Thrombo-inflammatory response in hospitalised patients with COVID-19: a single institution experience.

BACKGROUND: Severe COVID-19 causes acute inflammation, which is complicated by venous thromboembolism events (VTE). However, it is unclear if VTE risk has evolved over time since the COVID-19 outbreak. AIMS: To determine markers of thrombo-inflammation and rates of symptomatic VTE in patients hospitalised for COVID-19 in a metropolitan hospital in Sydney, Australia. METHODS: A retrospective, single-centre, cohort study was performed by reviewing electronic medical records of consecutive patients admitted to Royal Prince Alfred Hospital between March 2020 and September 2021. This period included three waves of COVID-19 outbreaks in Australia with the ancestral, alpha and delta variants. Standard coagulation assays and inflammatory markers were recorded over 4 weeks. RESULTS: A total of 205 patients were consecutively admitted during the study period. Activated partial thromboplastin time, neutrophil count and C-reactive protein (CRP) were significantly increased in patients hospitalised in the intensive care unit (ICU) compared with non-ICU patients. The use of anti-inflammatory medication increased in 2021 compared with 2020. The mortality rate was 7.3% in our cohort. Ninety-four per cent of patients received anticoagulation with 6.3% of patients developing VTE. CONCLUSION: We observed lower rates of VTE compared to the internationally reported rate for the same period. We conclude that in the setting of controlled hospital admission rate and standard anticoagulation guidelines, COVID-19 resulted in similar thrombo-inflammatory response and VTE rates over the first 1.5 years of the pandemic.

Venous anomalies and thromboembolism.

Patients with venous anomalies are at increased risk of developing venous thromboembolism (VTE) and subsequent complications, but they are often under-recognised. While unprovoked VTE may trigger testing for inherited thrombophilias and malignancy screening, anatomic variants are considered less often. Venous anomalies increase the risk due to venous flow disturbance, resulting in hypertension, reduced flow velocity and turbulence. Recognition is important as endovascular or surgical intervention may be appropriate, these patients have a high rate of VTE recurrence if anticoagulation is ceased, and the anomalies can predispose to extensive VTE and severe post-thrombotic syndrome (PTS). In this case series, we present representative cases and radiological images of May-Thurner syndrome (MTS), inferior vena cava (IVC) variants and venous aneurysms, and review the available literature regarding optimal diagnosis and management in each condition.

Tinzaparin for venous thromboembolism in patients with renal impairment: a single-centre, prospective pilot study.

BACKGROUND: Low molecular weight heparins (LMWH) are used extensively for prophylaxis and treatment of venous thromboembolism (VTE), bridging therapy for warfarin and standard of care in cancer-associated VTE (CA-VTE). Tinzaparin has the highest molecular weight of all LMWH and relies least on renal clearance to Cockcroft-Gault creatinine clearance (CrCl) of 20 mL/min. Previous pharmacological studies have demonstrated safety and effectiveness in elderly patients. Prospective clinical trials have confirmed these findings to CrCl 20 mL/min and in CA-VTE. We describe the pilot program developed at Concord Repatriation General Hospital for tinzaparin. AIMS: We aim to confirm the deliverability of tinzaparin in patients with renal insufficiency. METHODS: Twenty patients were established on tinzaparin as therapeutic anticoagulation with CrCl or CKD-EPI estimated glomerular filtration rate (eGFR) 20-50 mL/min with an indication for anticoagulation. Tinzaparin was given as a subcutaneous injection at 175 units/kg as a single daily dose, rounded to the nearest vial size. Tinzaparin anti-Xa levels were tested at Days 2, 7 and 14 (±1 day) and transition to oral anticoagulants were allowed at clinician discretion. RESULTS: No accumulation of tinzaparin was seen into Day 14. Two patients required dose-adjustment, five patients had bleeding complications (two major, three minor) and four patients died during follow-up, all attributable to patients' comorbidities. CrCl and body surface area-standardised CrCl were significantly correlated with tinzaparin anti-Xa level only on Day 2, and this effect was lost when patients with CrCl >50 mL/min were excluded. Data from our cohort confirm the deliverability of therapeutic tinzaparin in patients with CrCl or CKD-EPI eGFR 20-50 mL/min. Bleeding and death outcomes were also comparable to other trials using tinzaparin in CA-VTE. CONCLUSION: For patients with renal insufficiency, tinzaparin represents an attractive alternative anticoagulant with once-daily administration in a range of potential indications.

