Jennifer Curnow

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.

Reduced fibrinolysis and increased fibrin generation can be detected in hypercoagulable patients using the overall hemostatic potential assay

Background: Routinely available coagulation assays are not capable of detecting clinically defined hypercoagulable states. A number of global coagulation assays have been developed with the potential to evaluate hypercoagulability, which predisposes to the common clinical events of arterial and venous thromboembolism (VTE). Objectives: We hypothesized that the overall hemostatic potential (OHP) assay would show abnormal fibrin generation and lysis in patients with clinically defined hypercoagulable states. Methods: We used the OHP assay as described by Blombäck and colleagues [ 1,2 ] in 161 clinically hypercoagulable patients with arterial or VTE, pregnancy complications or autoimmune disease. Eighty patients had associated antiphospholipid antibodies (APLA). Ninety‐eight normal plasma donors were tested for comparison. Results: We derived three new assay parameters for correlation with hypercoagulable states: the maximum optical density, maximum slope, and delay in onset of fibrin generation. We found significantly different assay results for all patients’ parameters examined when compared with controls, indicating both increased fibrin generation and reduced fibrinolysis in hypercoagulable patients. The findings were similar whether samples were collected in association with an acute thrombotic event or not. Estimated assay sensitivity for detection of a clinically defined hypercoagulable state was 96%. Conclusions: The OHP assay is a simple, inexpensive global test that is useful for assessing patients with hypercoagulable states including APLA. OHP results are significantly abnormal in hypercoagulable groups compared with controls, indicating that both increased fibrin generation and reduced fibrinolysis contribute to hypercoagulable states. The assay may ultimately assist in tailoring clinical management to patients’ individual requirements.

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.

Treatment of von Willebrand Disease

Congenital von Willebrand disease (VWD) and acquired von Willebrand syndrome (AVWS) reflect conditions caused by von Willebrand factor (VWF) deficiency and/or defects. VWD is the most common inherited bleeding disorder and AVWS arises from a variety of causes. Since VWF stabilizes and protects factor VIII (FVIII) in the circulation, this is also reduced in many patients with VWD. The treatment of VWD and AVWS therefore primarily entails replacement of VWF, and sometimes FVIII, to protect against bleeding. This may entail the use of VWF concentrates (currently plasma-derived) and/or FVIII concentrates (currently plasma-derived or more increasingly recombinant forms), and/or desmopressin to release endogenous VWF in subgroups of patients. For AVWS additional treatment of the underlying condition is also required. Adjunct therapies include antifibrinolytics. Globally, various formulations exist for both VWF and FVIII concentrates and are differentially available based on manufacturer marketing or regulatory approvals/clearances in different geographies. Also, guidelines for treatment of VWD vary for different localities and recombinant VWF is undergoing clinical trials. The current review provides an overview of the treatment of VWD as currently practiced in developed countries, and also provides a glimpse towards the future.

Detection of hypofibrinolysis in stable coronary artery disease using the overall haemostatic potential assay

INTRODUCTION Patients with stable coronary artery disease (CAD) are at risk of arterial thrombosis causing myocardial infarction. Detection of global haemostatic markers of hypercoagulability and hypofibrinolysis may be important for risk stratification and individualised treatment. We examined overall haemostatic potential (OHP) and thrombin generation in a group of stable CAD patients. We also sought to investigate associations between fibrinolytic inhibitors and abnormal global fibrinolysis in these patients. MATERIALS AND METHODS Blood samples were collected from 56 patients defined by coronary anatomy as symptomatically stable CAD. Medications were recorded. Samples were analysed using the global coagulation assays OHP and thrombin generation (calibrated automated thrombogram, CAT), platelet aggregometry measured by Multiplate®, and levels of plasminogen activator inhibitor-1 (PAI-1) antigen measured by ELISA. Results were compared with a reference group of healthy controls. RESULTS Stable CAD patients displayed increased fibrin and thrombin generation and impaired fibrinolysis (decreased overall fibrinolytic potential, OFP, and increased clot lysis time) compared with healthy controls. No effect of antiplatelet agents or other medications on these parameters was observed using platelet-poor plasma. After multivariate adjustment, OFP of healthy individuals was significantly associated with fibrinogen, but in CAD patients PAI-1 became an important determinant. CONCLUSIONS Hypercoagulability of plasma is observed in stable CAD, with both increased thrombin generation and reduced fibrinolytic potential making a significant contribution. The OHP assay may provide a simple method of identifying hypercoagulability in individual patients.

