Cheng Hock Toh

Guidelines for the diagnosis and management of disseminated intravascular coagulation

The diagnosis of disseminated intravascular coagulation (DIC) should encompass both clinical and laboratory information. The International Society for Thrombosis and Haemostasis (ISTH) DIC scoring system provides objective measurement of DIC. Where DIC is present the scoring system correlates with key clinical observations and outcomes. It is important to repeat the tests to monitor the dynamically changing scenario based on laboratory results and clinical observations. The cornerstone of the treatment of DIC is treatment of the underlying condition. Transfusion of platelets or plasma (components) in patients with DIC should not primarily be based on laboratory results and should in general be reserved for patients who present with bleeding. In patients with DIC and bleeding or at high risk of bleeding (e.g. postoperative patients or patients due to undergo an invasive procedure) and a platelet count of <50 × 109/l transfusion of platelets should be considered. In non‐bleeding patients with DIC, prophylactic platelet transfusion is not given unless it is perceived that there is a high risk of bleeding. In bleeding patients with DIC and prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), administration of fresh frozen plasma (FFP) may be useful. It should not be instituted based on laboratory tests alone but should be considered in those with active bleeding and in those requiring an invasive procedure. There is no evidence that infusion of plasma stimulates the ongoing activation of coagulation. If transfusion of FFP is not possible in patients with bleeding because of fluid overload, consider using factor concentrates such as prothrombin complex concentrate, recognising that these will only partially correct the defect because they contain only selected factors, whereas in DIC there is a global deficiency of coagulation factors. Severe hypofibrinogenaemia (<1 g/l) that persists despite FFP replacement may be treated with fibrinogen concentrate or cryoprecipitate. In cases of DIC where thrombosis predominates, such as arterial or venous thromboembolism, severe purpura fulminans associated with acral ischemia or vascular skin infarction, therapeutic doses of heparin should be considered. In these patients where there is perceived to be a co‐existing high risk of bleeding there may be benefits in using continuous infusion unfractionated heparin (UFH) due to its short half‐life and reversibility. Weight adjusted doses (e.g. 10 μ/kg/h) may be used without the intention of prolonging the APTT ratio to 1·5–2·5 times the control. Monitoring the APTT in these cases may be complicated and clinical observation for signs of bleeding is important. In critically ill, non‐bleeding patients with DIC, prophylaxis for venous thromboembolism with prophylactic doses of heparin or low molecular weight heparin is recommended. Consider treating patients with severe sepsis and DIC with recombinant human activated protein C (continuous infusion, 24 μg/kg/h for 4 d). Patients at high risk of bleeding should not be given recombinant human activated protein C. Current manufacturers guidance advises against using this product in patients with platelet counts of <30 × 109/l. In the event of invasive procedures, administration of recombinant human activated protein C should be discontinued shortly before the intervention (elimination half‐life ≈20 min) and may be resumed a few hours later, dependent on the clinical situation. In the absence of further prospective evidence from randomised controlled trials confirming a beneficial effect of antithrombin concentrate on clinically relevant endpoints in patients with DIC and not receiving heparin, administration of antithrombin cannot be recommended. In general, patients with DIC should not be treated with antifibrinolytic agents. Patients with DIC that is characterised by a primary hyperfibrinolytic state and who present with severe bleeding could be treated with lysine analogues, such as tranexamic acid (e.g. 1 g every 8 h).

A Randomized Trial of Genotype-Guided Dosing of Warfarin

BACKGROUND The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy. METHODS We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation. RESULTS A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR ≥4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001). CONCLUSIONS Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. (Funded by the European Commission Seventh Framework Programme and others; ClinicalTrials.gov number, NCT01119300.).

Circulating Histones Are Mediators of Trauma-associated Lung Injury

RATIONALE Acute lung injury is a common complication after severe trauma, which predisposes patients to multiple organ failure. This syndrome largely accounts for the late mortality that arises and despite many theories, the pathological mechanism is not fully understood. Discovery of histone-induced toxicity in mice presents a new dimension for elucidating the underlying pathophysiology. OBJECTIVES To investigate the pathological roles of circulating histones in trauma-induced lung injury. METHODS Circulating histone levels in patients with severe trauma were determined and correlated with respiratory failure and Sequential Organ Failure Assessment (SOFA) scores. Their cause-effect relationship was studied using cells and mouse models. MEASUREMENTS AND MAIN RESULTS In a cohort of 52 patients with severe nonthoracic blunt trauma, circulating histones surged immediately after trauma to levels that were toxic to cultured endothelial cells. The high levels were significantly associated with the incidence of acute lung injury and SOFA scores, as well as markers of endothelial damage and coagulation activation. In in vitro systems, histones damaged endothelial cells, stimulated cytokine release, and induced neutrophil extracellular trap formation and myeloperoxidase release. Cellular toxicity resulted from their direct membrane interaction and resultant calcium influx. In mouse models, cytokines and markers for endothelial damage and coagulation activation significantly increased immediately after trauma or histone infusion. Pathological examinations showed that lungs were the predominantly affected organ with edema, hemorrhage, microvascular thrombosis, and neutrophil congestion. An anti-histone antibody could reduce these changes and protect mice from histone-induced lethality. CONCLUSIONS This study elucidates a new mechanism for acute lung injury after severe trauma and proposes that circulating histones are viable therapeutic targets for improving survival outcomes in patients.

