Overall haemostatic potential assay for prediction of outcomes in venous and arterial thrombosis and thrombo-inflammatory diseases.

Thromboembolic diseases including arterial and venous thrombosis are common causes of morbidity and mortality globally. Thrombosis frequently recurs and can also complicate many inflammatory conditions through the process of 'thrombo-inflammation,' as evidenced during the COVID-19 pandemic. Current candidate biomarkers for thrombosis prediction, such as D-dimer, have poor predictive efficacy. This limits our capacity to tailor anticoagulation duration individually and may expose lower risk individuals to undue bleeding risk. Global coagulation assays, such as the Overall Haemostatic Potential (OHP) assay, that investigate fibrin generation and fibrinolysis, may provide a more accurate and functional assessment of hypercoagulability. We present a review of fibrin's critical role as a central modulator of thrombotic risk. The results of our studies demonstrating the OHP assay as a predictive biomarker in venous thromboembolism, chronic renal disease, diabetes mellitus, post-thrombotic syndrome, and COVID-19 are discussed. As a comprehensive and global measurement of fibrin generation and fibrinolytic capacity, the OHP assay may be a valuable addition to future multi-modal predictive tools in thrombosis.

A ten-year comparison of treatment and outcomes of cancer-associated thrombosis to non-cancer venous thromboembolism: from traditional anticoagulants to direct oral anticoagulants.

DOACs have emerged as first-line treatment in most cancer-associated thrombosis (CAT), representing a paradigm shift in its management. However, CAT management remains challenging and requires careful risk-benefit considerations. A retrospective analysis of CAT presentations to a tertiary referral centre from January 2011 to December 2020. Outcomes in CAT patients were compared to VTE patients without malignancy. Subgroup analysis was also conducted for CAT according to anticoagulation type. 514 CAT cases from 491 patients were identified from 3230 total VTE cases. CAT patients had higher rates of major VTE (PE and/or proximal DVT) compared to patients without malignancy (78.4% vs. 66.8%, p < 0.001). CAT patients also had higher rates of VTE recurrence (HR 1.66, 95%CI 1.23-2.26), major bleeding (HR 3.41, 95%CI 2.36-4.93), VTE-related mortality (HR 2.59, 95%CI 1.46-4.62) and bleeding-related mortality (HR 2.66, 95%CI 1.05-6.73). There were no significant differences in rates of VTE recurrence, major bleeding, VTE-related mortality or fatal bleeding between CAT patients treated with DOACs, enoxaparin or warfarin. In the subgroup of CAT treated with DOACs, there was no significant difference in rates of GI bleeding compared to the enoxaparin subgroup (HR 0.17, 95%CI 0.02-1.26). CAT was associated with a larger clot burden and higher rates of VTE recurrence, major bleeding and mortality compared to VTE patients without malignancy in this large real-world study. This study demonstrated no significant differences in complication rates for CAT patients treated with DOACs over enoxaparin, suggesting that DOACs can be safely used in most cases of CAT.

Thrombosis Risk Assessment in Myeloproliferative Neoplasm-Is There a Role for Viscoelastic Testing?

Philadelphia chromosome-negative myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia, and myelofibrosis. They are associated with increased thrombotic events, and the primary goal of therapy, in particular those with polycythemia vera and essential thrombocythemia, is the prevention of thrombotic complications typically with antiplatelet therapy and/or cytoreduction. While several patient-, disease-, and genomic-related factors have been identified to influence thrombotic risks, there are no routine laboratory investigations to date that are sufficiently accurate to assess the underlying procoagulant state and predict the thrombotic risks. Conventional coagulation testing only measures time to clot formation and cannot reliably predict bleeding and thrombotic risks. Global coagulation assays such as thromboelastography, thrombin, and fibrin generation may provide a more thorough assessment of hemostatic function. Thromboelastography and thromboelastometry are viscoelastic tests which measure the mechanical properties of the hemostatic process, including the global dynamics of clot formation, stabilization, and dissolution. While viscoelastic testing is gaining traction in the investigations of coagulopathies and goal-directed blood product replacement in trauma and massive transfusion settings, the role of these assays in thrombosis is less well defined. Here, we provide a review of the current evidence of the role of viscoelastic testing in myeloproliferative neoplasm, particularly in the thrombotic risk assessment.

