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Dabigatran is an oral direct thrombin inhibitor (DTI) licensed for stroke prevention in atrial fibrillation and likely to be soon approved in Europe for treatment of venous thrombosis. Predictable pharmacokinetics and a reduced risk of intracranial haemorrhage do not negate the potential risk of haemorrhage. Unlike warfarin, there is no reversal agent and measurement of the anticoagulant effect is not 'routine'. The prothrombin time/international normalised ratio response to dabigatran is inconsistent and should not be measured when assessing a patient who is bleeding or needs emergency surgery. The activated partial thromboplastin time (APTT) provides a qualitative measurement of the anticoagulant effect of dabigatran. Knowledge of the time of last dose is important for interpretation of the APTT. Commercially available DTI assays provide a quantitative measurement of active dabigatran concentration in the plasma. If a patient receiving dabigatran presents with bleeding: omit/delay next dose of dabigatran; measure APTT and thrombin time (consider DTI assay if available); administer activated charcoal, with sorbitol, if within 2 h of dabigatran ingestion; give tranexamic acid (1 g intravenously if significant bleeding); maintain renal perfusion and urine output to aid dabigatran excretion. Dabigatran exhibits low protein binding and may be removed by dialysis. Supportive care should form the mainstay of treatment. If bleeding is life/limb threatening, consider an additional haemostatic agent. There is currently no evidence to support the choice of one haemostatic agent (FEIBA, recombinant factor VIIa, prothrombin complex concentrates) over another. Choice will depend on access to and experience with available haemostatic agent(s).

Introduction: 'Safety indicators' in the anticoagulant management of atrial fibrillation (AF) are listed in the UK NHS Improvement Document, 'Anticoagulation for AF', aiming to promote quality services. Acceptable clinical event rates are not quantified in the document., Objective: To provide clinical evaluation of the relevant safety indicators using data from a recent large European Action on Anticoagulation (EAA) study., Results: 469 clinical events were recorded in 5839 outpatients in the EAA study. The safety indicators listed in the NHS Improvement Document were related to these patients with AF. The relevance of the 'safety indicators' is confirmed by the EAA study for patients starting oral anticoagulation and for those already receiving oral anticoagulation, and quantified., Conclusion: The EAA clinical study provides a quantitative basis for the safety indicators' in AF listed in the NHS Commissioning Support Document and emphasises the importance of the document.

Heparin induced thrombocytopenia thrombosis (HIT/T) is associated with a high morbidity and mortality. Diagnosis is essentially clinical and negative results of laboratory assays do not exclude the diagnosis. Treatment involves stopping all heparin immediately and giving an alternative thrombin inhibitor. The adoption of low molecular weight heparins is one reason for the reduced incidence of this disease in recent years.

This study aimed to determine the frequency of fatal pulmonary emboli in hospitalised medical patients by a retrospective necropsy review and prospective non-interventional patient follow up study. The main outcome measure, necropsy proven fatal pulmonary embolism, was determined from 400 consecutive necropsy records and 200 consecutive medical inpatient episodes. Fatal pulmonary embolism was recorded in 29 of 400 necropsies; 17 were medical patients. Thirty one of 200 consecutive medical patients died. Fourteen necropsies were performed and revealed pulmonary embolism as the cause of death in five patients. The incidence of necropsy proven fatal pulmonary embolism was therefore 2.5% (95% confidence intervals 0.8% to 5.7%). Therefore, one in 40 medical patients had pulmonary embolism recorded as the cause of death at necropsy. As the necropsy rate was only 45% the incidence of fatal pulmonary embolism may be greater. There is, therefore, a need to perform more large prospective studies to confirm the incidence of fatal pulmonary embolism in medical patients and to identify risk factors and effective antithrombotic prophylaxis.

