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Background: Rotational thromboelastometry (ROTEM ® ) is a point-of-care test of coagulation. ROTEM ® -defined hypercoagulability has been identified in pregnant women and in non-pregnant patients with diabetes mellitus. Pregnancy is known to be a hypercoagulable state, but the influence of gestational diabetes mellitus (GDM) on coagulation is unknown., Aim: The aim of this study was to assess the combined effect of pregnancy and GDM on coagulation using ROTEM ® and to compare this to healthy pregnant women presenting for elective caesarean delivery., Materials and Methods: Ethics approval was granted for recruitment of women presenting for elective caesarean delivery. Women with pre-existing conditions affecting coagulation were excluded. Group N included health pregnant women at term and Group G included pregnant women at term with GDM. Data regarding GDM management and glycaemic control were collected. Poor glycaemic control was defined by markers of accelerated fetal growth and elevated fasting or postprandial blood glucose levels. The ROTEM ® parameters (extrinsically activated thromboelastometric test (EXTEM) / fibrin polymerisation test (FIBTEM) amplitude at five minutes, coagulation time, maximum clot firmness and clot formation time) were compared between the two groups using Student's t-test., Results: There were 75 women in Group N and 21 women in Group G. Mean age and median body mass index values were comparable for both groups. There were no statistical differences found between the EXTEM and FIBTEM parameters analysed for the two groups., Conclusions: There was no association between GDM and increased hypercoagulability as demonstrated by ROTEM ® parameters in healthy pregnant women presenting for elective caesarean delivery at term., (© 2022 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

In 145 previously healthy non-critically ill young adults, coronavirus disease 2019 (COVID-19)-related symptoms, risk factors for thrombosis, coagulation and inflammatory parameters were compared, with 29 patients reporting unusual thrombotic events (UTEs) and 116 not having thrombotic events. The inflammatory indices, coagulation and prothrombotic platelet phenotype (PTPP) were significantly higher in patients with UTEs versus those without. Patients with UTEs were categorised according to detection of thrombophilic genes (TGs), coagulation and inflammatory markers to the non-TG and TG subcohort. A total of 38 UTEs were identified, which included splanchnic vein thrombosis (SVT; 11), stroke (six), cerebral vein thrombosis (five), thrombotic microangiopathy (four), limb ischaemia and inferior vena cava thrombosis (three each), ST-segment elevation myocardial infarction (two), superior vena cava thrombosis (two), upper limb deep venous thrombosis and retinal vein thrombosis, one each. We found a 55% prevalence of TGs mainly heterozygous coagulation factor II, thrombin (FII)-G20210A, Janus kinase 2 (JAK2)-V617F, protein-S, and antithrombin III deficiency with a high (76·9%) prevalence of venous UTEs, multiple vessels thrombosis, and recurrence rate among the TG versus non-TG subcohort. The presence of JAK2-V617F, and FII-G20210A mutations was linked with SVT. Thrombosis in the non-TG subcohort was associated with more haemorrhagic problems, thrombosis progression and a significantly higher level of inflammatory markers, PTPP, mean platelet volume, von Willebrand factor, and factor VIII, which remained high for up to 6 months, as well as elevated D-dimer. Acquired and inherited thrombophilia with endotheliopathy appeared to be a relevant mechanism to explain the occurrence of UTEs that are not correlated to COVID-19 severity., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Impact of the gestational changes on cardiac contractility is not clearly defined. Our aim was to evaluate subtle changes of the right ventricular systolic function during pregnancy, assessed by new echocardiographic techniques, in a population tested for inherited thrombophilia. 87 pregnant women, with a mean age of 32 ± 4 years, genetically tested for inherited thrombophilia (22 with high-risk inherited thrombophilia and 65 control group) were included. All participants had four echocardiographic assessments, three during pregnancy (one in each trimester) and the forth at 6 months after giving birth. The right ventricular (RV) systolic function was assessed by fractional area change, ejection fraction (EF) by 3D echocardiography, tricuspid annular velocity by tissue Doppler, tricuspid annular plane systolic excursion, and strain by speckle tracking. Pulmonary artery pressure was estimated using the pressure gradient between right atrium and RV. Parameters of RV systolic function, at visits 2-4, had lower values compared with the first visit and were significantly lower in the high-risk thrombophilia group. Tricuspid regurgitation and pressure gradient between the right atrium and the RV had a significant increase during pregnancy for all subjects. At visit 1, there were no differences between groups, but at the next three visits there were higher values of the gradient in the high-risk thrombophilia group. High-risk inherited thrombophilia impacts the RV contractility, with higher pulmonary artery pressure. Further studies are needed to assess long-term impact on RV of high-risk inherited thrombophilia., (© 2020 Wiley Periodicals LLC.)

