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Background:Traditionally, a fibrinogen level > 1 g L−1has been viewed as the critical plasma concentration required for hemostasis. No definitive trial has investigated the plasma fibrinogen hemostatic threshold and fibrinogen replacement in complex surgical patients with acquired bleeding. Objectives:To explore the plasma fibrinogen level required for hemostasis in cardiothoracic surgery patients and assess the association of fibrinogen replacement therapy (using cryoprecipitate or fibrinogen concentrate) with reducing postoperative bleeding rate. Patients/Methods:Data from a prospectively collated database were used to examine the relationship between postoperative plasma fibrinogen level and the postoperative rate of bleeding within the hour of plasma fibrinogen measurement (n = 430) and to explore the effect of cryoprecipitate infusion (n = 76) or fibrinogen concentrate administration (n = 8) on postoperative bleeding rate. Results: A low plasma fibrinogen level was significantly associated with bleeding, with an odds ratio of 3.06 for every 1 g L−1decrease in fibrinogen (95% confidence interval 1.05–8.90) with adjustment for confounders. A fibrinogen threshold associated with excess bleeding was not identified, but this relationship was a continuum. There was no reduction in bleeding following administration of cryoprecipitate or fibrinogen concentrate to raise the post‐infusion fibrinogen level to a median of 2.00 and 1.70 g L−1, respectively. Conclusions:There is a continuum of bleeding severity with reducing fibrinogen concentration. Fibrinogen concentrate or cryoprecipitate infusion did not significantly reduce bleeding rate; however, confirmation by a randomized controlled trial is required. It remains uncertain whether low postoperative fibrinogen levels are causally associated with postoperative bleeding.

Orally active small molecules that selectively and specifically inhibit coagulation serine proteases have been developed for clinical use. Dabigatran etexilate, rivaroxaban and apixaban are given at fixed doses and do not require monitoring. In most circumstances, these drugs have predictable bioavailability, pharmacokinetic effects, and pharmacodynamic effects. However, there will be clinical circumstances when assessment of the anticoagulant effect of these drugs will be required. The effect of these drugs on laboratory tests has been determined in vitro by spiking normal samples with a known concentration of active compound, or ex vivo by using plasma samples from volunteers and patients. Data on the sensitivity of different reagents are now available, and so guidance as to the effect and interpretation of a test result is now possible. Laboratories should be aware of the sensitivity of their own assays to each drug. This may be achieved by using appropriate calibrated plasma samples.

Summary. Background:In patients with unprovoked venous thromboembolism (VTE), the optimal duration of anticoagulation is anchored on estimating the risk of disease recurrence.

Aim:To determine if the mode of presentation of venous thromboembolism (VTE), as deep vein thrombosis (DVT) or pulmonary embolism (PE), predicts the likelihood and type of recurrence. Methods:We carried out a patient‐level meta‐analysis of seven prospective studies in patients with a first VTE who were followed after anticoagulation was stopped. We used Kaplan‐Meier analysis to determine the cumulative incidence of recurrent VTE according to mode of presentation, and multivariable Cox regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for mode of and extent of DVT as potential risk factors for recurrence. Results:The 5‐year cumulative rate of recurrent VTE in 2554 patients was 22.6%. In 869 (36.1%) patients with PE, the 5‐year rate of any recurrence (DVT or PE) was 22.0%, and recurrence as PE was 10.6%. In 1365 patients with proximal DVT, the 5‐year recurrence rate was 26.4%, and recurrence with PE was 3.6%. The risk of recurrence as PE was 3.1‐fold greater in patients presenting with symptomatic PE than in patients with proximal DVT (HR, 3.1; 95% CI, 1.9–5.1). Patients with proximal DVT had a 4.8‐fold higher cumulative recurrence rate than those with distal DVT (HR, 4.8; 95% CI, 2.1–11.0). Conclusion:Whilst DVT and PE are manifestations of the same disease, the phenotypic expression is predetermined. Patients presenting with PE are three times more likely to suffer recurrence as PE than patients presenting with DVT. Patients presenting with calf DVT are at low risk of recurrence and at low risk of recurrence as PE.