Overall haemostatic potential (OHP) assay can risk stratify for venous thromboembolism recurrence in anticoagulated patients.

Assessing the risk of recurrent venous thromboembolism (VTE), particularly when patients are anticoagulated, remains a major challenge largely due to the lack of biomarkers. Blood was sampled from adult VTE patients recruited between January 2018 and September 2020, while receiving therapeutic anticoagulation. Results were compared to 144 healthy subjects (34.7% male, median age 42 years). Overall haemostatic potential (OHP) assay, a spectrophotometric assay, was performed on platelet-poor plasma, in which fibrin formation (triggered by small amounts of thrombin (overall coagulation potential, OCP)) and fibrinolysis (by the addition of thrombin and tissue plasminogen activator (OHP)) are simultaneously measured. Results were obtained from 196 patients (52.6% male, mean age 57.1 years). Compared to healthy subjects, VTE patients displayed significantly higher OCP (39.6 vs 34.5 units, p < 0.001) and OHP (9.3 vs 6.4 units, p < 0.001) as well as lower overall fibrinolytic potential (75.6 v s81.1%, p < 0.001). All 16 VTE recurrences, including 11 unprovoked, occurred above an OCP cut-off of 40th percentile (recurrence rate 4.32/100 patient-years (100PY), 95% confidence interval (CI) 2.39-7.80, p = 0.002). Of 97 patients who subsequently discontinued anticoagulation, all unprovoked VTE recurrences (n = 9) occurred above the 40th OCP percentile (recurrence rate 9.10/100PY, 95% CI 4.74-17.49, p = 0.005) and the 40th OHP percentile (recurrence rate 8.46/100PY, 95% CI 4.40-16.25, p = 0.009). Our pilot study demonstrates that the OHP assay can detect a hypercoagulable and hypofibrinolytic state in anticoagulated VTE patients and may be able to risk stratify VTE recurrence, allowing for more individualised decision on long-term anticoagulation. Further larger prospective studies are required.

Management of venous thromboembolism in morbidly obese patients: a 10-year review.

Obesity is a known risk factor for venous thromboembolism (VTE) and poses a unique set of challenges in anticoagulation management. We report a 10-year experience of VTE management in morbidly obese patients. We conducted a retrospective analysis of VTE presentations to Northern Health, Victoria, Australia, from January 2011 to December 2020, with median follow-up of 44 months. Morbidly obese patients (defined as weighing > 120 kg) were compared to those ≤ 120 kg. Patients with active malignancy were excluded. 194 VTE cases with weight > 120 kg were compared to 2168 cases weighing ≤ 120 kg. Patients > 120 kg were more likely to present with unprovoked VTE (59.3% vs. 45.2%, p < 0.001) and major VTE (74.7% vs. 67.4%, p = 0.028). Overall, patients > 120 kg were more likely to develop VTE recurrence after anticoagulation cessation (7.80 vs. 3.92 per 100-patient-years, HR 1.97, 95%CI 1.29-3.00), while there were no significant differences in major bleeding or 30-day all-cause mortality. There were no significant differences in outcomes in patients > 120 kg treated with warfarin compared to direct oral anticoagulants (DOAC), or when comparing those treated with an uncapped (1 mg/kg BD) vs. capped (< 1 mg/kg) enoxaparin dosing regimen. Morbid obesity is associated with increased clot burden at presentation and VTE recurrence following anticoagulation cessation, without significant differences in bleeding compared to those ≤ 120 kg. There were no significant differences in morbidly obese patients' outcomes when treated with warfarin or DOAC, or when treated with an uncapped or capped enoxaparin dosing strategy. Larger randomised controlled trials evaluating the safety of DOACs and different enoxaparin dosing strategies in patients > 120 kg are warranted.

A systematic review of venous thromboembolism mechanical prophylaxis devices during surgery.