Monitoring Therapy during Treatment of von Willebrand Disease

&NA; von Willebrand factor (VWF) is an adhesive plasma protein that primarily acts to bridge platelets to sites of vascular injury and thus prevent bleeding. von Willebrand disease (VWD) is the most common inherited bleeding disorder and is caused by deficiency and/or defects of VWF, leading to low levels of plasma VWF or dysfunctional VWF. Factor VIII (FVIII) is also reduced in many patients with VWD, since VWF stabilizes and protects FVIII from degradation. Treatment of VWD primarily entails replacement of VWF, and sometimes FVIII, to protect against bleeding. This may entail use of VWF/FVIII concentrates, and/or desmopressin (1‐deamino‐8‐D‐arginine vasopressin) to release endogenous VWF in some patients. Adjunct therapies include antifibrinolytics and hormonal therapies in women. Optimal treatment of VWD entails measuring the effects of treatment, either as a trial before surgery or during therapeutic management. This is usually accomplished by performance of the same tests that are used to help diagnose VWD, although additional monitoring (clinically and/or by laboratory testing) may also be performed. The current review provides an overview of the treatment of VWD but is primarily focused on the monitoring of such therapy.

Global hypercoagulability in patients with schizophrenia receiving long-term antipsychotic therapy

BACKGROUND Patients with schizophrenia are at increased risk of venous thromboembolism. The mechanisms underlying this association are poorly understood. AIMS We investigated whether there is a global hypercoagulable state in patients with schizophrenia utilising the overall haemostatic potential (OHP) assay which assesses overall coagulation potential (OCP), haemostatic potential (OHP) and fibrinolytic potential (OFP). METHOD Citrated plasma was collected for OHP assays from patients with schizophrenia on long-term antipsychotic treatment and compared with healthy age- and sex-matched controls. Time courses of fibrin formation and degradation were measured by spectrophotometry (absorption of 405nm) after the addition of tissue factor and tissue plasminogen activator to plasma. RESULTS Ninety patients with schizophrenia (antipsychotic treatment-15.9±9.7years) and 30 controls were recruited. Patients with schizophrenia had higher rates of smoking and levels of inflammatory markers (high-sensitivity C-reactive protein and neutrophil-to-lymphocyte ratio) than controls. Whilst D-dimer, fibrinogen and platelet count did not differ between patients with schizophrenia and controls, the OCP (54.0±12.6 vs 45.9±9.1, p=0.002) and OHP (12.6±5.8 vs 7.2±3.7, p<0.001) were higher, and OFP was lower (76.6±9.8% vs 84.9±6.4%, p<0.001) in patients with schizophrenia, implying both a hypercoagulable and hypofibrinolytic state in these patients. Importantly, abnormalities in overall coagulation were independently predicted by levels of plasminogen-activator-inhibitor-1, fibrinogen, platelet count, inflammatory markers and plasma triglycerides, suggesting a multifactorial aetiology. CONCLUSION Patients with schizophrenia have evidence of a global hypercoagulable and hypofibrinolytic state which may contribute to their increased risk of venous thromboembolism.

