Laura Young

Bleeding risk with dabigatran in the frail elderly.

In an audit of patients who had bleeding events during treatment with dabigatran, common factors included advanced age, impaired renal function, low body weight, and prescriber error.

Idarucizumab for Dabigatran Reversal — Full Cohort Analysis

Background Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran. Methods We performed a multicenter, prospective, open‐label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures. Results A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals. Conclusions In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE‐VERSE AD ClinicalTrials.gov number, NCT02104947.)

New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management

New oral anticoagulants (NOAC) are becoming available as alternatives to warfarin to prevent systemic embolism in patients with non‐valvular atrial fibrillation and for the treatment and prevention of venous thromboembolism. An in‐depth understanding of their pharmacology is invaluable for appropriate prescription and optimal management of patients receiving these drugs should unexpected complications (such as bleeding) occur, or the patient requires urgent surgery. The Australasian Society of Thrombosis and Haemostasis has set out to inform physicians on the use of the different NOAC based on current available evidence focusing on: (i) selection of the most suitable patient groups to receive NOAC, (ii) laboratory measurements of NOAC in appropriate circumstances and (iii) management of patients taking NOAC in the perioperative period, and strategies to manage bleeding complications or ‘reverse’ the anticoagulant effects for urgent invasive procedures.

Recommendations for the diagnosis and treatment of deep venous thrombosis and pulmonary embolism in pregnancy and the postpartum period

Venous thromboembolism (VTE) in pregnancy and the postpartum is an important cause of maternal morbidity and mortality; yet, there are few robust data from clinical trials to inform an approach to diagnosis and management. Failure to investigate symptoms suggestive of pulmonary embolism (PE) is a consistent finding in maternal death enquiries, and clinical symptoms should not be relied on to exclude or diagnose VTE. In this consensus statement, we present our recommendations for the diagnosis and management of acute deep venous thrombosis (DVT) and PE. All women with suspected DVT in pregnancy should be investigated with whole leg compression ultrasonography. If the scan is negative and significant clinical suspicion remains, then further imaging for iliofemoral DVT maybe required. Imaging should be undertaken in all women with suspected PE, as the fetal radiation exposure with both ventilation/perfusion scans and CT pulmonary angiography is within safe limits. Low‐molecular‐weight heparin (LMWH) is the preferred therapy for acute VTE that occur during pregnancy. In observational cohort studies, using once‐daily regimens appears adequate, in particular with the LMWH tinzaparin; however, pharmacokinetic data support twice‐daily therapy with other LMWH and is recommended, at least initially, for PE or iliofemoral DVT in pregnancy. Treatment should continue for a minimum duration of six months, and until at least six weeks postpartum. Induction of labour or planned caesarean section maybe required to allow an appropriate transition to unfractionated heparin to avoid delivery in women in therapeutic doses of anticoagulation.

Recommendations for the prevention of pregnancy-associated venous thromboembolism.

Pregnancy is a risk factor for venous thromboembolism (VTE), an important cause of maternal morbidity and mortality. Although there is a 4–5‐fold increased risk compared to that of nonpregnant women of the same age, the absolute risk is low at no more than two episodes of VTE per 1000 pregnancies. There is uncertainty about which women require thromboprophylaxis during pregnancy or postpartum because of a lack of data from appropriate clinical trials. For this reason, recommendations for prophylaxis should be made only after explaining the available evidence to the patient and taking into account her perception of the balance of risk and benefit in thromboprophylaxis. The aim of these recommendations is to provide clinicians with practical advice to assist in decisions regarding thromboprophylaxis in women considered to be at risk of VTE during pregnancy and the postpartum. The authors are clinicians from across New Zealand and Australia representing the fields of haematology, obstetric medicine, anaesthesiology, maternal–fetal medicine and obstetrics. Authors were invited to review the relevant literature and then worked collaboratively to devise recommendations and resolve areas of controversy. The recommendations contained herein were reached by consensus and represent the opinion of the panel. The absence of randomised clinical trials in this area limits the strength of evidence that can be used, and it is acknowledged that they represent level C evidence. The panel advocates for appropriate clinical studies to be carried out in this patient population to address the inadequacy of present evidence.

New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Australasian Society of Thrombosis and Haemostasis.

New oral anticoagulants (NOAC) are becoming available as alternatives to warfarin to prevent systemic embolism in patients with non‐valvular atrial fibrillation and for the treatment and prevention of venous thromboembolism. An in‐depth understanding of their pharmacology is invaluable for appropriate prescription and optimal management of patients receiving these drugs should unexpected complications (such as bleeding) occur, or the patient requires urgent surgery. The Australasian Society of Thrombosis and Haemostasis has set out to inform physicians on the use of the different NOAC based on current available evidence focusing on: (i) selection of the most suitable patient groups to receive NOAC, (ii) laboratory measurements of NOAC in appropriate circumstances and (iii) management of patients taking NOAC in the perioperative period, and strategies to manage bleeding complications or ‘reverse’ the anticoagulant effects for urgent invasive procedures.

Thrombosis on a Mechanical Aortic Valve whilst Anti-coagulated With Dabigatran

There is currently limited evidence on the safety and efficacy of novel oral anticoagulants in patients with mechanical heart valves. This case report describes a patient with a St Jude aortic valve replacement who suffered valve thrombosis and an embolic stroke when anti-coagulated with the direct thrombin inhibitor dabigatran etexilate.

Audit of community‐based anticoagulant monitoring in patients with thromboembolic disease: is frequent testing necessary?

Oral anticoagulant monitoring is managed by general practitioners in Auckland. An audit of this service in 452 patients demonstrated that anticoagulant control was in line with recommended international guidelines, with 58.3% of international normalized ratio (INR) measurements in the therapeutic range. However, the frequency of testing was high, with the majority of patients (68%), including those on long‐term treatment, having INR measurements at weekly intervals. We question the need for such frequent INR testing. (Intern Med J 2004; 34: 639−641)

Survival in patients with malignancy and venous thromboembolism by tumour subtype and thrombus location

Background:  Although the association between malignancy and venous thromboembolism (VTE) is firmly established, less is known about the survival following VTE among different malignant subtypes.

Two missense mutations identified in venous thrombosis patients impair the inhibitory function of the protein Z dependent protease inhibitor.

Protein Z-dependent protease inhibitor (ZPI) is a plasma inhibitor of factor (F)Xa and FXIa. In an earlier study, five mutations were identified within the ZPI gene of venous thrombosis patients and healthy controls. Two of these were nonsense mutations and three were missense mutations in important regions of the protein. Here we report that two of these latter three mutations, F145L and Q384R, impair the inhibitory function of ZPI in vitro. Recombinant wild-type and mutant proteins were prepared; stability in response to thermal challenge was similar. Inhibition of FXa in the presence of the cofactor protein Z was reduced 68-fold by the Q384R mutant; inhibition of FXIa by the F145L mutant was reduced two- to three-fold compared to the wild-type ZPI. An analysis of all five ZPI mutations was undertaken in a cohort of venous thrombosis patients (n=550) compared to healthy controls (n=600). Overall, there was a modest increase in incidence of these mutations in the thrombosis group (odds ratio 2.0, 1.05-3.7, p=0.044). However, in contrast to W324X (nonsense mutation), the Q384R missense mutation and R88X nonsense mutation were evenly distributed in patients and controls; F145L was rare. The final mutation (S143Y) was also rare and did not significantly alter ZPI function in laboratory studies. The F145L and particularly the Q384R mutation impaired the function of the coagulation inhibitor ZPI; however, there was no convincing association between these mutations and venous thrombosis risk. The functional role for ZPI in vivo has yet to be clarified.