much more needs to be understood about how coagulopathy and bleeding in trauma are altered by transfusion practices and, most importantly, whether this translates into improved survival. There is a need for randomized controlled trials to answer these questions. The approach described in this report provides a framework for incorporating new evidence.

Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects

Inherited thrombocytopenias are a heterogeneous group of disorders characterized by abnormally low platelet counts which can be associated with abnormal bleeding. Next-generation sequencing has previously been employed in these disorders for the confirmation of suspected genetic abnormalities, and more recently in the discovery of novel disease-causing genes. However its full potential has not yet been exploited. Over the past 6 years we have sequenced the exomes from 55 patients, including 37 index cases and 18 additional family members, all of whom were recruited to the UK Genotyping and Phenotyping of Platelets study. All patients had inherited or sustained thrombocytopenia of unknown etiology with platelet counts varying from 11×109/L to 186×109/L. Of the 51 patients phenotypically tested, 37 (73%), had an additional secondary qualitative platelet defect. Using whole exome sequencing analysis we have identified “pathogenic” or “likely pathogenic” variants in 46% (17/37) of our index patients with thrombocytopenia. In addition, we report variants of uncertain significance in 12 index cases, including novel candidate genetic variants in previously unreported genes in four index cases. These results demonstrate that whole exome sequencing is an efficient method for elucidating potential pathogenic genetic variants in inherited thrombocytopenia. Whole exome sequencing also has the added benefit of discovering potentially pathogenic genetic variants for further study in novel genes not previously implicated in inherited thrombocytopenia.

Transfusion strategies for traumatic coagulopathy

Uncontrolled bleeding is the most common preventable cause of death for patients with severe injury. Coagulopathy inevitably accompanies severe bleeding, exacerbated by the ongoing blood loss and the treatments administered. There is debate about the underlying pathophysiological mechanisms of early traumatic coagulopathy and uncertainty about whether injury induces a unique coagulopathy when compared to other forms of major haemorrhage. This review describes current understanding of the coagulopathy of major blood loss and focuses on the early coagulation changes that occur following severe injury. It then reports on the contemporary management of coagulopathic bleeding using new transfusion strategies. Finally this review presents some practical points to the delivery of transfusion for major blood loss in the modern hospital setting.

Levels of procoagulant microvesicles are elevated after traumatic injury and platelet microvesicles are negatively correlated with mortality

Background Microvesicles (MV) have been implicated in the development of thrombotic disease, such as acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF). Trauma patients are at increased risk of late thrombotic events, particularly those who receive a major transfusion. The aims of this study were: (a) to determine whether there were increased numbers of pro-coagulant MV following injury; (b) to determine their cellular origin; and (c) to explore the effects of MV with clinical outcomes; in particular red cell transfusion requirements and death. Methods Trauma patients were recruited at a Level 1 trauma centre. The presence of MV procoagulant phospholipid (PPL) was assessed using 2 activity assays (PPL and thrombin generation). Enumeration and MV cellular origin was assessed using 2 colour flow cytometry. Results Fifty consecutive patients were recruited; median age 38 (IQR: 24–55), median ISS 18 (IQR: 9–27). Circulating procoagulant MV, rich in phospholipid, were significantly elevated following traumatic injury relative to controls and remained elevated at 72 h post-injury. Red cell/AnnV+ and platelet/AnnV+ MV numbers were 6-fold and 2-fold higher than controls, respectively. Patients who died (n=9, 18%) had significantly fewer CD41/AnnV+ MV and lower endogenous thrombin potential relative to patients who survived. Conclusions MV are elevated following traumatic injury and may be implicated in the increased risk of trauma patients to pro-thrombotic states such as MOF and ARDS. Lower levels of procoagulant MV are associated with mortality and further investigation of this association is warranted.

Thrombosis in inflammatory bowel disease: Are we tailoring prophylaxis to those most at risk?

Inflammatory bowel disease (IBD) is a disease-specific risk factor for incident and recurrent venous thromboembolism (VTE). The reasons are acquired, multifactorial, and related to prothrombotic aberrations during active disease, although the mechanisms remain incompletely elucidated. VTE represents a potentially life-threatening extraintestinal manifestation of IBD, but the associated morbidity and mortality can be reduced by appropriate use of thromboprophylaxis. Nevertheless, despite international guidelines advocating thromboprophylaxis in hospitalised patients with IBD, practice is highly variable, since 65% of gastroenterologists may not use pharmacological VTE prophylaxis in hospitalised patients with acute severe colitis. Furthermore, there is no guidance on appropriate prophylaxis for ambulatory outpatients with active disease who are at an appreciable risk of VTE. Thus the question: are we tailoring thromboprophylaxis to those patients with IBD who are most at risk?