PURPOSE: Hospitalisation and surgery are major risk factors for venous thromboembolism (VTE). Intermittent pneumatic compression (IPC) and graduated compression stockings (GCS) are common mechanical prophylaxis devices used to prevent VTE. This review compares the safety and efficacy of IPC and GCS used singularly and in combination for surgical patients. METHODS: Ovid Medline and Pubmed were searched in a systematic review of the literature, and relevant articles were assessed against eligibility criteria for inclusion along PRISMA guidelines. RESULTS: This review is a narrative description and critical analysis of available evidence. Fourteen articles were included in this review after meeting the criteria. Results of seven studies comparing the efficacy of IPC versus GCS had high heterogeneity but overall suggested IPC was superior to GCS. A further seven studies compared the combination of IPC and GCS versus GCS alone, the results of which suggest that combination mechanical prophylaxis may be superior to GCS alone in high-risk patients. No studies compared combination therapy to IPC alone. IPC appeared to have a superior safety profile, although it had a worse compliance rate and the quality of evidence was poor. The addition of pharmacological prophylaxis may make mechanical prophylaxis superfluous in the post-operative setting. CONCLUSION: IPC may be superior to GCS when used as a single prophylactic device. A combination of IPC and GCS may be more efficacious than GCS alone for high-risk patients. Further high-quality research is needed focusing on clinical relevance, safety and comparing combination mechanical prophylaxis to IPC alone, particularly in high-risk surgical settings when pharmacological prophylaxis is contraindicated.

Clinical predictors of pulmonary embolism for inpatients: are computed tomography pulmonary angiograms being requested appropriately?

BACKGROUND: The heterogeneity of inpatient pulmonary embolism (PE) presentations may lead to computed tomography pulmonary angiograms (CTPA) being over-requested. Current clinical predictors for PE, including Wells criteria and Pulmonary Embolism Rule-out Criteria (PERC), have predominantly focussed on outpatient and emergency department populations. AIM: To determine the clinical indicators for ordering inpatient CTPA and the predictors of positive scans for PE. METHODS: Consecutive inpatient CTPA (performed >24 h after admission) from January 2017 to December 2017 were retrospectively reviewed. Variables including baseline characteristics, vital signs and risk factors for PE were extracted. RESULTS: A total of 312 CTPA was reviewed (average patient age 67 years; 46% male) and 36 CTPA were positive for PE (11.5%). The average time to inpatient CTPA request was 7 days. Clinical indicators associated with positive scans were hypoxia (odds ratio (OR) 2.4; 95% confidence interval (CI) 1.1-5.6), tachypnoea (OR 2.5; 95% CI 1.2-6.0), recent surgery or immobilisation (OR 2.7; 95% CI 1.2-6.4), S1Q3T3 pattern on electrocardiogram (ECG; OR 7.2; 95% CI 1.4-35.7) and right bundle branch block pattern on ECG (OR 4.7; 95% CI 1.6-13.1). Hypotension, fever and malignancy were not significant. Both PERC and Wells criteria had poor positive predictive value (12% and 27% respectively), but the negative predictive value for PERC and Wells was 100% and 95.8% respectively. CONCLUSION: Inpatient CTPA appear to be over-requested and can potentially be rationalised based on a combination of clinical predictors and Wells criteria and/or PERC rule. Further prospective studies are needed to develop accurate clinical decision tools targeted towards inpatients.

Global coagulation assays in hypercoagulable states.

Thrombosis is one of the major global causes of morbidity and mortality, and predicting the risk of thrombotic and cardiovascular complications remains one of the key challenges in modern medicine. Conventional coagulation testing does not provide sufficient information, primarily because they measure the time to start of blood clotting and do not evaluate total thrombin generation. Possible adjunctive tools that may be helpful are global coagulation assays, which includes the assessment of the final products of the coagulation cascade, namely thrombin and fibrin. Whilst these assays have been more widely investigated in bleeding states, their role in thrombotic disorders is less established. We have previously investigated the use of assays such as thromboelastography, calibrated automated thrombogram and overall haemostatic potential assay in several hypercoagulable states including cardiovascular disease, haematological disorders and influence of hormone status as well as healthy controls. We provide a review of the use and limitations of global coagulation assays in healthy controls as well as hypercoagulable conditions.

Risk factors and early prediction of clinical deterioration and mortality in adult COVID-19 inpatients: an Australian tertiary hospital experience.

