Impact of perioperative direct oral anticoagulant assays: a multicenter cohort study.

BACKGROUND: There is little evidence to guide the perioperative management of patients on a direct oral anticoagulant (DOAC) in the absence of a last known dose. Quantitative serum titers may be ordered, but there is little evidence supporting this. AIMS: This multi-center retrospective cohort study of consecutive surgical in-patients with a DOAC assay, performed over a five-year period, aimed to characterize preoperative DOAC assay orders and their impact on perioperative outcomes. MATERIALS AND METHODS: Patients prescribed regular DOAC (both prophylactic and therapeutic dosing) with a preoperative DOAC assay were included. The DOAC assay titer was evaluated against endpoints. Further, patients with an assay were compared against anticoagulated patients who did not receive a preoperative DOAC assay. The primary endpoint was major bleeding. Secondary endpoints included perioperative hemoglobin change, blood transfusions, idarucizumab or prothrombin complex concentrate administration, postoperative thrombosis, in-hospital mortality and reoperation. Adjusted and unadjusted linear regression models were used for continuous data. Binary logistic models were performed for dichotomous outcomes. RESULTS: 1065 patients were included, 232 had preoperative assays. Assays were ordered most commonly by Spinal (11.9%), Orthopedics (15.4%), and Neurosurgery (19.4%). For every 10 ng/ml increase in titer, the hemoglobin decreases by 0.5066 g/L and the odds of a preoperative reversal increases by 13%. Compared to those without an assay, patients with preoperative DOAC assays had odds 1.44× higher for major bleeding, 2.98× higher for in-hospital mortality and 16.3× higher for receiving anticoagulant reversal. CONCLUSION: A preoperative DOAC assay order was associated with worse outcomes despite increased reversal administration. However, the DOAC assay titer can reflect the patient's likelihood of bleeding.

How we diagnose 2M von Willebrand disease (VWD): Use of a strategic algorithmic approach to distinguish 2M VWD from other VWD types.

INTRODUCTION: von Willebrand disease (VWD) is the most common inherited bleeding disorder and caused by an absence, deficiency or defect in von Willebrand factor (VWF). VWD is currently classified into six different types: 1, 2A, 2B, 2N, 2M, 3. Notably, 2M VWD is more often misdiagnosed as 2A or type 1 VWD than properly identified as 2M VWD. AIM: To describe an algorithmic approach to better ensure appropriate identification of 2M VWD, and reduce its misdiagnosis, as supported by sequential laboratory testing. METHODS: Comparative assessment of types 1, 2A, 2B and 2M VWD using various laboratory tests, including VWF antigen and several VWF activity assays, plus DDAVP challenge data, ristocetin-induced platelet agglutination (RIPA) data, multimer analysis and genetic testing. RESULTS: Types 1, 2A, 2B and 2M VWD give characteristic test patterns that can provisionally classify patients into particular VWD types. Notably, type 1 VWD shows low levels of VWF, but VWF functional concordance (VWF activity/Ag ratios >0.6), with both baseline assessment and post-DDAVP. Types 2A, 2B and 2M VWD show VWF functional discordance (low VWF activity/Ag ratio(s)) dependent on the defect, but type 2M separates from 2A/2B VWD based on specific test patterns, especially with collagen binding vs glycoprotein Ib binding assays. RIPA identifies 2B VWD. Multimers separate 2M from 2A/2B. CONCLUSION: We provide strategies to improve correct diagnosis of VWD, especially focussed on 2M VWD, and which can be used by most diagnostic haemostasis laboratories, reserving genetic analysis (if required) for confirmation.

The Australian experience with switching to extended half-life factor VIII and IX concentrates: On behalf of the Australian Haemophilia Centre Directors' Organisation.