Background The value of thrombophilia test acquisition in improving risk prediction beyond clinical presentation remains unknown. We investigated the effect of thrombophilia test acquisition on venous thromboembolism (VTE) outcomes. Methods and Results We performed a retrospective cohort study of adult patients over a 15-year period (September 2001 and May 2016) with first diagnosis of VTE in a single academic medical center. Participants were identified by International Classification of Diseases, Ninth Revision ( ICD-9 ), Current Procedural Terminology ( CPT ) codes and medication history. Participants with thrombophilia testing were matched to control participants without thrombophilia testing using a propensity model. Primary outcomes included recurrent VTE, anticoagulant use 12 months after the index VTE event, bleeding-related hospitalization, and death. From 3590 unique patients who met the inclusion criteria, 747 participants with VTE who underwent thrombophilia testing were matched to a control participant without testing. Tested participants were more likely to have a recurrent event (46.1% versus 28.5%; P <0.001) and an anticoagulant prescription 12 months from the index event (53.9% versus 37.1%; P <0.001) but had no significant difference in bleeding-related hospitalization (11.4% versus 11.8%; P =0.81) compared with untested participants. An abnormal thrombophilia test result, per se, did not predict recurrent VTE (47.8% versus 44.1%; P =0.13), longer duration anticoagulation (53.2% versus 54.8%; P =0.51), bleeding (11.5% versus 11.3%; P =0.70), or mortality (12.2% versus 16.1%; P =0.18) compared with participants who had normal test results. Conclusions The decision to perform thrombophilia testing, but not the test result, is associated with a high risk of recurrent VTE despite a greater likelihood of long-duration anticoagulation.

Background Inherited thrombophilias are well-established predisposing factors for venous thromboembolism, but their role in arterial thrombosis, such as arterial ischemic stroke, remains uncertain. We aimed to evaluate the association between inherited thrombophilia (factor V Leiden, prothrombin G20210A mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency) and risk of arterial ischemic stroke in adults. Methods and Results We searched PubMed, EMBASE, and Cochrane Library Databases from inception to December 31, 2018. We included case-control or cohort studies of adults reporting the prevalence of inherited thrombophilias in those with arterial ischemic stroke and subjects without arterial ischemic stroke. Two reviewers (T.C., E.D.) independently searched the literature and extracted data. Pooled odds ratios (ORs) and 95% CIs were calculated using random-effects model. We identified 68 eligible studies, which collectively enrolled 11 916 stroke patients and 96 057 controls. The number of studies reporting factor V Leiden, prothrombin G20210A mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency were 56, 45, 15, 17, and 12, respectively. Compared with controls, patients with arterial ischemic stroke were significantly more likely to have the following inherited thrombophilias: factor V Leiden (OR, 1.25; 95% CI, 1.08-1.44; I 2 =0%), prothrombin G20210A mutation (OR, 1.48; 95% CI, 1.22-1.80; I 2 =0%), protein C deficiency (OR, 2.13; 95% CI, 1.16-3.90; I 2 =0%), and protein S deficiency (OR, 2.26; 95% CI, 1.34-3.80; I 2 =8.8%). Statistical significance was not reached for antithrombin deficiency (OR, 1.25; 95% CI, 0.58-2.67; I 2 =8.8%). Conclusions Inherited thrombophilias (factor V Leiden, prothrombin G20210A mutation, protein C deficiency, and protein S deficiency) are associated with an increased risk of arterial ischemic stroke in adults. The implications of these findings with respect to clinical management of patients with ischemic stroke require further investigation.