The scoring system of the Scientific and Standardisation Committee on Disseminated Intravascular Coagulation of the International Society on Thrombosis and Haemostasis: a 5-year overview.

In 2001, the International Society on Thrombosis and Haemostasis (ISTH) Sub-Committee of the Scientific and Standardisation Committee (SSC) on Disseminated Intravascular Coagulation (DIC) proposed that the working definition of DIC be delineated into two phases. Non-overt DIC would represent subtle hemostatic dysfunction while overt DIC recognized its decompensated phase [1]. Central to the diagnosis is a scoring system rooted in rapid and readily available tests. This would then enable the diagnosis to be utilized widely and serve as the reference standard for diagnostic and therapeutic purposes. For overt DIC, a cumulative score of 5 or more from prolonged prothrombin time (PT), reduced platelets and fibrinogen, and elevated fibrin-related markers was proposed (Table 1). This required prospective confirmation. For nonovert DIC, scoring would incorporate abnormal trends and results in both simple global tests and molecular markers of coagulation (Table 2). Studies were required to establish feasibility and to derive a prognostic score.

Postnatal screening for thrombophilia in women with severe pregnancy complications.

Objective To examine the prevalence of maternal thrombophilia in women with severe preeclampsia/eclampsia, placental abruption, fetal growth restriction, and unexplained stillbirth. Methods We studied 102 women who had pregnancy complications and 44 healthy women with uncomplicated pregnancies. All women were tested 10 weeks postpartum for mutations of factor V Leiden, methylenetetrahydrofolate reductase (MTHFR) C677T, and G20210A prothrombin gene; deficiencies of protein C, protein S, and antithrombin III; and the presence of lupus anticoagulant and anticardiolipin antibodies. We aimed to recruit 100 cases and 300 controls to detect a 10% difference in thrombophilia between the groups. However, we were able to recruit only 44 controls. Results Abnormal thrombophilia screen was found in 54 women with pregnancy complications (53%) and in 17 women (39%) with normal pregnancies (odds ratio [OR] 1.8; 95% confidence interval [CI] 0.87, 3.67). Mutations encoding for factor V Leiden, G20210A prothrombin gene, and MTHFR C677T (homozygous) were identified in 18% of women with complications compared with 16% of controls (OR 1.1; 95% CI 0.44, 2.94). Activated protein C resistance, not due to factor V Leiden mutation, was the most common thrombophilic defect, found in 26% of women with pregnancy complications compared with 18% of controls Conclusion In our cohort of women with pregnancy complications, maternal thrombophilia was less common than previously thought, and multiple thrombophilias were not a major additional risk factor

Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children.

Cerebral malaria (CM) is a major cause of mortality in African children and the mechanisms underlying its development, namely how malaria-infected erythrocytes (IEs) cause disease and why the brain is preferentially affected, remain unclear. Brain microhemorrhages in CM suggest a clotting disorder, but whether this phenomenon is important in pathogenesis is debated. We hypothesized that localized cerebral microvascular thrombosis in CM is caused by a decreased expression of the anticoagulant and protective receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR) and that low constitutive expression of these regulatory molecules in the brain make it particularly vulnerable. Autopsies from Malawian children with CM showed cerebral fibrin clots and loss of EPCR, colocalized with sequestered IEs. Using a novel assay to examine endothelial phenotype ex vivo using subcutaneous microvessels, we demonstrated that loss of EPCR and TM at sites of IE cytoadherence is detectible in nonfatal CM. In contrast, although clotting factor activation was seen in the blood of CM patients, this was compensated and did not disseminate. Because of the pleiotropic nature of EPCR and TM, these data implicate disruption of the endothelial protective properties at vulnerable sites and particularly in the brain, linking coagulation and inflammation with IE sequestration.

Disseminated intravascular coagulation in obstetric disorders and its acute haematological management.