The thrombophilia paradox whereby thrombophilia testing identifies defects associated with an increased risk of a first venous thrombosis but not of a particularly high risk of recurrence is likely the result of limitations imposed by a limited dichotomous testing strategy compounded by test inaccuracy and imprecision. Consequently, the observed intermediate phenotype (defined by limited laboratory test results) is not fully concordant with the heritable genotype. The next generation of thrombophilia tests, which utilize either individual genomic analysis or global measurement of the composite plasma intermediate phenotype, may more accurately quantify the thrombophilic risk. In conjunction with clinical risk assessment a more quantitative measurement of hypercoagulability and definition of the prothrombotic state should facilitate transition of clinical management from a disease‐focused to a more patient‐focused strategy.

Summary.Venous thromboembolism (VTE) comprises deep vein thrombosis (DVT) with or without symptomatic pulmonary embolus (PE). The incidence of a first episode of VTE is 1.5 per 1000 person-years [1] (J Thromb Haemost, 2007;5:692–9) with a per-person lifetime incidence of 5% [2] (Arch Intern Med1998;158:585–93). The risk of recurrence after DVT and PE is similar but the pattern of recurrence tends to reflect the initial event, for example recurrence with PE is more common in patients with previous PE [3] (Circulation2003;107:122–30). At least 50% of patients, who present with symptomatic DVT, have asymptomatic PE and conversely, a majority presenting with symptomatic PE have asymptomatic DVT [3] (Circulation2003;107:122–30). This suggests that whilst DVT and PE are manifestations of the same pathology, the phenotypic expression of the disease is predetermined. This may be an important consideration for long-term anticoagulant therapy as the risk of fatal PE is the greatest in patients with previous PE [4] (Ann Intern Med2007;147:766–74). At present, the only factor reported to be associated with the pattern of VTE is the factor V Leiden mutation [5] (Thromb Haemost1999;81:345–8). This suggests that the kinetics of thrombin generation and the resulting fibrinolytic response may influence clot structure and likelihood of embolization.

Objective:To determine the predictive value of measurement of parameters of thrombin generation for unprovoked recurrent venous thrombosis.Methods:Measurements were made of thrombin generation in a prospective cohort study of 188 patients with a first episode of venous thrombosis that was unprovoked, or provoked by a non‐surgical trigger.Results:The endogenous thrombin potential (ETP) was the only parameter associated with unprovoked recurrent thrombosis in a multivariate model [hazard ratio (HR) 1.3 per 100 nmol L min−1increase, 95% confidence interval (CI) 1.0–1.6]. Patients with a high ETP had a significantly higher rate of unprovoked recurrence than those with a low ETP (HR 2.9, 95% CI  1.3–6.6, cumulative recurrence at 4 years 27% vs. 11%). Patients with an unprovoked first event had a significantly higher rate of unprovoked recurrence than those with a provoking factor (HR 2.7, 95% CI  1.2–6.1), and in these patients there was a significantly higher rate of unprovoked recurrence in association with a high ETP (HR 4.0, 95% CI  1.3–11.8). After adjustment for D‐dimer, thrombophilia, sex, and whether or not the first event was unprovoked, a high ETP remained a significant predictor of recurrence (HR 2.6, 95% CI  1.2–6.0).Conclusions:This study demonstrates a high rate of unprovoked recurrent venous thrombosis in patients presenting with a first episode of venous thrombosis and a high ETP.