Aims: Warfarin dose requirement varies significantly. We compared the clinically established doses based on international normalized ratio (INR) among patients with severe thrombosis and/or thrombophilia with estimates from genetic dosing algorithms., Methods: Fifty patients with severe thrombosis and/or thrombophilia requiring permanent anticoagulation, referred to the Helsinki University Hospital Coagulation Center, were screened for thrombophilias and genotyped for CYP2C9*2 (c.430C>T, rs1799853), CYP2C9*3 (c.1075A>C, rs1057910) and VKORC1 c.-1639G>A (rs9923231) variants. The warfarin maintenance doses (target INR 2.0-3.0 in 94%, 2.5-3.5 in 6%) were estimated by the Gage and the International Warfarin Pharmacogenetics Consortium (IWPC) algorithms. The individual warfarin maintenance dose was tailored, supplementing estimates with comprehensive clinical evaluation and INR data., Results: Mean patient age was 47 years (range 20-76), and BMI 27 (SD 6), 68% being women. Forty-six (92%) had previous venous or arterial thrombosis, and 26 (52%) had a thrombophilia, with 22% having concurrent aspirin. A total of 40% carried the CYP2C9*2 or *3 allele and 54% carried the VKORC1-1639A allele. The daily mean maintenance dose of warfarin estimated by the Gage algorithm was 5.4 mg (95% CI 4.9-5.9 mg), and by the IWPC algorithm was 5.2 mg (95% CI 4.7-5.7 mg). The daily warfarin maintenance dose after clinical visits and follow-up was higher than the estimates, mean 6.9 mg (95% CI 5.6-8.2 mg, P < 0.006), with highest dose in patients having multiple thrombophilic factors (P < 0.03)., Conclusions: In severe thrombosis and/or thrombophilia, variation in thrombin generation and pharmacodynamics influences warfarin response. Pharmacogenetic dosing algorithms seem to underestimate dose requirement., (© 2019 The British Pharmacological Society.)

Background & Aims: The long-term impact of sustained virological response (SVR) after direct-acting antivirals (DAAs) on the hypercoagulability associated with HCV cirrhosis is unknown. We longitudinally evaluated the effect of DAAs treatment on cirrhotic coagulopathy., Methods: Pro- and anticoagulant factor levels and thrombin generation were assessed in patients with HCV-related cirrhosis at baseline, end of therapy (EOT), at 12, 24 and 48 weeks (W) after EOT., Results: Fifty-eight patients were enrolled (86% Child's A). SVR was 100%. Median factor VIII activity significantly decreased at EOT, 12 weeks and 24 weeks compared with baseline, whereas protein C significantly increased at 24 weeks and 48 weeks. Cirrhotic patients showed a slight but sustained increase in endogenous thrombin potential (ETP) with a statistically significant difference at EOT, 12 weeks, 24 weeks and 48 weeks compared with baseline. Conversely, thrombomodulin-modified ETP was elevated before treatment and decreased over time to normal levels at 24 weeks and 48 weeks. The ETP ratio decreased slowly at EOT and 12 weeks, and was significantly decreased at 24 weeks and 48 weeks compared with baseline (P < .001 for both comparisons), being not statistically different from ETP ratio measured in healthy controls. Child's B patients showed a significantly higher ETP ratio compared to Child's A at baseline and did not show any significant improvement in ETP ratio through 12 weeks. Two Child's B patients developed PVT with an incidence rate of 1.1% p-yrs (95%CI, 0.18 to 3.58)., Conclusions: DAAs therapy in HCV-related cirrhotic patients is associated with significant changes in thrombin generation suggesting a reversal of hypercoagulability particularly in Child's A patients., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Retinal venous occlusion represents a common retinal disorder that untreated often leads to severely reduced vision. While general risk factors for vascular disease are known to increase the risk of an event, the role of thrombophilia is controversial. The purpose of this systematic review was to evaluate the evidence for thrombophilia investigation in patients presenting with retinal venous occlusion. Eligible studies were identified by a MESH-based search in PubMed 11-13 of March 2015. The level of evidence was stated according to the guidelines published by the GRADE working group using three levels for quality of evidence: high, moderate and low. A total of 118 studies relating to the study question were identified. After excluding case stories, commentaries, cross-sectional studies and reviews/expert opinions, 28 original papers and two meta-analyses were included in the final qualitative synthesis. The majority of studies were small case-control studies, and only one large cohort study was identified. No randomized controlled trials were retrieved. All the studies were categorized as low quality of evidence. Systematic thrombophilia screening in patients presenting with retinal venous occlusion cannot be recommended., (© 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Conventional coagulation tests are frequently prolonged after liver surgery, suggesting a post-operative hypocoagulability. However, these tests are unreliable for assessment of the haemostatic status in these patients. In contrast, thrombin generation testing measures the true balance between pro- and anti-coagulant factors., Aim: To study the perioperative coagulation status in patients undergoing hemi-hepatectomy using thrombin generation assays., Methods: We examined thrombin generation profiles in serial plasma samples taken from seventeen patients undergoing right hemi-hepatectomy. Results were compared to ten patients undergoing pancreatic resection and twenty-four healthy volunteers. In addition, we measured conventional coagulation tests and plasma levels of several haemostatic proteins., Results: Following liver resection, the endogenous thrombin potential (ETP) slightly decreased until post-operative day 7. However, in the presence of thrombomodulin, the ETP increased [from 542 nM*min (417-694) at baseline to 845 nM*min (789-1050) on post-operative day 3] to values higher than that in healthy subjects (558 nM*min (390-680); P < 0.001), which contrasts with substantially prolonged PT levels. Normal to decreased thrombin generation was observed following pancreatic resection. Thrombin generation was only slightly affected by thrombomodulin after hemi-hepatectomy, while thrombin generation in healthy subjects decreased profoundly upon addition of thrombomodulin. This hypercoagulability following liver resection may be explained by decreased levels of protein C, S, and antithrombin and by elevated levels of factor VIII., Conclusions: Thrombin generation in the presence of thrombomodulin revealed hypercoagulability in patients following liver resection. These results support the recently advocated restrictive use of plasma during liver resection and the exploration of more extensive use of post-operative thrombosis prophylaxis., (© 2014 John Wiley & Sons Ltd.)