BACKGROUND: Early recognition of severe COVID-19 is essential for timely patient triage. AIMS: To report clinical and laboratory findings and patient outcomes at a tertiary hospital in Melbourne, Australia. METHODS: This is a retrospective study of adult inpatients with COVID-19 admitted to Northern Health from March to September 2020. Data were extracted from electronic medical records. RESULTS: Key admission data were available for 182 patients (median age 67.0 years (interquartile range, 47.9-83.1); 51.1% female). Fifty-six (30.8%) were from residential care. One hundred and seventeen (64.3%) patients were assigned Goals of Patient Care (GOPC) A or B and 65 (35.7%) GOPC C or D. Comorbidities were present in 135 patients (74.2%). 63.2% of patients received antibiotics, 6.6% had antivirals, 45.6% received systemic glucocorticoid and 3.3% had tocilizumab. Fifty-six (30.8%) developed clinical deterioration (24 requiring ventilation, 21 receiving critical care, 34 died). Overall, inhospital clinical deterioration was significantly associated with older age (P < 0.001), history of diabetes (P = 0.038), lower lymphocyte count (P = 0.002) and platelet count (P = 0.004), higher neutrophil-to-lymphocyte ratio (P = 0.002), elevated fibrinogen (P = 0.004), higher serum ferritin (P = 0.027) and C-reactive protein (CRP; P = 0.002). The accuracy of the 4C Deterioration model was moderate, with an area under the curve (AUC) of 0.79 (95% confidence interval (CI), 0.68-0.90) compared with an AUC of 0.77 (95% CI, 0.76-0.78) in the original validation cohort. CONCLUSIONS: In the present study, high neutrophil-to-lymphocyte ratio, abnormal d-dimer, high serum CRP and ferritin appear to be useful prognostic markers.

Global coagulation assays in healthy controls: are there compensatory mechanisms within the coagulation system?

Global coagulation assays (GCAs) may provide a more comprehensive individual hemostatic profiling. We aim to evaluate GCAs (thromboelastography, thrombin generation) in healthy controls, and correlate results with age, gender, lipid status, tissue factor pathway inhibitor (TFPI) and P-selectin. Blood samples were collected from healthy controls (> 18 years of age) not taking anticoagulation or antiplatelet agents and without known cardiovascular disease. Thromboelastography (TEG) was performed on citrated whole blood while calibrated automated thrombogram (CAT), P-selectin (endothelial marker) and TFPI (principle inhibitor of tissue factor-initiated coagulation) were performed on platelet-poor plasma. 153 healthy controls (mean age 42 years, 98 females (64%)) were recruited. Female controls demonstrated more hypercoagulable TEG and CAT parameters while those over 50 years of age demonstrated more hypercoagulable TEG parameters despite comparable thrombin generation. Paradoxically, individuals with "flattened" thrombin curves (lower velocity index (rate of thrombin generation) despite preserved endogenous thrombin potential (amount of thrombin)) were more likely to be male (49% vs 20%, p = 0.003) with increased low-density lipoprotein cholesterol (3.3 vs 2.6 mmol/L, p = 0.003), P-selectin (54.2 vs 47.3 ng/mL, p = 0.038) and TFPI (18.7 vs 8.6 ng/ml, p = 0.001). In addition to reduced velocity index and thrombin peak, controls in the highest TFPI tertile also demonstrated a poorer lipid profile. GCAs can detect subtle changes of the hemostatic profile. Interestingly, reduced thrombin generation was paradoxically associated with increased cardiovascular risk factors, possibly attributable to increased TFPI. This finding may suggest compensation by the coagulation system in response to endothelial activation and represent a biomarker for early cardiovascular disease. A larger prospective study evaluating these assays in the cardiovascular disease population is ongoing.

Retrospective review of D-dimer testing for venous thrombosis recurrence risk stratification: is this a useful test in the real world?