Background: The aim of the study was to determine the predictive value of D‐dimer measurement for unprovoked recurrent venous thrombosis and the influence of sex, age and type of first event (unprovoked or provoked). Methods: Prospective cohort study of 272 patients with a first episode of venous thrombosis that was unprovoked or provoked by a non‐surgical trigger. Findings: The cumulative rate of unprovoked recurrence in patients with a positive D‐dimer was 20% at 5 years [5.5/100 patient‐years, 95% confidence interval (CI) 3.7–7.8] and in patients with a negative D‐dimer 17% (4.1/100 patient‐years, 95% CI 2.3–6.9). The rates are not different (hazard ratio 1.3, 95% CI 0.7–2.5). After adjustment for clinical risk factors a positive D‐dimer result was significantly associated with an increased risk of unprovoked recurrent thrombosis (hazard ratio 2.0, 95% CI 1.01–3.9). The strongest indicator of risk of recurrence was male sex (hazard ratio 3.3 unadjusted and 2.9 after adjustment). The only determinant of D‐dimer in a linear regression model was age (P<0.001). Conclusions:The analysis indicates that clinical risk factors confound the association between D‐dimer and risk of recurrence and when adjusted for these confounders a positive D‐dimer result is significantly associated with unprovoked recurrence. The clinical utility of D‐dimer measurement in individual patients should be interpreted in conjunction with clinical risk factors.

Background: We have analyzed the influence of gender on risk of recurrence after a first episode of venous thromboembolism (VTE). Methods: The Cambridge Venous Thromboembolism Study (CVTE) is a single‐center study of a cohort of unselected patients with a first episode of objectively proven VTE. Results: Recurrence rates were significantly higher in men compared with women [log rank χ2 = 11.82; hazard ratio (HR) 2.66; 95% confidence interval (CI) 1.49, 4,77; P = 0.0006]. The cumulative recurrence rate at 2 years was 19.2% in men and 7.7% in women. There was no evidence of a difference in recurrence between men with or without thrombophilia (log rank χ2 = 0.03; HR 1.08; 95% CI 0.49, 2.37; P = 0.855). The high recurrence rate in men compared with women was still observed when only patients with idiopathic VTE were analyzed (log rank χ2 = 4.38; HR 2.31; 95% CI 1.027, 5.20; P = 0.0363). The recurrence risk was highest in men with a first idiopathic event at 25.7% compared with 11.7% for women in the same category. Conclusion: The risk of recurrent VTE is higher in men than in women.

Background:Measurement of thrombin generation by calibrated automated thrombography (CAT) could fulfill the requirements of a global test of coagulability and is potentially applicable to routine clinical laboratory practice. The purpose of this study was to determine if corn trypsin inhibitor (CTI) could be used to abolish contact factor activation in this assay, thus allowing accurate measurement of low tissue factor (TF) concentration‐triggered thrombin generation on samples taken in a routine clinical setting. Methods:The endogenous thrombin potential (ETP) was measured by CAT. Results:The study demonstrated that addition of CTI after plasma separation is not sufficient and blood must be drawn into tubes containing CTI if in‐vitrocontact factor‐activated thrombin generation is to be abolished. Contact factor‐activated thrombin generation is completely inhibited at a CTI concentration of 18.3 µg mL−1whole blood. Increasing the CTI concentration above this level does not lead to suppression of the TF‐triggered ETP. At a TF concentration of 2 pmol, ETPs were significantly lower in the presence of CTI (P <0.001). The difference (no CTI minus CTI) between results ranged from − 1 to 2159 nM min−1(median − 754). Whilst the low concentration TF‐ETP assay was not optimized to distinguish degrees of coagulability between patient samples, there was a significant difference in ETP between normal and hemophilia samples and samples from patients with a clinical prothrombotic tendency. Conclusions:CTI can be applied to ETP measurement by CAT. This permits the use of CAT in a low TF‐triggered thrombin generation assay without concern for the effect of interference from in‐vitrocontact factor activation and the optimum reagent conditions for using CAT as a global test of coagulability in clinical practice can now be defined.

