Prospective cohort study on the use of low molecular weight heparin calibrated anti-Xa assay for measurement of direct oral Xa inhibitors in ex vivo patient samples.

Drug-specific anti-Xa chromogenic assays are recommended for measurement of direct anti-Xa inhibitor levels but are not routinely available in many institutions. We performed a prospective study to determine: (1) the relationship between low molecular weight heparin (LMWH) calibrated anti-Xa measurements and apixaban or rivaroxaban levels measured using drug-specific anti-Xa assays and, (2) if a LMWH calibrated anti-Xa assay can be used to detect clinically significant apixaban or rivaroxaban levels. Haematology outpatients on rivaroxaban or apixaban for at least 72 h were recruited for this study. Anti-Xa LMWH assay was performed using the Innovance Heparin Anti-Xa kit/calibrator. Drug-specific levels were determined using STA-Liquid anti-Xa kit/STA-Apixaban or STA-Rivaroxaban calibrators. Serial dilutions with pooled normal plasma were performed for specimens with anti-Xa LMWH activity greater than 1.50 ng/mL to obtain anti-Xa levels within the reportable range (0.10-1.50 ng/mL) and multiplied by the dilution factor to determine actual anti-Xa level. Seventy-five (39 rivaroxaban, 36 apixaban) specimens from 67 patients (mean age 60.3 years; 53.3% males) were available for analysis. Rivaroxaban levels ranged from <25 to 500 ng/mL while apixaban levels ranged from <20 to 236.1 ng/mL. For both rivaroxaban and apixaban, there was linear and good correlation (R2 = 0.96) between direct oral anticoagulants and anti-Xa LMWH levels. Using the correlation equation from our data, a rivaroxaban concentration of 50 ng/mL [International Society on Thrombosis and Haemostasis (ISTH) threshold for consideration of antidotes in bleeding patients] and 30 ng/mL (ISTH threshold for consideration of reversal agents prior to interventions), corresponds to anti-Xa LMWH levels of 0.50 and 0.35 IU/mL, respectively. For apixaban the corresponding anti-Xa LMWH levels were 0.35 and 0.20 IU/mL, respectively. In conclusion, LWWH calibrated anti-Xa assay can be used in emergency situations to screen for clinically significant apixaban or rivaroxaban levels when drug-specific calibrators are not available.

COVID-19 and immunothrombosis: Pathophysiology and therapeutic implications.

The coagulopathy of COVID-19 is characterised by significantly elevated D Dimer and fibrinogen, mild thrombocytopenia and a mildly prolonged PT/APTT. A high incidence of thrombotic complications occurs despite standard thromboprophylaxis. The evidence to date supports immunothrombosis as the underlying mechanism for this coagulopathy which is triggered by a hyperinflammatory response and endotheliopathy. A hypercoagulable state results from endothelial damage/activation, complement activation, platelet hyperactivity, release of Extracellular Neutrophil Traps, activation of the coagulation system and a "hypofibrinolytic" state. Significant cross-talk occurs between the innate/adaptive immune system, endothelium and the coagulation system. D dimer has been shown to be the most reliable predictor of disease severity, thrombosis, and overall survival. In this context, targeting pathways upstream of coagulation using novel or repurposed drugs alone or in combination with other anti-thrombotic agents may be a rational approach to prevent the mortality/morbidity due to COVID-19 associated coagulopathy.

Incidence of residual perfusion defects by lung scintigraphy in patients treated with rivaroxaban compared with warfarin for acute pulmonary embolism.

Residual perfusion defects (RPD) as detected by lung scintigraphy occur in over 50% of patients with acute pulmonary embolism (PE) treated with vitamin K antagonists but there is lack of data in patients treated with direct oral anticoagulants. The aim of this retrospective study was to estimate the incidence of RPD detected by ventilation perfusion (VQ) scan at 3-6 months in patients with first acute symptomatic PE treated with rivaroxaban compared to warfarin. Consecutive eligible patients treated with rivaroxaban as part of a previous study were identified. The Monash Health Radiology database was used to identify a historical cohort of age matched (± 5 years) patients treated with warfarin. Follow-up VQ scans were classified as normal (no perfusion defect) or abnormal (matched or unmatched perfusion defects) by two independent nuclear medicine physicians blinded to treatment. Any disagreement was resolved by consensus. One hundred and ninety patients with PE (95 in each cohort) were included (mean age 56.8 years; 41.1% males; 54.2% unprovoked). In the overall cohort, 31.1% had RPD with a significantly lower incidence of RPD in rivaroxaban treated patients 23.2% (95% CI 15.8-32.6), compared to warfarin 38.9% (95% CI 29.8-49.0). Treatment with rivaroxaban was associated with a significantly lower incidence of RPD detected by VQ scan at 3-6 months compared to warfarin. This supports recent in-vitro data suggesting an indirect enhancement of fibrinolysis by direct oral Xa inhibitors but requires confirmation in larger studies.

Spontaneous Fractures in the Setting of Extensive Craniocervical Pneumatization: Case Report and Literature Review.

BACKGROUND: Cranial pneumatization in humans is normally confined to the paranasal sinuses and the petrous and mastoid parts of the temporal bones. CASE DESCRIPTION: We present a case of left-sided fractures of the occipital condyle and lateral mass of the atlas in the setting of extensive craniocervical pneumatization but in the absence of trauma, with a resulting unilateral hypoglossal nerve palsy. CONCLUSIONS: We discussed the possible etiology of this rare disease, its management, and prognosis.

Utility of a Nurse-Led Pathway for Patients with Acute Venous Thromboembolism Discharged on Rivaroxaban: A Prospective Cohort Study.