Venous thromboembolism [TE] is a multifactorial disease and protein C deficiency [PCD] constitutes a major risk factor. In the present study the prevalence of PCD and the clinical presentation at TE onset, including neonatal purpura fulminans, in a cohort of children are reported. In 367 unselected children (0·1-19 years) recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. Twenty-five of 338 children (7·4%) had PCD. Mean age at first TE onset was 10 years (range 0·1-18). Leading thromboembolic manifestations were neonatal purpura fulminans (n = 5), TE of cerebral veins (n = 3), stroke (n = 2) deep veinthrombosis (DVT) of the leg (n = 10), DVT & pulmonary embolism (n = 2) and DVT & pelvic veins (n = 3). Concomitant risk factors for TE were identified in 12 patients, whereas 13 children spontaneously developed TE. A positive family history of DVT was found in 10 children. In this unselected cohort of paediatric patients with symptomatic TE the overall prevalence of PCD was 7·4%; 1·5% presented with neonatal purpura fulminans. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high-risk population., (© 2014 John Wiley & Sons Ltd.)

Haemostatic and vascular biology mechanisms appear to play an important role in the pathogenesis of placenta-mediated pregnancy complications. Although low-dose aspirin (LDA) has a modest effect in preventing preeclampsia, antithrombotic interventions, LDA and low molecular weight heparin (LMWH) have not definitively proven their effectiveness in women with placenta-mediated pregnancy complications selected by previous pregnancy outcome alone. Given the heterogeneous aetiology of placenta-mediated pregnancy complications, it is critical to stratify patients according to maternal and fetal characteristics and disease mechanisms rather than simply by pregnancy outcome, such as miscarriage. Such stratification could identify those who could benefit from antithrombotic interventions in pregnancy. We lack data on genome-wide association studies, biomarkers and trials of interventions applied to specific homogeneous populations. Future studies should focus on elaborating different disease mechanisms and examining antithrombotic interventions in specific and more homogeneous groups, such as thrombophilic women with well-characterized placenta-mediated pregnancy complications, stratified by disease severity and pathological findings. Because of fetal safety concerns with new anticoagulants, the intervention should focus on heparins alone or in combination with LDA. Thus, placenta-mediated pregnancy complications deserve precision medicine, defining disease by mechanism rather than outcome with interventions focused on a more personalized approach., (© 2014 John Wiley & Sons Ltd.)