Predicting the risk of recurrence after venous thromboembolism (VTE) remains an important clinical challenge. Post-anticoagulation cessation D-dimer has previously been shown to be associated with increased VTE recurrence in unprovoked major VTE, however this is not routinely used clinically and has not been validated in provoked VTE and isolated distal DVT (IDDVT). We aimed to retrospectively evaluate this practice in the real-world setting including examining its use in provoked VTE and IDDVT. Consecutive patients diagnosed with DVT or PE between January 2013 and December 2016 were retrospectively evaluated. Clinical features, VTE risk factors, recurrence and bleeding rates were evaluated for patients with normal and abnormal post-anticoagulation D-dimer, as well as those patients who did not undergo D-dimer testing. Patients with active malignancy, superficial vein thrombosis and inadequate follow-up were excluded. Of the 1033 patients with a diagnosis of VTE in the study period, 173 were included in the "D-dimer tested" group, and 254 in the "D-dimer un-tested" comparison group. Abnormal post-anticoagulation D-dimer was significantly associated with VTE recurrence (HR 5.96, 95% CI 2.15-14.57, p < 0.001). Abnormal D-dimer was also associated with high risk of VTE recurrence in travel-provoked VTE (67.61 events per 100 patient-years), and unprovoked IDDVT (HR 14.37, 95% CI 1.75-117.83, p = 0.013). Males with abnormal post-anticoagulation D-dimer were associated with the highest risk of VTE recurrence (HR 12.95, 95% CI 2.78-60.20, p = 0.001). Patients with unprovoked proximal DVT and/or PE who underwent D-dimer testing had a lower VTE recurrence rate compared to those who did not have D-dimer testing (HR 0.28, 95% CI 0.10-0.80, p = 0.017). We confirm the utility of post-anticoagulation cessation D-dimer testing to stratify VTE recurrence risk in the real-world setting, including potentially a role of this assay for predicting subsequent VTE in travel-provoked VTE and unprovoked IDDVT.

Real-world direct oral anticoagulant experience in atrial fibrillation: falls risk and low dose anticoagulation are predictive of both bleeding and stroke risk.

BACKGROUND: Clinical trials have demonstrated that direct oral anticoagulants (DOAC) are non-inferior to vitamin K antagonist for stroke prevention in non-valvular atrial fibrillation (AF) with comparable safety outcomes; however, real-world Australian data are limited. AIMS: To evaluate local real-world DOAC use focussing on safety, particularly in high-risk patients. METHODS: A retrospective evaluation of 658 patients commenced or continued on DOAC between September 2013 and September 2016 for non-valvular AF at Northern Hospital, a tertiary hospital in Victoria, Australia was performed. RESULTS: Factor Xa inhibitors were more commonly prescribed than direct thrombin inhibitors (83.3 vs 16.7%) for AF management. The median patient age was 75 years. The rate of clinically significant bleeding on anticoagulation was 3.13 per 100 person-years (including four deaths) with risk factors including history of bleeding (hazard ratio (HR) 3.52, 95% confidence interval (CI) 1.22-10.17), concurrent antiplatelet therapy (HR 2.62, 95% CI: 1.11-6.20) and high falls risk (HR 2.76, 95% CI: 1.26-6.08). Patients on low-dose DOAC had significantly higher bleeding risk compared with those on full dose (5.05 vs 1.82 per 100 person-years). The rate of thrombotic stroke despite anticoagulation was 1.34 per 100 person-years with risk factors including low dose anticoagulation (P = 0.034), high falls risk (P = 0.046) and previous stroke (P = 0.028). CONCLUSIONS: DOAC use in real-world Australian practice is safe and effective, consistent with international data. Low dose anticoagulation and falls risk are associated with increased bleeding and thrombotic risk demonstrating overlapping risk factors. Careful individualised patient risk assessment is still required as low dose anticoagulation is not without risks.

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

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.

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

OBJECTIVES: 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. METHODS: Retrospective evaluation of VTE events in non-cancer patients from July 2011 to December 2012 at two tertiary institutions in Australia with a minimum follow-up of 24 months. RESULTS: A total of 747 VTE cases were identified, and following exclusion of cases with mortality within 30 days of presentation (n=26), unprovoked cases (40.2%) had a higher risk of recurrence (4.6 vs 2.3/100 event-years, P=.01). Provoking factors included surgery (40.4%), injury (16.7%), medical-related factors including non-surgical hospitalisation or active infection (22.0%), travel (13.2%) and oestrogen related (6.5%). Air travel had the highest recurrence rate of 5.9/100 event-years, comparable to unprovoked VTE. VTE provoked by surgery showed lower recurrence rate at 1.8/100 event-years (P=.03). 62.5% of patients with provoked VTE recurred with an unprovoked event. CONCLUSION: Transient provoking factors for VTE are heterogeneous with varying potency and should not be considered a single entity. The high recurrence rate after travel-provoked VTE suggests that it is a "minor," if not negligible provoking factor with higher thrombotic predisposition.