Understanding vaccine-induced thrombotic thrombocytopenia (VITT).

Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare, but serious, syndrome characterised by thrombocytopenia, thrombosis, a markedly raised D-dimer and the presence of anti-platelet factor-4 (PF4) antibodies following COVID-19 adenovirus vector vaccination. VITT occurs at a rate of approximately 2 per 100 000 first-dose vaccinations and appears exceedingly rare following second doses. Our current understanding of VITT pathogenesis is based on the observations that patients with VITT have antibodies that bind to PF4 and have the ability to form immune complexes that induce potent platelet activation. However, the precise mechanisms that lead to pathogenic VITT antibody development remain a source of active investigation. Thrombosis in VITT can manifest in any vascular bed and affect multiple sites simultaneously. While there is a predilection for splanchnic and cerebral venous sinus thrombosis, VITT also commonly presents with deep vein thrombosis and pulmonary embolism. Pillars of management include anticoagulation with a non-heparin anticoagulant, intravenous immunoglobulin and 'rescue' therapies, such as plasma exchange for severe cases. VITT can be associated with a high mortality rate and significant morbidity, but awareness and optimal therapy have significantly improved outcomes in Australia. A number of questions remain unanswered, including why VITT is so rare, reasons for the predilection for thrombosis in unusual sites, how long pathological antibodies persist, and the optimal duration of anticoagulation. This review will provide an overview of the presentation, diagnostic workup and management strategies for patients with VITT.

Biology and therapy of multiple myeloma.

Genetic sequencing of the myeloma genome has not revealed a specific disease-determining genetic alteration. Multiple disease subclones exist at diagnosis and vary in clinical importance with time and drug sensitivity. New diagnostic criteria have identified indications for early introduction of therapy. Autologous stem cell transplantation remains an essential component of therapy in young and fit patients. The use of continual suppressive (maintenance) therapy has been established as an important component in therapy. Immune therapies and the harnessing of the innate immune system offer great promise for future treatments. Since 2005, quality of life, supportive therapies, and survival have dramatically improved over a decade of remarkable progress. The common manifestations of multiple myeloma, such as bone pain, fatigue and weight loss, may be non-specific and are often initially ignored or missed by patients and medical practitioners.

The changing face of cerebral venous sinus thrombosis - emerging new causes and treatments.

Cerebral venous sinus thrombosis (CVST) is an uncommon site of venous thromboembolism. CVST more commonly affects younger people and women, in stark contrast to other forms of venous thrombosis where incidence increases with age and overall affects men. Traditional risk factors for the development of CVST include endogenous and exogenous estrogen (combined oral contraceptives and pregnancy and the puerperium), thrombophilias and rare haematologic disorders. New and emerging risk factors include obesity, polycystic ovary syndrome, COVID-19 infection, and vaccine-induced thrombocytopenia and thrombosis (VITT) and VITT-like disorders. Management centres around anticoagulation, managing the underlying cause, and consideration of invasive measures including endovascular thrombolysis and/or thrombectomy and craniectomy for severe cases. This review discusses the emerging risk factors and their identification, evidence for treatment including the use of direct oral anticoagulants, and the role of invasive management options.

Exploring the effects of Factor Xa inhibitors on thrombin generation in people with haemophilia.