Background: Sepsis leads to disruption of hemostasis, making early evaluation of coagulation essential. The aim of this study was to provide a detailed investigation of coagulation and the use of blood products in patients with severe sepsis or septic shock, admitted to a multidisciplinary intensive care unit., Methods: Thirty-six patients with severe sepsis or septic shock were included in this prospective observational study. Blood samples and information on transfusion of blood products were obtained for up to 3 consecutive days, and day 7 if the patient was still in the intensive care unit. Thromboelastometry (ROTEM(®)), analyses of thrombin generation, and conventional coagulation tests were performed., Results: ROTEM(®) revealed an overall normo-coagulable state among patients with severe sepsis or septic shock. Conventional coagulation analyses showed divergent results with hypercoagulable trends in terms of reduced antithrombin and acute phase response with increased fibrinogen and fibrin d-dimer, and on the other hand, coagulation disturbances with a decreased prothrombin time and prolonged activated partial thromboplastin time. This hypocoagulabe state was supported by a delayed and reduced thrombin generation. Twelve patients experienced 21 independent transfusion episodes with fresh frozen plasma. Of these, only five (22%) transfusions were performed because of active bleeding., Conclusion: ROTEM(®) demonstrated an overall normo-coagulation, whereas the conventional coagulation tests and thrombin generation analyses mainly reflected hypocoagulation. Given the dynamic and global features of ROTEM(®), this analysis may be a relevant supplementary tool for the assessment of hemostasis in patients with severe sepsis or septic shock., (© 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Traditionally, perioperative bleeding complications were a major concern during orthotopic liver transplantation, but a tremendous decline in transfusion requirements has been reported over the last decade. In recent years, there has been an increasing awareness towards perioperative thrombotic complications, including liver vessel thrombosis, and systemic venous and arterial thromboembolic events. Whereas a number of these thrombotic complications were previously categorized as surgical complications, increasing clinical and laboratory evidence suggest a role for the haemostatic system in thrombotic complications occurring during and after transplantation. High levels of the platelet adhesive protein von Willebrand factor with low levels of its regulator ADAMTS13, an increased potential to generate thrombin, and temporary hypofibrinolysis are all indicative of increased haemostatic potential after transplantation. Clinical evidence for a role of the haemostatic system in post-operative thromboses includes a higher thrombotic risk in patients with various acquired thrombotic risk factors. Although data on efficacy of anticoagulant therapy after liver transplantation are scarce, one study has shown a significant decrease in the risk for late hepatic artery thrombosis by antithrombotic therapy with aspirin. These findings suggest that antihaemostatic therapy in prevention or treatment of thromboembolic complications after liver transplantation may be relevant. Studies on efficacy and safety of these interventions are required as many of the thrombotic complications have a pronounced negative impact on graft and patient survival., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Recurrent pregnancy loss (RPL) affects 1% pregnancies and is multi-factorial in origin. The role of the acquired thrombophilia antiphospholipid syndrome (APS) as a common and potentially treatable cause of RPL is well established but this is less so for inherited thrombophilia. In obstetric APS the combination of aspirin and heparin has improved outcomes. By analogy, the use of low molecular weight heparin (LMWH) has become commonplace in women with inherited thrombophilia and also those with unexplained miscarriage to help safeguard the pregnancy. This review will examine the pathophysiological role of thrombophilia in pregnancy loss, and the evidence for anticoagulant-based intervention. The limited data supporting the use of heparin for women with RPL and inherited thrombophilia suggests adoption of a more cautious and judicious approach in this setting., (© 2012 Blackwell Publishing Ltd.)

Testing for hereditary thrombophilia typically includes tests for activated protein C resistance (APC-R) and/or factor V Leiden, protein C, protein S, antithrombin, and prothrombin G20210A. New options for these assays have become available in recent years, with different advantages and disadvantages among the currently available methods. Potential interferences for each assay type are discussed, including lupus anticoagulants, heparin, warfarin, direct thrombin inhibitors (such as argatroban, dabigatran, hirudin, or bivalirudin), rivaroxaban, factor deficiencies or elevations, factor V Leiden, and specific mutations that the assay(s) might not be able to detect. Causes of acquired deficiencies are also described, as these must be carefully excluded before diagnosing a hereditary deficiency of protein C, protein S, or antithrombin., (Copyright © 2012 Wiley Periodicals, Inc.)

