Real-world decision-making in the management of patients presenting with major bleeding on rivaroxaban: the Auckland regional experience.

BACKGROUND: Rivaroxaban is used increasingly as an oral anticoagulant; however, a specific reversal agent is not currently available in the Australasian setting. There is also variation across international consensus guidelines regarding advice on the management of bleeding. AIMS: To review the real-world management of rivaroxaban-associated major bleeding across the public hospitals of New Zealand's largest city. METHODS: A retrospective cohort analysis was performed of patients prescribed rivaroxaban who presented to four metropolitan hospital Emergency Departments between 1 August 2018 and 31 May 2021 with major bleeding as defined by the International Society on Thrombosis and Haemostasis. RESULTS: One hundred and twelve patients were identified, accounting for 115 major bleeding presentations. Upper gastrointestinal (34%) and intracranial (31%) bleeding sites were most common. Procedural intervention was required in 44% of patients. Haemostatic management involved tranexamic acid (TXA) in 26%, prothrombin complex concentrate (PCC) in 55% (dose range 1000-6000 IU or 10-65 IU/kg), vitamin K in 16% and fresh frozen plasma in 1%. Rivaroxaban was discontinued permanently following 56 (49%) events, switched to another anticoagulant in 24 (21%) and withheld in 30 (26%) from 2 days to 3 months (median 8.5 days). All-cause mortality at 90 days after bleeding was 17% (19 patients), and the incidence of combined venous and arterial thrombotic events was 10%. CONCLUSIONS: There is considerable heterogeneity in the acute clinical management of patients presenting with rivaroxaban-related major bleeding. The use of PCC and dosage administered is inconsistent. TXA was utilised in only approximately one-quarter of all cases. Evidence-based guidance for treating rivaroxaban-related bleeding would improve the management of these patients and potentially improve clinical outcomes.

Real-world experience with limited screening for occult malignancy in patients presenting with spontaneous venous thromboembolism: a single-centre, retrospective cohort study.

Spontaneous venous thromboembolism (VTE) may represent the first manifestation of previously undiagnosed malignancy; however, contemporary international guidelines call for a limited approach to screening for malignancy in such patients. This retrospective cohort study of 328 patients presenting to the Auckland City Hospital Thrombosis Unit identified 17 patients who were subsequently diagnosed with some form of malignancy within 12 months of their presentation. Review of their history, physical examination and limited age and gender-appropriate cancer screening investigations as described by the National Institute for Clinical Excellence and International Society of Thrombosis and Haemostasis guidelines revealed that all 17 would have been safely diagnosed by the 'limited' screening approach endorsed by these guidelines, thus presenting a 'real-world' basis for clinicians to pursue 'limited' screening for malignancy in their everyday practice in patients with spontaneous VTE.

Diagnosis and treatment of MYH9-RD in an Australasian cohort with thrombocytopenia.

MYH9-related disorders (MYH9-RDs) caused by mutation of the MYH9 gene which encodes non-muscle myosin heavy-chain-IIA (NMMHC-IIA), an important motor protein in hemopoietic cells, are the most commonly encountered cause of inherited macrothrombocytopenia. Despite distinguishing features including an autosomal dominant mode of inheritance, giant platelets on the peripheral blood film accompanied by leucocytes with cytoplasmic inclusion bodies (döhle-like bodies), these disorders remain generally under-recognized and often misdiagnosed as immune thrombocytopenia (ITP). This may result in inappropriate treatment with corticosteroids, immunosupressants and in some cases, splenectomy. We explored the efficacy of next generation sequencing (NGS) with a candidate gene panel to establish the aetiology of thrombocytopenia for individuals who had been referred to our center from hematologists in the Australasian region in whom the cause of thrombocytopenia was suspected to be secondary to an inherited condition but which remained uncharacterized despite phenotypic investigations. Pathogenic MYH9 variants were detected in 15 (15/121, 12.4%) individuals and the pathogenecity of a novel variant of uncertain significance was confirmed in a further two related individuals following immunofluorescence (IF) staining performed in our laboratory. Concerningly, only one (1/17) individual diagnosed with MYH9-RD had been referred with this as a presumptive diagnosis, in all other cases (16/17, 94.1%), a diagnosis was not suspected by referring clinicians, indicating a lack of awareness or a failing of our diagnostic approach to these conditions. We examined the mean platelet diameter (MPD) measurements as a means to better identify and quantify platelet size. MPDs in cases with MYH9-RDs were significantly larger than controls (p < 0.001) and in 91% were greater than a previously suggested threshold for platelets in cases of ITP. In addition, we undertook IF staining in a proportion of cases and confirm that this test and/or NGS are satisfactory diagnostic tests. We propose that fewer cases of MYH9-RDs would be missed if diagnostic algorithms prioritized IF and/or NGS in cases of thrombocytopenia associated with giant platelets, even if döhle-like bodies are not appreciated on the peripheral blood film. Finally, our report describes the long-term use of a thrombopoietin agonist in a case of MYH9-RD that had previously been diagnosed as ITP, and demonstrates that treatment with these agents may be possible, and is well tolerated, in this group of patients.