SummaryThese guide‐lines provide a framework for the local arrangement of near patient testing (NPT) services for haematology tests. The guidance may be applied to medical and surgical units within hospitals (e.g. ITU, renal dialysis units, casualty) as well as general practitioners' surgeries, for blood counts and coagulation testing. The professional head of the central laboratory must take responsibility for all aspects of the NPT service, although there should be full discussion with the clinical departments involved and joint ownership of the results. NPT operators must be trained and accredited by the central laboratory. Equipment selected should normally have received a satisfactory evaluation report from the Medical Devices Agency (MDA), and should generate results that are comparable with those of the central laboratory. If a full MDA operation evaluation has not been performed, the purchaser should perform a local assessment according to the protocol in this document. The suitability of the equipment, imprecision, and comparability must be studied. The NPT equipment must be properly maintained and calibrated, and a record of patient identity, date and time of testing, reagent lot numbers, and operator must be kept. The central laboratory must participate in a suitable external quality assessment programme (EQA), and provide systems for EQA and internal quality control (IQC) of the NPT site.

Assessment of chronic hepatitis C virus infection requires a liver biopsy in most circumstances. There is a reluctance to perform liver biopsy in haemophiliacs because of a perceived risk of haemorrhage, although with adequate factor concentrate replacement in patients without factor concentrate inhibitors it should be safe. We report a 4-year experience of liver biopsy in patients with haemophilia infected with chronic hepatitis C virus. Of 55 patients seropositive for anti-HCV, 35 have undergone liver biopsy; the median age of this group was 33 years (range 13-68). Seven patients had a normal liver. 22 had portal tract inflammation, four with lymphoid aggregates. Mild piecemeal necrosis was observed in only two and no bile duct injury was found. 11 patients had mild mixed micro- and macro-vesicular fat. 19 patients had no evidence of fibrosis despite an estimated median duration of disease of 20 years (range 8-43). In the remaining 16 patients the maximum degree of fibrosis achieved was stage III. Patients with more significant fibrosis could not be identified on the basis of ALT or HCV RNA. There were no complications of liver biopsy in this series. Liver biopsy following a well-defined protocol in chronic hepatitis C virus haemophiliac carriers is safe in the absence of factor concentrate inhibitors. In this young group of patients without HIV infection there was no evidence of significant liver disease despite a considerable duration of disease. Performing liver biopsy allows accurate information to be given to the patient and avoids unnecessary therapy. The relative youth of this group may be important in the light of the benign histology.

Acute cellular rejection and hepatic vessel thrombosis are significant postoperative complications of liver transplantation. The study investigated changes in endothelial cell-related hemostatic proteins in the peripheral circulation of patients after liver transplantation, and assays for hemostatic parameters were compared with data from routine hematologic and biochemical investigations, together with clinical information.

OBJECTIVE--To determine whether HIV (Human Immunodeficiency Virus) antibody positive adults are capable of mounting an effective immune response when immunized with polyvalent pneumococcal vaccine. DESIGN--28 patients (nine homosexual men, one bisexual man, three heterosexual females, 10 injecting drug abusers, five haemophiliacs) and 11 healthy volunteers, were immunised with Pneumovax II and titres of IgG1 and IgG2 specific antibody measured before and 1 month after immunisation. Magnitude of immune response was related to CD4 T-lymphocyte count at time of immunisation to establish whether responses are better in early disease. MAIN OUTCOME MEASURES--Based on our data in healthy volunteers we defined an adequate response to Pneumovax II as a post immunisation IgG2 antibody level at least 50% greater than the pre immunisation level. RESULTS--The magnitude of the response was significantly higher in the normal volunteers (U = 95; p = 0.0328). Adequate IgG2 responses were seen in 11/11 normals but in only 14/28 HIV seropositives (chi 2 = 8.58; p < 0.01). Poor responses were unrelated to the CD4 T-lymphocyte count at immunisation. Absolute IgG2 deficiency accounted for the poor response in only 1 HIV patient. CONCLUSION--50% of HIV antibody seropositive individuals fail to mount adequate immune responses to polyvalent pneumococcal vaccine. Non responders are unlikely to be protected. [ABSTRACT FROM PUBLISHER]