INTRODUCTION: Extended half-life (EHL) factor (F) VIII and FIX concentrates became available to selected haemophilia A (HA) and haemophilia B (HB) patients in Australia in March 2018. AIM: To determine factor utilization and bleeding outcomes during the first 6 months of prophylaxis with EHL concentrates, and compare it to the last 6 months of prophylaxis with standard half-life (SHL) concentrates. METHODS: A national, retrospective study was performed using data extracted from the Australian Bleeding Disorders Registry (ABDR). Patients with ≥3 months of EHL exposure were analysed. RESULTS: A total of 129 HA patients (86 Adynovate, 43 Eloctate) and 64 HB (Alprolix) patients were included in the study. For HA, switching to EHL FVIII resulted in decreased injection frequency (3 to 2 per week), improved 'reduced adherence' rates (18% to 7%), decreased median annualized bleeding rate (ABR; 2.0 to 0.0) and increased proportion of patients with zero bleeds (44% to 64%). Actual factor utilization increased by 20 IU/kg/wk on Adynovate and 4 IU/kg/wk on Eloctate. For HB, switching to EHL FIX resulted in decreased injection frequency (2 to 1 per week), improved 'reduced adherence' rates (35% to 11%), decreased median ABR (3.0 to 2.0) and increased proportion of patients with zero bleeds (31% to 46%). Actual factor utilization decreased by 4 IU/kg/wk. There was no clinically significant inhibitor development. CONCLUSION: Compared to SHL, EHL FVIII resulted in improved bleeding outcomes, albeit at the expense of increased factor utilization. EHL FIX resulted in improved bleeding outcomes despite decreased factor utilization.

Dental extractions on direct oral anticoagulants vs. warfarin: The DENTST study.

BACKGROUND: Conflicting recommendations exist addressing the management of direct oral anticoagulants (DOACs) for invasive dental procedures. OBJECTIVES: To determine the safety of DOAC continuation compared to warfarin continuation for dental extractions with regards to bleeding outcomes. METHODS: A single-center, prospective, cohort study was performed to compare 7-day bleeding outcomes between patients who continued their DOAC, and patients on warfarin with an International Normalized Ratio (INR) between 2.0 and 4.0. Blood tests including oral anticoagulant drug levels were measured immediately prior to extraction. The gauze used to apply pressure to the socket was weighed before and after extraction to estimate blood loss. Patients were contacted by phone 2 and 7 days after extraction. RESULTS: Eighty-six patients on a DOAC had a total of 145 teeth extracted, and 21 patients on warfarin had 50 teeth extracted. There were no major bleeding events. The rate of minor plus clinically relevant nonmajor bleeding was comparable between the DOAC and warfarin cohorts (36% and 43%, respectively; odds ratio, 0.75; 95% confidence interval, 0.29-1.98). Preextraction apixaban and dabigatran levels were comparable between bleeders and nonbleeders, while rivaroxaban levels were higher in those who bled. The weight change of gauze used to tamponade the socket was similar between the 2 cohorts. CONCLUSION: Dental extractions on patients continuing DOACs led to bleeding rates similar to patients on warfarin with an INR between 2.0 and 4.0. There is no need to adjust DOAC dosing prior to dental extractions.

Acquired platelet function disorders.

The possibility of an acquired platelet function disorder should be considered in patients who present with recent onset muco-cutaneous bleeding. Despite the availability of newer and faster platelet function assays, light transmission aggregometry (LTA) remains the preferred diagnostic test. This review examines and discusses the causes of acquired platelet dysfunction; most commonly drugs, dietary factors, medical disorders and procedures. In addition to well-known antiplatelet therapies, clinicians should be alert for newer drugs which can affect platelets, such as ibrutinib. There is little clinical trial evidence to guide the management of acquired platelet function defects, but we summarise commonly employed strategies, which include addressing the underlying cause, antifibrinolytic agents, desmopressin infusions, and in selected patients, platelet transfusions.

To Maintain or Cease Non-Vitamin K Antagonist Oral Anticoagulants Prior to Minimal Bleeding Risk Procedures: A Review of Evidence and Recommendations.

For procedures associated with minimal bleeding risk, there are data and experience to support the practice of continuing vitamin K antagonists rather than interrupting therapy, to prevent exposing patients to the undue risk of developing thromboembolism during anticoagulation cessation. Despite the increasing use of non-vitamin K oral anticoagulants (NOACs), there is little evidence to guide the management of these drugs around minimal bleeding risk procedures. This review examines and discusses the major society guidelines and recommendations addressing the management of NOACs around minimal bleeding risk procedures. Additionally, it summarizes the existing evidence, and highlights the gaps in knowledge where evidence is not yet available. Finally, recommendations are made to assist the proceduralist deal with this area of limited evidence.

Lessons learnt from local real-life experience with idarucizumab for the reversal of dabigatran.