Low-dose aspirin for preventing recurrent venous thromboembolism.

BACKGROUND: Patients who have had a first episode of unprovoked venous thromboembolism have a high risk of recurrence after anticoagulants are discontinued. Aspirin may be effective in preventing a recurrence of venous thromboembolism. METHODS: We randomly assigned 822 patients who had completed initial anticoagulant therapy after a first episode of unprovoked venous thromboembolism to receive aspirin, at a dose of 100 mg daily, or placebo for up to 4 years. The primary outcome was a recurrence of venous thromboembolism. RESULTS: During a median follow-up period of 37.2 months, venous thromboembolism recurred in 73 of 411 patients assigned to placebo and in 57 of 411 assigned to aspirin (a rate of 6.5% per year vs. 4.8% per year; hazard ratio with aspirin, 0.74; 95% confidence interval [CI], 0.52 to 1.05; P=0.09). Aspirin reduced the rate of the two prespecified secondary composite outcomes: the rate of venous thromboembolism, myocardial infarction, stroke, or cardiovascular death was reduced by 34% (a rate of 8.0% per year with placebo vs. 5.2% per year with aspirin; hazard ratio with aspirin, 0.66; 95% CI, 0.48 to 0.92; P=0.01), and the rate of venous thromboembolism, myocardial infarction, stroke, major bleeding, or death from any cause was reduced by 33% (hazard ratio, 0.67; 95% CI, 0.49 to 0.91; P=0.01). There was no significant between-group difference in the rates of major or clinically relevant nonmajor bleeding episodes (rate of 0.6% per year with placebo vs. 1.1% per year with aspirin, P=0.22) or serious adverse events. CONCLUSIONS: In this study, aspirin, as compared with placebo, did not significantly reduce the rate of recurrence of venous thromboembolism but resulted in a significant reduction in the rate of major vascular events, with improved net clinical benefit. These results substantiate earlier evidence of a therapeutic benefit of aspirin when it is given to patients after initial anticoagulant therapy for a first episode of unprovoked venous thromboembolism. (Funded by National Health and Medical Research Council [Australia] and others; Australian New Zealand Clinical Trials Registry number, ACTRN12605000004662.).

Two Weeks of Low Molecular Weight Heparin for Isolated Symptomatic Distal Vein Thrombosis (TWISTER study).

