Prahlad Ho

Direct oral anticoagulants in frail older adults: a geriatric perspective.

Direct oral anticoagulants (DOACs) have changed the paradigm of anticoagulation management, improving patient convenience as well as possibly reducing the incidence of spontaneous intracranial hemorrhage. However, concerns remain with these agents because of the lack of monitoring capacity and availability of readily accessible specific antidotes. This is particularly pertinent in the older population, specifically the frail older adults who have multiple comorbidities, higher risk of falls, and increased bleeding risk. This group has not been specifically studied in the DOAC randomized controlled trials and, hence, extrapolation of these data into this population should be done cautiously. We provide a review of the use of DOACs in the older frail population from both hematological and geriatric perspectives, as well as propose an algorithm for how these agents may be used in this frail population.

High-Dose Methotrexate for the Treatment of Relapsed Central Nervous System Erdheim-Chester Disease

Erdheim-Chester disease (ECD) is a rare multisystem non-Langerhans histiocytosis. CNS involvement is a major complication, which is often rapidly progressive and confers a poor prognosis. However, treatment of CNS ECD is difficult due to poor CNS penetrance by the most effective chemotherapeutic drugs commonly used in this disorder (e.g., interferon and cladribine). We describe a case of a 60-year-old lady with a 5-year history of stable systemic ECD who presented with new brainstem lesions and rapid, steroid-refractory neurological deterioration which required immediate intervention. High-dose methotrexate was chosen due to its rapid onset of action and excellent CNS penetration. Her neurological deterioration was quickly arrested with significant functional improvement, which was sustained for 4 months with consolidation doses of high-dose methotrexate. Subsequent treatment with cladribine and interferon did not confer any appreciable clinical improvement. High-dose methotrexate is effective in controlling rapidly progressive CNS ECD and should be considered as a salvage agent prior to commencement of more definitive treatment.

Retrospective review on isolated distal deep vein thrombosis (IDDVT) — A benign entity or not?

INTRODUCTION Isolated distal deep venous thrombosis (IDDVT) is traditionally associated with less severe clinical sequelae, with ongoing debate on multiple aspects of its management. Despite numerous studies evaluating its acute management, there remains a paucity of data evaluating long-term complications such as recurrence and subsequent malignancy. We aim to evaluate the characteristics of IDDVT in institutions that routinely perform whole leg ultrasonography, and the risks of recurrence and complications in comparison to major venous thromboembolism (major VTE; defined as above-knee or proximal DVT and pulmonary embolism (PE)). METHODS Retrospective evaluation of consecutive IDDVT and major VTE from July 2011 to December 2012 in a hospital network in Melbourne, Australia. Patients were followed up for a minimum of 24months. Patients with active malignancy were excluded. RESULTS Of 1024 VTE cases, there were 164 non-cancer patients (92 males, 72 females, median age of 61years) with IDDVT. Compared to major VTE, IDDVT was more likely to be provoked (73% vs 59%, p<0.01), has shorter duration of anticoagulation (median 3.5months vs 6.0months, p<0.01) and less clinically significant bleeding (2.4% vs 6.7%, p=0.05), independent of duration of therapy. Recurrence was non-inferior compared to major VTE (10% vs 7%, p=0.36) and 60% recurred with major VTE. Three (1.8%) were subsequently diagnosed with cancer (vs 1.9% in major VTE, p=0.97). CONCLUSIONS IDDVT has non-inferior rates of recurrence and subsequent cancer detection compared to major VTE and hence, its clinical significance should not differ from major VTE. Further studies are required to determine the adequate length of anticoagulation.

New oral anticoagulants: an approach in older people

New oral anticoagulants have changed the paradigm of anticoagulation management, improving patient convenience as well as possibly reducing the incidence of spontaneous intracranial haemorrhage. However, concerns remain regarding these agents due to the lack of monitoring capacity and availability of readily accessible specific antidotes. This is particularly pertinent in the older population, specifically the frail elderly, who have multiple comorbidities, higher risk of falls requiring intervention and increased risk of bleeding. This group has not been specifically studied in randomised controlled trials and hence extrapolation of trial data to this population should be done carefully. No national guidelines exist for the safe prescription and monitoring of new oral anticoagulants in frail older people. In this article, we provide a review of the currently available new oral anticoagulants in Australia, with a geriatric haematological perspective, including evidence from clinical trials and subsequent meta‐analyses, the concerns regarding these new agents, and how these impact on the older population.

Retrospective evaluation of venous thromboembolism: Are all transient provoking events the same?

Venous thromboembolism (VTE) provoked by transient risk factors has traditionally been classified as a single entity with lower risk of recurrence. We evaluated the association between different categories of transient provoking factors and the relative risk of recurrence.

Venous thromboembolism management in Northeast Melbourne: how does it compare to international guidelines and data?

Venous thromboembolism (VTE) is a major cause of morbidity and mortality with significant heterogeneity in its management, both within our local practice and in international guidelines.