Venous thrombo-embolism (VTE) is increasingly recognized in paediatric practice. Few clinical trials have been performed in this area in children and management is largely extrapolated from adult practice where there is a considerable evidence base. This is likely to be unsatisfactory for a number of reasons. Firstly, there are significant differences in epidemiology and potential differences in the mechanisms for VTE in this age group. Secondly, many aspects of haemostasis are age-dependant, which has implications for the use of anticoagulants in the paediatric population. Thirdly, there are very limited data available on the safety and efficacy of anticoagulants to manage specific indications in paediatric practice, often with limited paediatric formulations available. In addition, children may survive for a prolonged period following these events so that long-term consequences may be highly significant in this age group. The aim of this guideline is to provide a rational basis for the investigation and management of children aged 1 month-16 years with VTE, including cerebral venous thrombosis (CVT). The guideline is targeted at healthcare professionals involved in the management of children and adolescents with VTE, particularly paediatric haematologists., (© 2011 Blackwell Publishing Ltd.)

Hereditary protein C deficiency is a hypercoagulable state associated with an increased risk for venous thrombosis. The recommended initial test for protein C is an activity (functional) assay, which may be clotting time based or chromogenic. The advantages and disadvantages of the various testing options are presented. The causes of acquired protein C deficiency are much more common than hereditary deficiency. Therefore, this article describes the appropriate steps to take when protein C activity is low, to confirm or exclude a hereditary deficiency. The causes of falsely normal results are also described, including lupus anticoagulants and direct thrombin inhibitors., (2010 Wiley-Liss, Inc.)

Thrombotic events in children have become an increasingly common problem, particularly in paediatric tertiary care hospitals. The prevalence of inherited thrombophilia in children who develop thrombosis varies substantially depending on the population. Children who develop thrombosis, as well as those who have not but have a positive family history, are frequently tested for inherited thrombophilia. The clinical utility of performing such tests has been questioned, in both adults and children. This review will examine the practise of testing for inherited thrombophilia in children, focusing on the rationale for testing and highlighting areas in which more evidence is needed prior to making strong recommendations. Future studies, many of which are currently being performed or proposed, are necessary to address many of the unanswered questions.

Patients with thrombophilia and/or a history of venous thromboembolism (VTE) exhibit a high risk of thrombosis during pregnancy. The present multicentre study prospectively assessed a prophylaxis strategy, based on a risk score, in pregnancies with increased risk of VTE. Among 286 patients included in the study, 183 had a personal history of VTE (63.98%) and 191 patients (66.8%) had a thrombophilia marker. Eighty nine (46.6%) thrombophilic women had a personal history of VTE. Patients were assigned to one of three prophylaxis strategies according to the risk scoring system. In postpartum, all patients received low molecular weight heparin (LMWH) prophylaxis for at least 6 weeks. In antepartum, LMWH prophylaxis was prescribed to 61.8% of patients with high risk of VTE. Among them, 37.7% were treated in the third trimester only and 24.1% were treated throughout pregnancy. In this cohort, one antepartum-related VTE (0.35%) and two postpartum-related VTE (0.7%) occurred. No case of pulmonary embolism was observed during the study period. The rate of serious bleeding was 0.35%. There was no evidence of heparin-induced thrombocytopenia or osteoporosis. The use of a risk score may provide a rational decision process to implement safe and effective antepartum thromboprophylaxis in pregnant women at high risk of VTE.

The significance of heritable thrombophilia in pregnancy failure is controversial. We surveyed all UK Early Pregnancy Units and 70% responded. The majority test routinely for heritable thrombophilias; 80%, 76% and 88% undertook at least one screening test in late miscarriage, recurrent miscarriage and placental abruption, respectively. The range of thrombophilias sought is inconsistent: testing for proteins C and S deficiency and F5 R506Q (factor V Leiden) is most prevalent. Detection of heritable thrombophilia frequently leads to administration of antithrombotics in subsequent pregnancies. Thus, thrombophilia testing and use of antithrombotics are widespread in the UK despite controversies regarding the role of heritable thrombophilia in the pathogenesis of pregnancy complications, and the lack of robust evidence for the efficacy of antithrombotic therapy.