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

BACKGROUND: 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. AIMS: To provide a holistic evaluation of 'real-world' Australian experience in the warfarin era, including how we compare to international guidelines. METHODS: Retrospective evaluation of VTE from July 2011 to December 2012 at two major hospitals in Melbourne, Australia. These results were compared to recommendations in the international guidelines. RESULTS: A total of 752 episodes involving 742 patients was identified. Contrary to international guidelines, an unwarranted heritable thrombophilia screen was performed in 22.0% of patients, amounting to a cost of AU$29 000. The duration of anticoagulation was longer compared to international recommendations, although the overall recurrence (3.2/100 person-years) and clinically significant bleeding rates (2.4/100 person-years) were comparable to 'real-world' data. Unprovoked VTE (hazard ratio 2.06; P = 0.01) was a risk factor for recurrence, and there was no difference in recurrence between major VTE (proximal deep vein thrombosis (DVT) and/or pulmonary embolism) and isolated distal DVT (3.02 vs 3.94/100 person-years; P = 0.25). Fourteen patients were subsequently diagnosed with malignancy, and patients with recurrent VTE had increased risk of prospective cancer diagnosis (relative risk 6.68; P < 0.001). CONCLUSIONS: While our 'real-world' VTE experience during the warfarin era largely correlates with international guidelines, there remains heterogeneity in the management strategies, including excessive thrombophilia screening and longer duration of anticoagulation. This audit highlights the need for national VTE guidelines, as well as prospective auditing of VTE management, in the direct oral anticoagulant era for future comparison.

Ten years of cerebral venous thrombosis: male gender and myeloproliferative neoplasm is associated with thrombotic recurrence in unprovoked events.

Cerebral venous thrombosis (CVT) is a rare venous thrombotic event. We review our local experience in the management of CVT in comparison to other venous thromboembolism (VTE) with specific focus on risk factors for thrombotic recurrence. Retrospective evaluation of consecutive CVT presentations from January 2005 to June 2015, at two major tertiary hospitals in Northeast Melbourne, Australia. This population was compared to a separate audit of 1003 consecutive patients with DVT and PE. Fifty-two patients (30 female, 22 male) with a median age of 40 (18-83) years, presented with 53 episodes of CVT. Twenty-nine episodes (55 %) were associated with an underlying risk factor, with hormonal risk factors in females being most common. The median duration of anticoagulation was 6 months with 11 receiving life-long anticoagulation. Eighty-one percent had residual thrombosis on repeat imaging, which was not associated with recurrence at the same or distant site. Nine (17 %) had CVT-related haemorrhagic transformation with two resultant CVT-related deaths (RR 22.5; p = 0.04). All three VTE recurrences occured in males with unprovoked events (RR 18.2; p = 0.05) who were subsequently diagnosed with myeloproliferative neoplasm (MPN). Compared to the non-cancer VTE population, non-cancer CVT patients were younger, had similar rate of provoked events and VTE recurrence, although with significantly higher rate of MPN diagnosis (RR 9.30 (2.29-37.76); p = 0.002) CVT is a rare thrombotic disorder. All recurrences in this audit occurred in male patients with unprovoked events and subsequent diagnosis of MPN, suggesting further evaluation for MPN may be warranted in patients with unprovoked CVT.

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.

Central nervous system multiple myeloma--potential roles for intrathecal therapy and measurement of cerebrospinal fluid light chains.

Central nervous system (CNS) multiple myeloma (MM) is exceedingly rare and portends a dismal prognosis. While immunomodulators have contributed to the improvement in survival in MM, they appear to have limited activity against CNS MM and, paradoxically, may contribute to the evolution of resistant MM clones capable of surviving within the CNS. We undertook a retrospective analysis to characterize the features of CNS MM and outcome in 17 patients from four institutions identified between 2000 and 2011. The median age was 58 years. Patients had received a median of three prior therapies and all had been exposed to at least one of the so-called novel anti-MM agents before the diagnosis of CNS MM. The median time to CNS disease from initial diagnosis was 36 months. Cerebrospinal fluid (CSF) light chain measurements produced discrepant results to serum light chain measurements in some patients. Treatments included systemic pharmacotherapy, intrathecal (IT) chemotherapy and/or radiotherapy (RT). The median overall survival (OS) from diagnosis of CNS MM was only 4 months. OS was significantly better in patients who received IT chemotherapy (20 months vs. 2 months, respectively; P < 0.02). We conclude that the systematic evaluation of IT therapy and diagnostic utility of CSF light chain measurements in CNS MM are warranted.