BACKGROUND: Idarucizumab is a specific antidote for the direct thrombin inhibitor oral anticoagulant dabigatran etexilate. It has been used with increasing frequency in Australia since it was granted Therapeutic Goods Administration approval in October 2016. AIMS: To assess idarucizumab usage, effect on coagulation parameters and clinical outcomes in patients who received idarucizumab in Western Sydney Local Health District (WSLHD). METHODS: A retrospective audit was conducted of all patients who received idarucizumab in WSLHD between September 2015 and December 2017. RESULTS: Of the 23 patients who received idarucizumab, 17 (74%) had bleeding, and 6 (26%) required urgent surgery/procedure. Thrombin time (TT) or activated partial thromboplastin time (APTT, when TT not available) remained prolonged at 24 h post-idarucizumab infusion in 10 of 20 (50%) patients. Renal impairment at admission was associated with prolonged TT/APTT at 24 h (P = 0.02). Of the six (26%) patients who died during hospital admission, five had raised TT/APTT at 24 h (P = 0.05). Two deaths were due to continued bleeding despite idarucizumab. Only 17% of patients received prohaemostatic treatments, and none received plasma derivatives. Despite assay availability, dabigatran drug level was only measured in eight patients. CONCLUSION: Idarucizumab helped achieve haemostasis in 15 bleeding patients and allowed 6 patients to undergo urgent surgery. Half the patients had prolonged TT/APTT at 24 h post-idarucizumab, which was more likely to occur in patients with impaired renal function.

Trenonacog alfa for prophylaxis, on-demand and perioperative management of hemophilia B.

INTRODUCTION: Current treatment for hemophilia B involves replacing the missing coagulation factor IX (FIX) with either plasma-derived or recombinant (r) FIX. Trenonacog alfa is the third normal half-life rFIX that has been granted FDA approval. Area covered: In this review, the authors examine trenonacog alfa for the treatment of hemophilia B including prophylaxis, on-demand and perioperative hemostasis. They compare the PK profile to nonacog alfa and evaluate the drug's efficacy and safety from published studies. Expert opinion: Trenonacog alfa appears to be an effective and safe treatment option for patients with hemophilia B with a PK profile similar to that of nonacog alfa. Despite the advent of extended half-life rFIX and other novel therapeutic approaches, normal half-life rFIX products, including trenonacog alfa, are likely to continue to have a place in hemophilia B treatment for at least the immediate future while the new landscape takes shape, particularly in countries that cannot afford the newer treatments.

A fatal case of acute HHV-6 myocarditis following allogeneic haemopoietic stem cell transplantation.

Human herpesvirus 6 (HHV-6) is an ubiquitous virus that can reactivate in immunocompromised hosts, resulting in diverse clinical sequelae. We describe a case of fatal acute HHV-6 myocarditis in a patient who underwent allogeneic haemopoietic stem cell transplantation (HSCT). To our knowledge, this is the first reported case of biopsy proven HHV-6 myocarditis post-HSCT.

Gene expression profiling of alcoholic liver disease in the baboon (Papio hamadryas) and human liver.

The molecular pathogenesis of alcoholic liver disease (ALD) is not well understood. Gene expression profiling has the potential to identify new pathways and altered molecules in ALD. Gene expression profiles of ALD in a baboon model and humans were compared using DNA arrays. Reverse transcriptase-polymerase chain reaction and immunohistochemistry were used for downstream analysis of array results. cDNA array analysis revealed differential expression of several novel genes and pathways in addition to genes known to be involved in ALD pathogenesis. Overall gene expression profiles were similar in both species, with a majority of genes involved with fibrogenesis and xenobiotic metabolism, as well as inflammation, oxidant stress, and cell signaling. Genes associated with stellate cell activation (collagens, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinase) were up-regulated in humans. Decreased expression of several metallothioneins was unexpected. Fourteen molecules related to the annexin family were up-regulated, including annexin A1 and A2. Immunofluorescence revealed a marked overexpression of annexin A2 in proliferating bile duct cells, hepatocyte cell surface, and selective co-localization with CD14-positive cells in human ALD. The gene expression profile of ALD is dominated by alcohol metabolism and inflammation and differs from other liver diseases. Annexins may play a role in the progression of fibrosis in ALD.