BACKGROUND: Treatment of low-risk patients with isolated symptomatic distal deep vein thrombi (IDDVT) is uncertain. OBJECTIVE: assess whether two weeks of therapeutic anticoagulation is efficacious/safe for IDDVT. PRIMARY OUTCOME: symptomatic three-month venous thromboembolism (VTE) incidence in the two-week anticoagulation group. Secondary outcomes included post-thrombotic syndrome (PTS) and bleeding. METHODS: Prospective multicentre cohort study. Consecutive low-risk IDDVT patients enrolled within 72 h of diagnosis and treated with therapeutic dose enoxaparin or rivaroxaban. At two weeks, patients had repeat complete whole leg compression ultrasound (CUS)/clinical review. If resolution of leg symptoms AND no radiological evidence of thrombus extension, anticoagulation was stopped. If ongoing symptoms and/or radiographic extension within distal veins, anticoagulation was continued for four more weeks. Patients with extension into the popliteal vein on two-week ultrasound were treated off-study. Patients were reviewed at three and six months. FINDINGS/INTERPRETATION: 241 eligible patients received ≥2 weeks anticoagulation. 167/241 (69%) were assigned to the 2-week anticoagulation group; 71/241 (30%) to the six-week anticoagulation group; 3/241 patients (1%) had extension into the popliteal vein on two-week CUS. Two patients in the two-week anticoagulation group had symptomatic IDDVT recurrence in ≤3 months; VTE recurrence 2/156; 1.3%(95% CI 0.05-4.85%). 69% of patients had complete resolution of symptoms within two weeks. Six-month PTS rates were 8/184, 4.4%(95% CI 2.1-8.5%). No major bleeding was reported. Our findings suggest it's safe/efficacious to stop therapeutic anticoagulation at two weeks in low-risk IDDVT patients with resolution of symptoms/no extension on ultrasound. This could replace 6-12 weeks of anticoagulation for ambulatory, low-risk IDDVT patients. TRIAL REGISTRATION: ClinicalTrials.govNCT01252420.

Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism.

CONTEXT: When unfractionated heparin is used to treat acute venous thromboembolism, it is usually administered by intravenous infusion with coagulation monitoring, which requires hospitalization. However, subcutaneous administration of fixed-dose, weight-adjusted, unfractionated heparin may be suitable for inpatient and outpatient treatment of venous thromboembolism. OBJECTIVE: To determine if fixed-dose, weight-adjusted, subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin for treatment of venous thromboembolism. DESIGN, SETTING, AND PATIENTS: Randomized, open-label, adjudicator-blinded, noninferiority trial of 708 patients aged 18 years or older with acute venous thromboembolism from 6 university-affiliated clinical centers in Canada and New Zealand conducted from September 1998 through February 2004. Of the randomized patients, 11 were subsequently excluded from the analysis of efficacy and 8 from the analysis of safety. INTERVENTIONS: Unfractionated heparin was administered subcutaneously as an initial dose of 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours (n = 345). Low-molecular-weight heparin (dalteparin or enoxaparin) was administered subcutaneously at a dose of 100 IU/kg every 12 hours (n = 352). Both treatments could be administered out of hospital and both were overlapped with 3 months of warfarin therapy. MAIN OUTCOME MEASURES: Recurrent venous thromboembolism within 3 months and major bleeding within 10 days of randomization. RESULTS: Recurrent venous thromboembolism occurred in 13 patients in the unfractionated heparin group (3.8%) compared with 12 patients in the low-molecular-weight heparin group (3.4%; absolute difference, 0.4%; 95% confidence interval, -2.6% to 3.3%). Major bleeding during the first 10 days of treatment occurred in 4 patients in the unfractionated heparin group (1.1%) compared with 5 patients in the low-molecular-weight heparin group (1.4%; absolute difference, -0.3%; 95% confidence interval, -2.3% to 1.7%). Treatment was administered entirely out of hospital in 72% of the unfractionated heparin group and 68% of the low-molecular-weight heparin group. CONCLUSION: Fixed-dose subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin in patients with acute venous thromboembolism and is suitable for outpatient treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00182403.

Edoxaban for treatment of venous thromboembolism in patients with cancer. Rationale and design of the Hokusai VTE-cancer study.

Direct oral anticoagulants may be effective and safe for treatment of venous thromboembolism (VTE) in cancer patients, but they have not been compared with low-molecular-weight heparin (LMWH), the current recommended treatment for these patients. The Hokusai VTE-cancer study is a randomised, open-label, clinical trial to evaluate whether edoxaban, an oral factor Xa inhibitor, is non-inferior to LMWH for treatment of VTE in patients with cancer. We present the rationale and some design features of the study. One such feature is the composite primary outcome of recurrent VTE and major bleeding during a 12-month study period. These two complications occur frequently in cancer patients receiving anticoagulant treatment and have a significant impact. The evaluation beyond six months will fill the current gap in the evidence base for the long-term treatment of these patients. Based on the observation that the risk of recurrent VTE in patients with active cancer is similar to that in those with a history of cancer, the Hokusai VTE-cancer study will enrol patients if whose cancer was diagnosed within the past two years. In addition, patients with incidental VTE are eligible because their risk of recurrent VTE is similar to that in patients with symptomatic disease. The unique design features of the Hokusai VTE-cancer study should lead to enrolment of a broad spectrum of cancer patients with VTE who could benefit from oral anticoagulant treatment.