Thrombophilia can be identified in about half of all patients presenting with venous thrombosis. Testing has increased tremendously for various indications, but whether the results of such tests help in the clinical management of patients has not been settled. Here, we review the most commonly tested thrombophilic abnormalities, i.e. protein C, protein S, and antithrombin deficiencies, the F5 R506Q (factor V Leiden) and F2 G20210A (prothrombin G20210A) mutations, and elevated levels of coagulation factor VIII, and their association with venous and arterial thrombosis as well as pregnancy complications. We conclude that testing for hereditary thrombophilia generally does not alter the clinical management of patients with venous or arterial thrombosis or pregnancy complications. Because testing for thrombophilia only serves limited purpose this should not be performed on a routine basis.

Objectives: There is increasing evidence that inflammation and hypercoagulability play an important role in the pathophysiology of acute ischaemic stroke. We examined the in-hospital prognostic value on mortality of C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-alpha), fibrinogen and D-dimer in middle-aged ischaemic stroke patients., Materials and Methods: We recruited 231 consecutive patients <66 years with acute ischaemic stroke. CRP, TNF-alpha, fibrinogen and D-dimer levels were determined within 12 h from admission., Results: Fifteen (6.5%) patients died during hospitalization. CRP, fibrinogen and D-dimer levels were significantly higher in patients who died compared with those who survived but only CRP and fibrinogen were independently associated with death, after adjusting for various confounding factors. For 1 mg/l increase in CRP there was a 20% higher risk of dying while for 10 mg/dl increase in fibrinogen the additive risk was 18%. CRP levels >18 mg/l and fibrinogen levels >490 mg/dl were the optimal points that discriminated those who died from the rest., Conclusions: CRP and fibrinogen levels can predict independently the risk of early death in middle-aged ischaemic stroke patients emphasizing the role of inflammation and coagulation in the evolution of ischaemic stroke.

Laboratory testing for the identification of heritable thrombophilia in high-risk patient groups have become common practice; however, indiscriminate testing of all patients is unjustified. The objective of this study was to evaluate the cost-effectiveness of universal and selective history-based thrombophilia screening relative to no screening, from the perspective of the UK National Health Service, in women prior to prescribing combined oral contraceptives and hormone replacement therapy, women during pregnancy and patients prior to major orthopaedic surgery. A decision analysis model was developed, and data from meta-analysis, the literature and two Delphi studies were incorporated in the model. Incremental cost-effectiveness ratios (ICERs) for screening compared with no screening was calculated for each patient group. Of all the patient groups evaluated, universal screening of women prior to prescribing hormone replacement therapy was the most cost-effective (ICER 6824 pounds). In contrast, universal screening of women prior to prescribing combined oral contraceptives was the least cost-effective strategy (ICER 202,402 pounds). Selective thrombophilia screening based on previous personal and/or family history of venous thromboembolism was more cost-effective than universal screening in all the patient groups evaluated.

Objective: Venous sinus thrombosis (VST) is the second most common intracranial complication of acute otitis media (AOM). There is some evidence that hereditary and acquired prothrombotic disorders are risk factors for VST. The aim of the present study was to evaluate whether children with AOM complicated VST have a prothrombotic tendency, which might have important therapeutic and preventive implications., Study Design: Retrospective., Methods: The files of children hospitalized at Schneider Children's Medical Center of Israel, a tertiary referral center, from 1999 to 2002, because of AOM complicated by acute mastoiditis and VST were reviewed. All children underwent laboratory work-up for hypercoagulability., Results: Seven children met the study criteria. Of these, five had prothrombotic disorders, namely elevated levels of lipoprotein apolipoprotein (Lp[a]) (n = 4), antibodies to beta 2-glycoprotein and to cardiolipin (markers of antiphospholipid syndrome) (n = 4), and heterozygosity for factor V Leiden mutation (n = 1). One child had three abnormalities, two children had two abnormalities, and two children had one abnormality., Conclusions: A prothrombotic tendency may exist in children with AOM complicated by mastoiditis and VST. Further studies are needed to evaluate its extent.