As activation of the coagulation pathway is a physiological response to injury, the development of disseminated intravascular coagulation (DIC) is a warning signal to the clinician that the primary pathological disease state is decompensating. In pregnancy, DIC can occur in several settings, which include emergencies such as placental abruption and amniotic fluid embolism as well as complications such as pre-eclampsia. Whilst the acuteness of the event and the proportionality in the coagulant and fibrinolytic responses may vary between these different conditions, a common theme for pregnancy-associated DIC is the pivotal role played by the placenta. Removal of the placenta is the linchpin to treatment in most cases but appropriate blood product support is also key to management. This is necessary because DIC itself can have pathological consequences that translate clinically into a worse prognosis for affected patients. This article will describe how pregnancy-associated DIC can be diagnosed promptly and how treatment should be managed strategically. It also discusses the latest developments in our understanding of haemostatic mechanisms within the placenta and how these may have relevance to new diagnostic approaches as well as novel therapeutic modalities.

Disseminated intravascular coagulation: old disease, new hope

Disseminated intravascular coagulation has long been associated with increased mortality in patients with sepsis. An effective treatment is now available, and the authors of this review describe how improved understanding and earlier diagnosis could lead to targeted treatment and improved prognosis Although the first clinical observations on disseminated intravascular coagulation (DIC) were reported in the 19th century,1 this condition of widespread and disordered coagulation has probably afflicted mankind for as long as trauma and infection have beset us. Indeed, DIC is generally associated with an adverse outcome by most clinicians, and its acronym has been synonymous with “death is coming.” However, a drug targeted at the coagulopathy of severe sepsis (activated protein C) has now emerged as the first successful treatment for the condition.2 We provide an updated overview of DIC and how its onset may indicate the turning point from which an adaptive response becomes maladaptive and potentially injurious to the host. Precise laboratory definition of this process could provide a therapeutic window in critical illness that may finally deliver an improved outcome. A systematic search of PubMed with the search term “disseminated intravascular coagulation” and related keywords yielded 10 262 publications, most of which related to pathophysiology and case reports. Owing to a lack of systematic controlled clinical trials, many recommendations are based on expert opinion and consensus driven guidelines rather than a secure evidence base. However, an increasing number of randomised controlled trials studying the diagnosis and management of DIC have been reported in the past five years, and we have incorporated these in the review. DIC represents a continuum in clinical-pathological severity, characterised by the increasing loss of localisation or compensated control in intravascular activation of coagulation. It has definable phases that characterise patients at risk for increased mortality. The International Society of Thrombosis …

Autocrine VEGF mediates the antiapoptotic effect of CD154 on CLL cells.

CD154 is an important regulator of chronic lymphocytic leukaemia (CLL)-cell survival. In CLL, high serum levels of VEGF are a feature of advanced disease, and we and others have previously shown that CLL cells produce and secrete this growth factor. Since CD154 stimulates VEGF production in other cell types, and VEGF is known to promote cell survival, we examined whether the cytoprotection of CLL cells by CD154 involves VEGF. We report for the first time that treatment of CLL cells with CD154 results in increased VEGF production and demonstrate involvement of NF-κB in this process. Moreover, we show that CD154-induced CLL-cell survival is reduced by anti-VEGF-neutralising antibody and by inhibiting VEGF receptor (VEGFR) signalling with SU5416. However, addition of exogenous VEGF alone or blocking secreted autocrine VEGF had little or no effect on CLL-cell survival. We therefore conclude that CLL-cell cytoprotection in the presence of CD154 requires combined signalling by both CD40 and VEGFR. This combined signalling and resulting cytoprotection were shown to involve NF-κB activation and increased survivin production. In conclusion, our findings identify autocrine VEGF as an important mediator of the antiapoptotic effect of CD40 ligation, and thus provide new insights into CLL-cell rescue by CD154 in lymphoreticular tissues.

Performance and prognostic importance of a new clinical and laboratory scoring system for identifying non-overt disseminated intravascular coagulation.

A template for diagnosing the non-overt phase of disseminated intravascular coagulation (DIC) has recently been proposed. However, validation of its performance and the proposal of a defining score are required. The aim was to assess feasibility of the non-overt DIC scoring template and its potential prognostic significance. Consecutive patients admitted to a university hospital intensive care unit were initially assessed over 2 months. Following this, a 12-month study examined the prognostic performance of the derived scores prospectively. Outcome parameters were overt DIC and 28-day mortality. The 2-month study, involving 66 patients and 919 time points, demonstrated practical feasibility and prognostic associations for mortality with scores of 5 and greater. The 12-month study involving 450 patients showed that the mortality rate was 29% (105 of 360) and 78% (70 of 90) for scores below 5 and scores of 5 or above, respectively. The mortality rate for overt DIC was also 78% (38 of 49). The non-overt DIC scoring template is workable and has prognostic relevance. A score of 5 and greater is recommended as diagnostic of non-overt DIC.