Thrombin generation estimates the anticoagulation effect of direct oral anticoagulants with significant interindividual variability observed

&NA; Direct oral anticoagulants (DOACs) are increasingly being used, primarily due to their drug stability and patient convenience. Although these drugs have been evaluated to be well tolerated in numerous clinical trials, their impact on in-vivo anticoagulation effect, variability and therapeutic drug level remains unknown. Hence, we aim to study the effect and variability of DOACs on thrombin generation via the calibrated automated thrombogram. Anonymized coagulation specimens from outpatients on warfarin were collected. Pooled normal plasma samples were spiked with increasing concentrations of dabigatran, rivaroxaban and apixaban. Similarly, plasma samples with normal coagulation profiles were spiked with two concentrations each of dabigatran, rivaroxaban and apixaban. Thrombin generation via calibrated automated thrombogram was run using the above samples and compared with a dataset of normal controls. Increasing international normalized ratio was associated with a reduction of endogenous thrombin potential (ETP) and thrombin peak and increasing lag time. Factor Xa inhibitors produced a flattened thrombin generation curve with a reduction of thrombin peak and relative preservation of ETP. Direct thrombin inhibitors produced a reduction of both ETP and thrombin peak and increasing lag time. Seventy-one citrated plasma samples (26 dabigatran, 21 rivaroxaban and 24 apixaban) were evaluated. The two concentrations produced a reduction of thrombin generation parameters with significant interindividual variability compared with neat plasma of 35–93, 13–31 and 18–71% and for dabigatran, rivaroxaban and apixaban, respectively. Thrombin generation can measure the anticoagulation effect of commonly used DOACs, with each drug having a unique thrombin generation profile. The variability noted using the same concentration suggests significant interindividual pharmacodynamic differences, which maybe relevant with respect to efficacy as well as bleeding side effects. Further delineation of the modifiers of interindividual differences is required in the in-vivo setting.

Extensive cerebral venous sinus thrombosis after romiplostim treatment for immune thrombocytopenia (ITP) despite severe thrombocytopenia.

1 Panichpisal K, Gandhi S, Nugent K, Anziska Y. Acute quadriplegia from hyperkalemia: a case report and literature review. Neurologist 2010; 16: 390–3. 2 Yoshino T, Meguro S, Soeda Y, Itoh A, Kawai T, Itoh H. A case of hypoglycemic hemiparesis and literature review. Ups J Med Sci 2012; 117: 347–51. 3 Chiang WF, Yeh FC, Lin SH. Unilateral paralysis associated with profound hypokalemia. Am J Emerg Med 2012; 30: 2100.e5–7. 4 U.S. Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 26. Nutrient Data Laboratory Home Page, 2013 [cited 2014 Oct 4]. Available from URL: http://www.ars.usda.gov/ba/bhnrc/ndl

An evaluation of global coagulation assays in myeloproliferative neoplasm

&NA; Myeloproliferative neoplasms (MPN) are independent risks for thrombotic events. Routine laboratory tests are inadequate to evaluate the underlying procoagulant state. Global coagulation assays such as thromboelastography, thrombin and fibrin generation may provide better assessment of coagulation activation and thereby of thrombosis risk. Participants with MPN were recruited. Thromboelastography was performed on citrated whole blood while thrombin generation using calibrated automated thrombogram, fibrin generation using overall haemostatic potential assays and P-selectin were quantified on platelet-poor plasma. Thirty-eight MPN patients (median age: 65 years) were recruited. There were 26 patients with essential thrombocythemia (68.4%), eight polycythemia vera (20.5%), three primary myelofibrosis and one MPN, unclassifiable. Compared with normal controls, there was no difference in maximum amplitude although lysis time (LY30) was significantly higher (2.9 vs. 0.6%, adjusted P < 0.01) using thromboelastography. Calibrated automated thrombogram showed higher thrombin peak (260.8 vs. 222.6 nmol/l; P < 0.01) and velocity index (91.1 vs. 65.0 nmol/l/min; P < 0.01) with comparable endogenous thrombin potential. Fibrin generation parameters were significantly reduced with preserved overall fibrinolytic potential, whereas P-selectin was markedly increased (108.9 vs. 49.3 ng/ml, P < 0.01). This study demonstrated unique differences between MPN population and normal controls using a combination of global coagulation assays. The presence of high lysis time (LY30) and reduced fibrin generation in MPN patients were contradictory to the prothrombotic nature and may represent a compensatory effort to achieve equilibrium within the Virchows triad. Both markers may be important prognostic indicators of thrombosis in MPN and further prospective studies to confirm these findings are proposed.

Direct Oral Anticoagulants and the Paradigm Shift in the Management of Venous Thromboembolism

&NA; The advent of direct oral anticoagulants (DOACs) has revolutionized anticoagulation management in both stroke prevention and venous thromboembolism (VTE) treatment/prevention. Clinical trials and secondary real‐world data have shown that DOACs have similar efficacy and, in some cases, improved bleeding safety profiles compared with vitamin K antagonists. Together with benefits of patient convenience, this has shifted the risk‐benefit ratio toward long‐term anticoagulation. However, current VTE risk assessment models are based on vitamin K antagonists and do not take into account the new paradigm of DOACs. Therefore, challenges to the thrombosis community remain to determine patients who would benefit from long‐term anticoagulation in the DOAC era. Here, the authors review the current literature on risks and benefits of DOACs and their potential role in long‐term VTE thromboprophylaxis as well as in current risk assessment models. The increasing use of DOACs, led by their convenience of use and generally lower bleeding rates, calls for a reevaluation of the current models as the benefits of long‐term anticoagulation may begin to outweigh risks and inconvenience associated with their predecessors.