Novel fibrinogen truncation with deletion of Bbeta chain residues 440-461 causes hypofibrinogenaemia.

A 24-year-old male with hepatitis C was initially diagnosed with hypofibrinogenaemia during investigations prior to a liver biopsy. He had a low functional and gravimetric fibrinogen concentration of 1.0 mg/mL and DNA sequencing of all exons, exon-intron boundaries and promoter regions of the fibrinogen Aalpha, Bbeta, and gamma genes revealed a single heterozygous g-->a mutation at nucleotide 8035 of the Bbeta gene. This creates a premature stop at the Trp 440 codon and results in a 22-residue truncation of the Bbeta chain. Analysis of purified plasma fibrinogen by SDS PAGE, reverse phase HPLC and ESI MS, however, failed to detect any of the truncated chains in the plasma fibrinogen. The non-expression of aberrant molecules was further confirmed by functional analysis, which revealed normal fibrin polymerisation. The principal structural feature of the independently folding betaD domain is its five-stranded anti-parallel beta sheet. The deletion here of residues 440 to 461 removes the second strand from this sheet structure and appears to impact on the viability of the nascent chain and its ability to be incorporated into mature fibrinogen molecules. The mutation does not however provoke the formation of hepatic inclusion bodies.

Prognostic significance of residual venous obstruction in patients with treated unprovoked deep vein thrombosis: a patient-level meta-analysis.

Residual venous obstruction (RVO) could improve the stratification of the risk of recurrence after unprovoked deep vein thrombosis (DVT), but results from clinical studies and study-level meta-analyses are conflicting. It was the objective of this analysis to determine if RVO is a valid predictor of recurrent venous thromboembolism (VTE) in patients with a first unprovoked DVT who had received at least three months of anticoagulant therapy. Individual patient data were obtained from the datasets of original studies, after a systematic search of electronic databases (Medline, Embase, Cochrane Library), supplemented by manual reviewing of the reference lists and contacting content experts. A multivariate, shared-frailty Cox model was used to calculate hazard ratios (HRs) for recurrent VTE, including, as covariates: RVO; age; sex; anticoagulation duration before RVO assessment; and anticoagulation continuation after RVO assessment. A total of 2,527 patients from 10 prospective studies were included. RVO was found in 1,380 patients (55.1%) after a median of six months from a first unprovoked DVT. Recurrent VTE occurred in 399 patients (15.8%) during a median follow-up of 23.3 months. After multivariate Cox analysis, RVO was independently associated with recurrent VTE (HR = 1.32, 95% confidence interval [CI]: 1.06-1.65). The association was stronger if RVO was detected early, i.e. at three months after DVT (HR = 2.17; 95% CI: 1.11-4.25), but non-significant if detected later, i.e. >6 months (HR = 1.19; 95% CI: 0.87-1.61). In conclusion, after a first unprovoked DVT, RVO is a weak overall predictor of recurrent VTE. The association is stronger if RVO is detected at an earlier time (3 months) after thrombosis.

Two missense mutations identified in venous thrombosis patients impair the inhibitory function of the protein Z dependent protease inhibitor.