In the present study, the Pro C(R) Global test was evaluated as a screening test for estimation of the activity of the main plasma components of the anticoagulant protein C (PC) / protein S (PS) pathway; 300 patients with a history of thrombosis were investigated for Pro C(R) Global. It was positive in 74 patients. Tests for estimation of PC, PS, activated protein C resistance (APCR), and lupus anticoagulant (LAC) were performed in all the patients with abnormal Pro C(R) Global and in 10 patients with normal Pro C(R) Global. In all, 66 of the 74 patients had a defect in PC/PS/APCR or LAC; 18 patients had both PC and PS deficiency, 25 had PS deficiency alone, 10 had PC deficiency alone, one had APCR alone, eight had PS, PC deficiency with APCR, and four had PS deficiency with APCR. In the 10 patients who tested negative with the Pro C(R) Global test, PC, APCR, and LAC were negative in all. However, PS deficiency was seen in two of them. The sensitivity and specificity of Pro C(R) Global, calculated with respect to positivity of PC, PS, LAC, or APCR as the gold standard, were 97% and 50%, respectively. The diagnostic accuracy of the assay was 88.1%. It is thus recommended that Pro C(R) Global can be used effectively as a screening test to detect abnormality in the PC/PS/APCR/LAC pathway., (Copyright 2003 Wiley-Liss, Inc.)

The association between malignancy and clinical thrombosis has been recognized for nearly 140 years. The purpose of this review is to examine our current understanding of thrombosis as a complication of cancer and cancer therapy. The review includes a discussion of the epidemiology, pathophysiology, diagnosis and treatment., (Copyright 2002 Wiley-Liss, Inc.)

These guidelines address developmental aspects of neonatal haemostasis and thrombosis, the laboratory investigation of the neonate, and the diagnosis and clinical management of haemostatic and thrombotic conditions occurring in this period (defined as the first 4 weeks of life following birth). Relevant scientific papers were identified by a systematic literature review from Medline 1975-2000 using index terms which incorporated the various component subjects of these guidelines. Further publications were obtained from the references cited and from reviews known to the members of the working party and to the Haemostasis and Thrombosis Task Force. Evidence and graded recommendations presented in these guidelines are in accordance with the US Agency for Health Care Policy and Research, as described in the Appendix. It will be noted that there is a lack of a strong evidence base for many of the recommendations suggested, as the appropriate clinical and laboratory trials have not been and perhaps never will be undertaken in neonates. Most of the recommendations are therefore of Grade C evidence levels IV: higher levels are mentioned specifically throughout the document when relevant.

Objectives: In this study the frequency of inherited thrombophilic risk factors in a population of German CVT patients and their influence on clinical outcome were evaluated., Material and Methods: Twenty-five patients (age 37.1 +/- 16.3 years) with CVT were screened for inherited coagulation disorders. All participants received a full clinical follow-up (mean follow-up period 4.8 +/- 6.4 years)., Results: Inherited thrombophilic risk factors were identified in 9 (36%) of the 25 patients studied. Four were found positive for the heterozygous factor V Leiden mutation, 2 were heterozygous carriers of the prothrombin-G20210A-polymorphism. APC resistance proved to be a reliable screening method for factor V Leiden mutation, whereas genetic evaluation for protein S and C deficiencies failed to demonstrate any mutations despite the identification of 1 patient with a protein C and protein S deficiency each. One patient suffered from a familial plasminogen deficiency. These 9 patients had a less favorable outcome (P < 0.05)., Conclusion: Our results demonstrate that screening for inherited thrombophilia should be an integral part in the diagnostic work up of CVT patients. Patients with inherited coagulopathies tended to have a less favorable outcome, corroborating recommendations for a longer period of oral anticoagulation.

An 11-y-old girl who presented with cellulitis and clinical signs of deep vein thrombosis (DVT) is reported here. She developed staphylococcal sepsis, recurrent septic emboli and a large vegetation on the tricuspid valve. The patient was found to be heterozygous for the Arg506Gln mutation in factor Va and had low levels of protein C and protein S during the sepsis. The coexistence of the two thrombophilic states may explain the severe thromboembolic manifestations.