Optimal management of cardiovascular disease (CVD) in people with haemophilia (PWH) is a growing issue, given the continuing improvement in life expectancy among PWH. The evolving treatment paradigms targeting higher trough levels and the advent of non-factor replacement therapies (NFRT) means much of the 'protection' PWH were thought to have against CVD may be lost. There is a paucity of evidence regarding the safety of using anticoagulants in PWH. We designed a study assessing the thrombin generation (TG) of PWH of different severities and treatments, compared to non-haemophilia patients receiving a Factor Xa (FXa) inhibitor (apixaban or rivaroxaban), healthy controls, and assessing TG parameters of adding FXa inhibitor to the plasma of PWH receiving emicizumab prophylaxis. In total, 40 patients were included. TG was initiated with 5pM tissue factor (TF) using the calibrated automated thrombinoscope. Compared to those with mild haemophilia, patients receiving a FXa inhibitor had higher endogenous thrombin potential (ETP) (1278.42 vs 1831.36) and velocity index (40.71 vs 112.56), but both had a similar peak height (154.0 vs 262.63) and time to peak (both 5.83). People with severe haemophilia receiving emicizumab had significantly improved TG parameters compared to those not receiving emicizumab - ETP 1678.11 vs 809.96 and peak height 233.8 vs 92.05; however, when FXa inhibitor was added their TG parameters deteriorated to the severe haemophilia range (ETP 1179.60 and peak height 103.05). TG may provide additional useful information regarding the use of anticoagulants in PWH.

Reducing the risk of atherosclerotic cardiovascular disease in people with hemophilia: the importance of primary prevention.

Revolutionary advances in the treatment of hemophilia has led to a significant improvement in life expectancy. Associated with this has been an increase in age-related diseases especially atherosclerotic cardiovascular disease (CVD). While people with hemophilia (PWH) develop atherosclerosis at rates similar to those of the general population, rates of atherothrombosis and mortality related to CVD have been much lower, due to their hypocoagulable state. Changing treatment paradigms, aimed at reducing the risk of bleeding by improving hemostasis to levels approaching normality, has meant that the protection they are thought to have had may be lost. CVD risk factors are just as common in PWH as in the general population, but appear to be undertreated. In particular, primary prevention of CVD is vital in all individuals, but particularly in PWH as treatment of established CVD can be difficult. Active identification and management of CVD risk factors, such as obesity, physical inactivity, hypertension, and hypercholesterolemia, is required. In particular, statins have been shown to significantly reduce cardiovascular and all-cause mortality with few adverse events and no increased risk of bleeding in the general population, and their use needs urgent assessment in PWH. Further longitudinal research into preventing CVD in PWH, including accurate CVD risk assessment, is required to optimize prevention and management.

The Efficacy and Safety of DOACs in Inherited Antithrombin Deficiency: A Cohort Study from a Tertiary Referral Center.

BACKGROUND: Individuals with inherited antithrombin deficiency (IATD) have a high risk of venous thromboembolism (VTE). Most VTEs are managed with direct oral anticoagulants (DOACs), but the utility of DOACs in antithrombin deficiency (ATD) is unreported. MATERIALS AND METHODS: Patients with IATD treated with DOAC were identified from our institutions' IATD registry. We assessed patients' characteristics, ATD type, and initial VTE characteristics, thrombosis recurrence and bleeding rates. RESULTS: Thirty-three patients received DOACs for 73 (38.5-111.5) months (median (interquartile range)). Prior to taking DOACs, 12 (36%) patients had VTE recurrence: these occurred after anticoagulation was ceased (4), nonadherence to VKA prior to DOAC use (3), or during heparin use in pregnancy (5). There were no VTE recurrences on standard-dose DOAC, except in a noncompliant patient receiving dabigatran. There was one recurrence with compliant DOAC use-a patient receiving rivaroxaban 10 mg. Six (18%) patients experienced clinically relevant bleeding, which was predominantly menorrhagia (5/6). One major bleeding event, intracranial hemorrhage, occurred in a patient receiving full-dose rivaroxaban who had refractory hypertension (0.5 events/100 patient-years). In this cohort, compliant DOAC users had an overall VTE recurrence rate of 0.5/100 patient-years, whereas with low-dose DOACs the event rate was 3.5/100 patient-years. CONCLUSION: Standard-dose DOACs appear efficacious and relatively safe in IATD.