Acute pulmonary embolism during warfarin therapy and long-term risk of recurrent fatal pulmonary embolism

The clinical characteristics and long-term outcomes of patients presenting with acute pulmonary embolism (PE) during treatment with warfarin have not been described. Clinical details of all patients admitted to a tertiary institution from 2000-2007 with acute PE were retrieved retrospectively, baseline warfarin status and the international normalised ratio (INR) were recorded, and their outcomes tracked using a statewide death registry. Of 923 patients with clearly documented warfarin status included in this study, 83 (9%) were taking warfarin. Mean (± standard deviation) day-1 INR of those taking warfarin was 2.3 ± 0.9, with 67% of patients therapeutically anti-coagulated (INR ≥2.0) at presentation (49 patients with INR <2.5 and 34 with INR ≥2.5). Patients taking warfarin on admission were more likely to have heart failure, atrial fibrillation and valvular heart disease, with similar prevalence of malignancy and ischaemic heart disease, compared to patients not on warfarin. Total mortality of the cohort (mean follow-up 4.0 ± 2.5 years) was 31.6% (in-hospital mortality 1.5%), and was similar between warfarin and no warfarin groups. There was however a greater than four-fold increased risk of post-discharge death due to recurrent PE for the patients taking warfarin on admission (hazard ratio [HR] 4.43, 95% confidence interval [CI] 1.36-14.42, p=0.01). Among patients taking warfarin on admission, day-1 INR <2.5 significantly increased long-term all-cause mortality compared to INR ≥2.5 (adjusted HR 2.51, 95% CI 1.08-5.86, p=0.03). In conclusion, patients presenting with PE during treatment with warfarin have an increased risk of death from recurrent PE. Admission INR appears to have independent long-term prognostic importance in these patients.

Persistent global hypercoagulability in long-term survivors of acute pulmonary embolism.

Hypercoagulable and/or hypofibrinolytic states are risk factors for venous thromboembolism (VTE) including acute pulmonary embolism. Current screening for thrombophilia is targeted towards identifying a specific defect and guidelines recommend a population-based rather than individualized strategy for anticoagulation treatment. We investigated whether there is a global hypercoagulable state in long-term survivors of pulmonary embolism no longer receiving therapeutic anticoagulation utilizing the overall haemostatic potential (OHP) assay, which assesses overall coagulation potential (OCP), OHP and overall fibrinolytic potential (OFP). Long-term survivors of acute pulmonary embolism were identified from a local registry and OHP assays were performed and compared with age and sex-matched controls without pulmonary embolism. Time courses of fibrin formation and degradation were measured by spectrophotometry (absorption 405 nm) after addition of tissue factor and tissue plasminogen activator to plasma. OHP assays were performed in 67 long-term survivors of single pulmonary embolism (7.9 ± 1.4 years after pulmonary embolism) and 20 age (61.7 ± 11.2 vs 56.6 ± 6.4 years, P = 0.06) and sex (P = 0.45)-matched controls. Survivors of pulmonary embolism were more hypercoagulable as reflected by significantly higher OCP (56.4 ± 13.0 vs 49.9 ± 6.9, P = 0.03) and had impaired fibrinolysis with higher OHP (12.6 ± 7.0 vs 5.9 ± 2.0, P < 0.001) and lower OFP (78.1 ± 9.4 vs 88.2 ± 2.9, P < 0.001) compared with controls. Importantly, these abnormalities in overall coagulation were independently predicted by levels of fibrinogen, platelet count, shortened activated partial thromboplastin time and inflammatory markers suggesting a multifactorial cause. Long-term survivors of pulmonary embolism demonstrate enhanced global coagulation and reduced fibrinolytic potential. Assessment of global coagulation may provide new insights into the aggregate effects of multiple prothombotic factors and long-term risk of VTE recurrence.

Histoplasma capsulatum in peripheral blood smears

A 39-year-old man with acquired immunodeficiency syndrome (AIDS; CD4 count 10 x 10 12 / 1) presented with weight loss, fevers and pancytopenia, with Hb 7·1 g / dl, platelet count 72 x 10 9 x l and white cell count 1·8 x 10 9 / l. A peripheral blood film revealed occasional circulating neutrophils containing intracytoplasmic oval, yeast-like organisms approximately 3 μm in length (top). Large numbers of yeast cells were present in association with mononuclear cells on buffy coat preparation (bottom), and within histiocytes and fat lobules on subsequent bone marrow trephine biopsy. Microbiological cultures of the bone marrow sample grew Histoplasma capsulatum variant capsulatum. With the institution of amphotericin B, fevers resolved and the peripheral blood count slowly recovered over the subsequent 6 weeks.