Protein Z-dependent protease inhibitor (ZPI) is a plasma inhibitor of factor (F)Xa and FXIa. In an earlier study, five mutations were identified within the ZPI gene of venous thrombosis patients and healthy controls. Two of these were nonsense mutations and three were missense mutations in important regions of the protein. Here we report that two of these latter three mutations, F145L and Q384R, impair the inhibitory function of ZPI in vitro. Recombinant wild-type and mutant proteins were prepared; stability in response to thermal challenge was similar. Inhibition of FXa in the presence of the cofactor protein Z was reduced 68-fold by the Q384R mutant; inhibition of FXIa by the F145L mutant was reduced two- to three-fold compared to the wild-type ZPI. An analysis of all five ZPI mutations was undertaken in a cohort of venous thrombosis patients (n=550) compared to healthy controls (n=600). Overall, there was a modest increase in incidence of these mutations in the thrombosis group (odds ratio 2.0, 1.05-3.7, p=0.044). However, in contrast to W324X (nonsense mutation), the Q384R missense mutation and R88X nonsense mutation were evenly distributed in patients and controls; F145L was rare. The final mutation (S143Y) was also rare and did not significantly alter ZPI function in laboratory studies. The F145L and particularly the Q384R mutation impaired the function of the coagulation inhibitor ZPI; however, there was no convincing association between these mutations and venous thrombosis risk. The functional role for ZPI in vivo has yet to be clarified.

Posttreatment ultrasound-detected residual venous thrombosis: a risk factor for recurrent venous thromboembolism and mortality.

PURPOSE OF REVIEW: The cumulative risk of recurrent venous thrombosis may rise to 30% over 8 years. Extended oral anticoagulation is effective but major bleeding is increased. To balance these risks attention has focused on identifying patients with the highest likelihood of recurrence for whom continued therapy is most beneficial. Another issue of interest has been the increased probability of death after venous thrombosis, due primarily to malignancy but also to vascular disease. RECENT FINDINGS: Unprovoked events and cancer are known to be associated with recurrent thrombosis. Residual posttreatment thrombosis confirmed by compression ultrasound is regarded as another risk for recurrence. Confounders in the published studies are the patient mix and the ultrasound technique employed. Other variables such as gender and D-dimer may also predict risk. Although arterial disease is increased in patients with venous thromboses, the association between idiopathic venous thromboembolism and atherosclerosis remains circumstantial. SUMMARY: There are no validated approaches for predicting recurrent venous events. Ultrasound interrogation for residual thrombosis after primary therapy may improve treatment stratification by defining patients suitable for extended anticoagulation.

The challenge arising from the cost of haemophilia care: an audit of haemophilia treatment at Auckland Hospital.

AIMS: To compare treatment patterns in adults and children with haemophilia and to estimate the financial impact of the changing practice of haemophilia care. METHODS: A retrospective audit of replacement coagulation factor usage in all patients with haemophilia treated at the Auckland Haemophilia Centre during 2001. RESULTS: A total of 69 males with haemophilia were included in the audit. Twelve children under 16 years old (nine on recombinant products) and six adults (all on plasma products) received prophylactic treatment. The remaining patients used treatment on demand. The cohort included eight patients with factor VIII inhibitors. The estimated cost of replacement products used was around 3 million dollars for the 23 children and 2.2 dollars million for the 46 adults. CONCLUSIONS: Children with severe haemophilia are predominantly treated with recombinant products on regular prophylaxis, whereas adults are largely treated on demand with plasma-derived products. This is in line with international practice as regular prophylaxis has been shown to improve the quality of life for people with haemophilia and in the long term is cost effective. The problem in the short term is that prophylaxis is significantly more expensive than on-demand treatment. We estimate that the cost of replacement product will increase by at least 5% per annum as the children with haemophilia grow.

Mutations within the protein Z-dependent protease inhibitor gene are associated with venous thromboembolic disease: a new form of thrombophilia.

Protein Z-dependent protease inhibitor (ZPI) is a serpin that inhibits the activated coagulation factors X and XI. The precise physiological significance of ZPI in the control of haemostasis is unknown although a deficiency of ZPI may be predicted to alter this balance. The coding region of the ZPI gene was screened for mutations using denaturing high-performance liquid chromatography. 16 mutations/polymorphisms within the coding region of ZPI were identified including two mutations, which generated stop codons at residues R67 and W303. We observed nonsense mutations within the ZPI gene in 4.4% of thrombosis patients (n = 250) compared with 0.8% of controls (n = 250). The difference in distribution of stop codon mutations between thrombosis patients and controls was significant (P = 0.02) with an odds ratio of 5.7 (95% confidence interval, 1.25-26.0). Our results suggest an association between ZPI deficiency and venous thrombosis and we propose that ZPI deficiency is potentially a new form of thrombophilia.