The highest risk of adverse events for patients with acute venous thromboembolism (VTE) is during the early anticoagulation period. However, no established model exists for early clinical monitoring of patients treated with non-vitamin K antagonist oral anticoagulants (NOACs). The authors' aim was to evaluate the utility of a nurse-led pathway to minimize adverse events in acute VTE patients starting on rivaroxaban. The rivaroxaban VTE treatment pathway is a prospective cohort study of consecutive patients with objectively confirmed VTE between July 2015 and May 2017. Primary outcome was the proportion of patients identified at major risk of adverse events (bleeding or recurrent VTE). Secondary outcomes were rates of interventions, major or clinically relevant nonmajor bleeding (CRNMB), recurrent VTE, and all-cause mortality at 90 days. Among 304 participants, 5% (n = 15) were identified to be at major and 9% (n = 28) at possible risk for adverse events. Appropriate interventions to prevent harm were required in 40 patients. Rates of major bleeding, CRNMB, recurrence, and all-cause mortality were 0.3% (95% confidence interval [CI]: 0.1-1.8), 7.2% (95% CI: 4.8-10.7), 1.0 (95% CI: 0.3-2.9), and 1.6% (95% CI: 0.7-3.8), respectively. In conclusion, following discharge of acute VTE patients, a nurse-led pathway identified one in seven (14%) patients at major or possible risk of adverse events. Preemptive interventions to reduce harm translated into the low rates of bleeding and recurrence. The authors' experience highlights the feasibility and importance of a structured clinical surveillance pathway for acute VTE patients initiating NOAC therapy.

Inflammatory regulation of stem-like cells in melanoma.

The link between inflammation, immunity and cancer is well established. In the last decade, there has been considerable excitement over cancer stem cells, believed to be a subset of tumour cells responsible for their initiation, propagation and resistance to conventional chemoradiotherapy. In this review, we discuss the characterization of cancer stem cells and describe their modulation by inflammation with a focus on melanoma.

Sensitivity of routine coagulation assays to direct oral anticoagulants: patient samples versus commercial drug-specific calibrators.

Most studies on the sensitivities of coagulation assays to direct oral anticoagulants (DOACs) are based on normal plasma spiked with anticoagulant in the laboratory. Recent studies have shown that reagent sensitivity varies significantly depending on whether spiked or patient samples are used. The aim of this study was to compare the sensitivities of routine coagulation assays in patient samples and commercial drug specific calibrators using commonly used activated partial thromboplastin time (APTT) and prothrombin time (PT) reagents (i.e., Actin FS and Neoplastine CI Plus for APTT and PT, respectively) in Australian laboratories. Samples collected at Pathology North Hunter (PN-H) for dabigatran (n=39), rivaroxaban, (n=56) or apixaban levels (n=22) between February 2013 and November 2015 were analysed and compared to two different commercial drug specific calibrators from different manufacturers for each DOAC. Our results show that dabigatran (Hyphen and Technoclone) and rivaroxaban (Stago) calibrators tend to overestimate the APTT but are similar to patient samples for PT. A cut-off DOAC level of 50 ng/mL based on results from patient samples within the laboratory can be used as the lower limit which will result in prolongation of APTT for dabigatran (sensitivity 96%, n=25) and PT for rivaroxaban (sensitivity 97%, n=29), respectively. Individual laboratories should be familiar with the sensitivity of their coagulation reagents to different DOACs including differences between patient samples versus different commercial drug specific calibrators.

Safety of anticoagulation in the treatment of venous thromboembolism in patients with haematological malignancies and thrombocytopenia: Report of 5 cases and literature review.

Venous thromboembolism (VTE) is relatively common among patients with haematological malignancies. Management is challenging because many of these patients are also thrombocytopenic and at increased risk of bleeding. Current recommendations regarding the treatment of VTE in thrombocytopenic patients with haematological malignancies are limited as there only few studies evaluating the safety and efficacy of anticoagulation in this population of patient. A literature review on the safety of antithrombotic therapy for treatment or prophylaxis of VTE in patients with haematological malignancies was undertaken. This includes a report on 5 patients with haematological malignancies at our institute who received enoxaparin for treatment of VTE while thrombocytopenic. Unlike previous case series which showed that the use of LMWH (low molecular weight heparin) is safe in this group of patients, major bleeding occurred in 2 patients, and was fatal in one case. More studies are required to evaluate the risk factors and safety of anticoagulation in these patients.

Isolated Cerebellar Spindle Cell Pseudotumor Caused by Mycobacterium Avium-Intracellulare Complex in a Patient without AIDS.

BACKGROUND: Spindle cell pseudotumors are formed by histiocytes in response to infection by Mycobacterium avium-intracellulare complex (MAC) and are rare in patients without AIDS. CASE DESCRIPTION: A 66-year-old man presented with neck pain, ataxia, and a history of sarcoidosis. A cerebellar lesion was identified on magnetic resonance imaging and surgically excised. Histopathology revealed this to be a spindle cell pseudotumor and MAC was isolated by bacterial culture of cerebrospinal fluid. Hematology revealed cluster of differentiation 4 lymphocytopenia but human immunodeficiency virus serology was negative. The patient was commenced on antimicrobial treatment that included a macrolide and remained well at 1 year follow-up. CONCLUSIONS: This rare presentation of isolated intracranial MAC was treated with surgical excision and antimicrobials with a good outcome.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN): a rare entity.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive haematological malignancy in the elderly, with a high frequency of cutaneous and bone marrow involvement and poor prognosis. We report a case of BPDCN with classic presentation and discuss its treatment and the value of different investigation tools used in diagnosis and response assessment.