Effective interventions to increase representation of under-served groups in randomised trials in UK and Ireland: a scoping literature review.

Background: Participants in clinical trials often do not reflect the populations that could benefit from the treatments being investigated. There are known barriers to trial participation for under-served groups, but limited evidence on strategies to alleviate these barriers to improve representation. This scoping review aimed to identify effective interventions and design features that improve the representation `of under-served groups in trials, focusing on the UK and Ireland. Methods: We included methodological research studies that reported interventions to improve representation of ethnic minority groups, socioeconomically disadvantaged groups, older people, or those with impaired capacity to consent to randomised controlled trials, conducted in the UK and Ireland, published between 2000-2021. Systematic searches were conducted in November 2021 and data were independently extracted by two authors and narratively synthesised. Results: Seven studies were included: one randomised controlled study embedded in five trials, one mixed-methods study, and five studies reporting 'lessons learnt' from one trial. We categorised the 47 reported interventions or strategies into nine broad themes: Recruitment sites, recruitment settings, community engagement, and communication with participants, incentives, inclusion criteria, flexibility, patient documentation, and the consent process. Only 28/47 interventions were evaluated, 23 of which were comparison of recruitment pathways.The randomised study found that a £100 incentive mentioned in the invitation letter increased positive responses overall across drug trials in cardiovascular disease and hypertension, but not for older people or those living in the most deprived areas. Invitation letters via GPs and working with communities were reported as successful recruitment pathways in recruiting different under-served populations. Conclusions: Interventions aiming to improve the recruitment of under-served groups in the UK and Ireland were reported across seven papers, but their effectiveness was rarely rigorously evaluated. Included studies were context specific. Using a variety of recruitment methods is likely to help achieve a more diverse cohort.

Not all people are included in medical research, even though they should be. This is especially true for people from certain groups, called 'under-served groups', and there has been a recent focus on improving inclusion of these groups in clinical trials. Researchers have developed tools to help plan studies that include under-served groups. These tools help researchers to consider who should be included in a study, identify barriers to including certain groups, and develop strategies to overcome those barriers. A team of researchers reviewed existing research to see what strategies have been successful in increasing the participation of under-served groups in clinical trials in the UK and Ireland. They looked at ethnic minority groups, people experiencing disadvantages in income, education, housing and/or employment (socioeconomic disadvantage), older people, and people with limited decision-making abilities (impaired capacity to consent). They found seven studies that provided helpful insights. Two of these studies were designed specifically to test different methods for recruiting under-served groups. The other five studies were based on lessons learned from trials that included these groups. One study found that offering a £100 incentive in recruitment letters led to an increase in responses, but not specifically for older people or people experiencing socioeconomic disadvantage. Another study found that letters from general practitioners were most effective for recruiting older adults. One study found that community engagement was successful for recruiting an ethnic minority group. Overall, the review concluded that there is little evidence for strategies that will increase the inclusion of under-served groups in clinical trials in the UK and Ireland. However, there are several promising approaches that could overcome barriers and make research more inclusive.

Measuring Emicizumab Levels in the Hemostasis Laboratory.

Emicizumab is a bi-specific antibody that in recent years has been introduced in many countries as a prophylactic agent for bleed prevention in cases of severe hemophilia A, and in some cases of moderate HA. It can be used in individuals with HA with and without FVIII inhibitors, because the drug is not a target for these inhibitors. Emicizumab was developed as a fixed weight-based dose and does not normally need laboratory monitoring, but in some circumstances such as a treated HA patient with unexpected bleeding episodes, a laboratory assay is justified. This chapter describes to performance of a one-stage clotting assay to measure emicizumab.