Aim: To determine the prevalence of a biochemically detectable hypercoagulable state, defined in terms of increased thrombin or plasmin generation, in patients with phenotypically characterised thrombophilia., Methods: Plasma concentrations of the prothrombin activation peptide F1.2 and fibrin degradation (FbDP) and fibrinogen degradation products (FgDP) were measured by enzyme immunoassay in 104 patients deficient in natural anticoagulants, and 35 unaffected relatives., Results: Increased concentrations of F1.2, FbDP, and FgDP were present in 18, 25, and 19 of 104 patients, respectively. There were no correlations between F1.2, FbDP, and FgDP concentrations, or between these parameters and concentrations of natural anticoagulants except for a negative correlation between protein C concentrations and FgDP (rho = -0.46, p = 0.009)., Conclusion: A biochemically detectable hypercoagulable state is present in some patients with asymptomatic thrombophilia. Markers of plasmin generation may be increased more frequently in thrombophilia than markers of thrombin generation. This finding should prompt the inclusion of markers of plasmin generation in prospective longitudinal cohort studies to determine the predictive value of a hypercoagulable state, defined by either excessive thrombin or plasmin generation, for the development of venous thromboembolism.

The Ciba Corning Biotrack 512 coagulation monitor requires a minimal degree of technical expertise to operate, and is already in use for near-patient testing. This study evaluated the monitor for possible use in decentralised control of oral anticoagulant treatment. The monitor compared well with Manchester Reagent, suggesting that it could be used in areas where this thromboplastin is used for centralised control. The inability of the monitor to allow for locally determined geometric mean normal prothrombin times in the calculation of the International Normalised Ratio (INR), and possibly the high International Sensitivity Index (ISI) of the thromboplastin used with the monitor, resulted in poor comparability with some other thromboplastins, particularly Thrombotest. These problems need to be addressed if the monitor is to be used for decentralised anticoagulant control.

The plasma of patients with myeloproliferative diseases was examined by polyethylene glycol (PEG) precipitation, analytical ultracentrifugation, and immunoaffinity chromatography for the presence of high molecular weight complexes of IgG and fibronectin. Abnormal circulating high molecular weight material was identified by ultracentrifugation in all patients. This was precipitated by PEG and was shown by exclusion chromatography to contain IgG in a high molecular weight form. Examination of plasma by immunoaffinity chromatography supported previous evidence for complex formation between IgG and fibronectin. These findings are further evidence that abnormal high molecular weight IgG complexes are a prominent feature of myeloproliferative disorders and implicate IgG fibronectin complex formation.

The incidence of mucocutaneous herpes simplex virus infection confirmed by culture and occurring during febrile neutropenic episodes was determined in 43 patients with haematological malignancy. The outcome of 72 episodes of neutropenic fever was determined and correlated with the presence or absence of herpes simplex virus (HSV) infection. Twenty four patients had mucocutaneous HSV infection during at least one episode. In 24 episodes in which HSV was isolated only 12.5% of fevers responded to antibiotics and 75% of fevers were otherwise unexplained. Conversely, in 48 episodes of neutropenic fever in which HSV was not isolated 67% of fevers responded to antibiotics and only 8.3% were unexplained. The difference in incidence of antibiotic resistant fever in the two groups was significant. There was, therefore, a strong association between mucocutaneous HSV infection and antibiotic resistant fever in immunosuppressed neutropenic patients. As most HSV infections are the result of virus reactivation, establishing the HSV serological state of patients would identify those at risk of infection and hence those in whom the prophylactic use of acyclovir would be indicated.

High concentrations of circulating immune complexes were detected by polyethylene glycol precipitation in 11 of 20 patients with myelofibrosis secondary to chronic myeloproliferative disease. Circulating immune complexes showed a positive correlation with plasma IgG concentrations both in patients and controls. Covariance analysis of the two groups showed significantly increased polyethylene glycol precipitable IgG in patients when adjusted for plasma IgG concentrations, indicating that the patients had significantly increased concentrations of complexed IgG. The immune complexes contained IgG, C3, and fibronectin and were inversely correlated with plasma fibronectin concentrations, suggesting that this major non-specific opsonin is important for the normal clearance of immune complexes. Therapeutic plasmapheresis efficiently removed circulating complexes and produced an increase in plasma fibronectin. This suggests that plasmapheresis may be useful for controlling immune complex mediated complications of these disorders.