A 10-year Australian experience of rare intraabdominal venous thrombosis with comparison to deep vein thrombosis and pulmonary embolism.

OBJECTIVE: Intra-abdominal venous thromboembolism is rare with heterogeneous management. We aim to evaluate these thrombosis and compare them to deep vein thrombosis and/or pulmonary embolism. METHOD: A 10-year retrospective evaluation of consecutive venous thromboembolism presentations (January 2011-December 2020) at Northern Health, Australia, was conducted. A subanalysis of intraabdominal venous thrombosis involving splanchnic, renal and ovarian veins was performed. RESULTS: There were 3343 episodes including 113 cases of intraabdominal venous thrombosis (3.4%) - 99 splanchnic vein thrombosis, 10 renal vein thrombosis and 4 ovarian vein thrombosis. Of the splanchnic vein thrombosis presentations, 34 patients (35 cases) had known cirrhosis. Patients with cirrhosis were numerically less likely to be anticoagulated compared to noncirrhotic patients (21/35 vs. 47/64, P  = 0.17). Noncirrhotic patients ( n  = 64) were more likely to have malignancy compared to those with deep vein thrombosis and/or pulmonary embolism (24/64 vs. 543/3230, P  < 0.001), including 10 patients diagnosed at time of splanchnic vein thrombosis presentation. Cirrhotic patients reported more recurrent thrombosis/clot progression (6/34) compared to noncirrhotic patients (3/64) (15.6 vs. 2.3 events/100-person-years; hazard ratio 4.7 (95% confidence interval 1.2-18.9), P  = 0.030) and other venous thromboembolism patients (2.6/100-person-years; hazard ratio 4.7, 95% confidence interval 2.1-10.7; P  < 0.001) with comparable major bleeding rates. All renal vein thrombosis were provoked including five malignant-related cases while three ovarian vein thrombosis occurred postpartum. No recurrent thrombotic or bleeding complications were reported in renal vein thrombosis and ovarian vein thrombosis. CONCLUSION: These rare intraabdominal venous thromboses are often provoked. Splanchnic vein thrombosis (SVT) patients with cirrhosis have a higher rate of thrombotic complications, while SVT without cirrhosis was associated with more malignancy. Given the concurrent comorbidities, careful assessment and individualized anticoagulation decision is needed.

DOAC-stop can remove direct oral anticoagulants and allow analysis by global coagulation assays.

INTRODUCTION: Activated charcoal based compounds such as DOAC-stop™ (DS) have been developed to remove direct oral anticoagulant (DOAC) interference in-vitro. However, few studies have used this approach with global coagulation assays (GCAs), such as thrombin generation assays, which are sensitive to the effect of DOACs. METHODS: Thrombin generation with and without thrombomodulin (TM) via the automated ST-Genesia system, and the overall haemostatic potential (OHP) assay, a spectrophotometric fibrin generation assay in which fibrin formation (triggered by small amounts of thrombin (overall coagulation potential, OCP)) and fibrinolysis (by the addition of thrombin and tissue plasminogen activator) were measured on (i) pooled normal plasma (PNP) spiked with varying amounts of rivaroxaban, apixaban, and dabigatran, and (ii) platelet poor plasma (PPP) from 21 non-anticoagulated adults, before and after DS addition. RESULTS: Following the addition of DS to spiked PNP without thrombomodulin, thrombin and velocity index increased by 21.9% and 42.6%, respectively, while ETP increased by 6.93%. A decrease in OCP (-10.6%) and OHP (-12.7%) was observed following DS. Similar changes were seen post-DS to plasma from non-anticoagulated patients. Also in this group, pre- and post-DS thrombin generation parameters showed high correlation, with the strongest observed for ETP (R2  = 0.94). There was a strong correlation for OHP parameters, with the closest seen with OCP (R2  = 0.96) and OHP (R2  = 0.95). CONCLUSION: DS causes some changes to the ETP and OHP assay, however, strong correlations were seen pre- and post-DS in all GCA parameters. These findings support the use of DS to facilitate GCA testing in anticoagulated individuals for evaluation of the underlying thrombotic state.