Venous Thromboembolism and Estrogen-Containing Gender-Affirming Hormone Therapy.

Gender-affirming therapy involves the use of hormones to develop the physical characteristics of the identified gender and suppressing endogenous sex hormone production. Venous thromboembolism (VTE) is a known risk of exogenous estrogen therapy, and while evidence of VTE risk among transgender women using modern gender-affirming hormone therapy (GAHT) is still emerging, it is thought to affect up to 5% of transgender women. Historically, GAHT was associated with a high risk of VTE; however, modern preparations are less thrombogenic mainly due to significantly lower doses used as well as different preparations. This review presents the available literature regarding the following four topics: (1) risk of VTE among transgender women receiving estradiol GAHT, (2) how the route of administration of estradiol affects the VTE risk, (3) perioperative management of GAHT, (4) VTE risk among adolescents on GAHT. There is a need for large, longitudinal studies of transgender women using GAHT to further characterize VTE risk and how this is affected by factors such as patient age, duration of GAHT use, tobacco use, body mass index, and comorbidities. Future studies in these areas could inform the development of clinical guidelines to improve the care of transgender people.

Adherence and persistence to direct factor Xa inhibitors in the community following newly diagnosed venous thromboembolism: a retrospective pharmacy-linkage study.

OBJECTIVES: To assess adherence and persistence to the direct factor Xa inhibitor oral anticoagulants in the community following newly diagnosed venous thromboembolism (VTE). METHODS: We retrospectively reviewed community pharmacy dispensing data on all patients with newly diagnosed VTE who were prescribed direct factor Xa inhibitors, apixaban or rivaroxaban, between January 2018 and December 2019 at our institution. Proportion of days covered (PDC) was used to assess adherence at 90 days, and 6- and 12 months. Persistence was measured by participants having both dispensed supply of a factor Xa inhibitor at the end of the treatment period and no significant gaps (maximum of 60 days) in supply. KEY FINDINGS: There were 225 patients identified. Overall PDC at 90 days, 6- and 12 months were 84.6%, 86.2% and 86.1%, respectively. Apixaban had a higher mean overall PDC than rivaroxaban (86.2% and 80.6%, respectively). Females demonstrated higher PDC compared with males (87.3% versus 81.2%). Overall, 133 patients (64%) were persistent with therapy. CONCLUSIONS: In patients with newly diagnosed VTE treated with a factor Xa inhibitor, adherence rates are high at >80%, with females and those prescribed apixaban exhibiting higher adherence. These findings may assist clinicians in identifying those patients with VTE at risk of poor adherence.

Pulmonary embolus.

BACKGROUND: Pulmonary embolism (PE) remains a common problem and can present with nonspecific symptoms and signs. Anticoagulation is the mainstay of management, the duration of which often depends on the clinical circumstances of the PE. OBJECTIVE: The aim of this article is to review the epidemiology, clinical presentation, diagnosis, management and long-term complications of PE. DISCUSSION: The incidence of PE appears to be increasing worldwide. Common risk factors include recent surgery, trauma, malignancy and oestrogen exposure. Diagnosis relies on a combination of clinical findings, laboratory tests and radiological imaging, often incorporating clinical prediction tools. Objectively confirmed PE requires anticoagulation, usually with a direct oral anticoagulant (DOAC), of at least three months' duration, but indefinite anticoagulation is being considered increasingly because of the heightened risk for recurrence following anticoagulation cessation, and overall safety of DOACs. Chronic thromboembolic pulmonary hypertension is rare but associated with significant morbidity and mortality.

Emicizumab assay evaluations and results from an Australian field study of emicizumab measurement.

Emicizumab is a recombinant, humanised bispecific antibody which acts as a FVIII mimetic and is a therapeutic option for haemophilia A. Plasma emicizumab levels may sometimes be required. Multiple one-stage clotting assays (OSA) and one human component chromogenic assay (CSA) were used to measure emicizumab both centrally and by a field study. The study samples drug concentrations range included within therapy range of 35-70 µg/mL. All assays were modified from traditional FVIII assays to enable replacement of plasma calibrators with emicizumab calibrators. Central laboratory OSA mean recovery levels (target) for six spike levels of emicizumab were close to target at 120.5 (120), 81.6 (80), 40.9 (40), 21.4 (20), 10.7 (10) and 5.5 (5) µg/mL. Field study OSA mean recoveries were similarly close to target. Between method coefficients of variation were <9% in both the central laboratory and field study assays, except for the 5 µg/mL sample which was 12.3%. CSA mean recoveries were within 10% of target at 80, 50 and 20 µg/mL levels. This study affirms that emicizumab can be measured by OSA using many types of activated partial thromboplastin time (APTT) reagents and is also measurable by the human CSA. The assays showed good precision, accuracy and linearity both locally and in a field study setting.

C-reactive protein, immunothrombosis and venous thromboembolism.

C-reactive protein (CRP) is a member of the highly conserved pentraxin superfamily of proteins and is often used in clinical practice as a marker of infection and inflammation. There is now increasing evidence that CRP is not only a marker of inflammation, but also that destabilized isoforms of CRP possess pro-inflammatory and pro-thrombotic properties. CRP circulates as a functionally inert pentameric form (pCRP), which relaxes its conformation to pCRP* after binding to phosphocholine-enriched membranes and then dissociates to monomeric CRP (mCRP). with the latter two being destabilized isoforms possessing highly pro-inflammatory features. pCRP* and mCRP have significant biological effects in regulating many of the aspects central to pathogenesis of atherothrombosis and venous thromboembolism (VTE), by directly activating platelets and triggering the classical complement pathway. Importantly, it is now well appreciated that VTE is a consequence of thromboinflammation. Accordingly, acute VTE is known to be associated with classical inflammatory responses and elevations of CRP, and indeed VTE risk is elevated in conditions associated with inflammation, such as inflammatory bowel disease, COVID-19 and sepsis. Although the clinical data regarding the utility of CRP as a biomarker in predicting VTE remains modest, and in some cases conflicting, the clinical utility of CRP appears to be improved in subsets of the population such as in predicting VTE recurrence, in cancer-associated thrombosis and in those with COVID-19. Therefore, given the known biological function of CRP in amplifying inflammation and tissue damage, this raises the prospect that CRP may play a role in promoting VTE formation in the context of concurrent inflammation. However, further investigation is required to unravel whether CRP plays a direct role in the pathogenesis of VTE, the utility of which will be in developing novel prophylactic or therapeutic strategies to target thromboinflammation.

Measurable Residual Disease in Acute Myeloid Leukemia Using Flow Cytometry: A Review of Where We Are and Where We Are Going.

The detection of measurable residual disease (MRD) has become a key investigation that plays a role in the prognostication and management of several hematologic malignancies. Acute myeloid leukemia (AML) is the most common acute leukemia in adults and the role of MRD in AML is still emerging. Prognostic markers are complex, largely based upon genetic and cytogenetic aberrations. MRD is now being incorporated into prognostic models and is a powerful predictor of relapse. While PCR-based MRD methods are sensitive and specific, many patients do not have an identifiable molecular marker. Immunophenotypic MRD methods using multiparametric flow cytometry (MFC) are widely applicable, and are based on the identification of surface marker combinations that are present on leukemic cells but not normal hematopoietic cells. Current techniques include a "different from normal" and/or a "leukemia-associated immunophenotype" approach. Limitations of MFC-based MRD analyses include the lack of standardization, the reliance on a high-quality marrow aspirate, and variable sensitivity. Emerging techniques that look to improve the detection of leukemic cells use dimensional reduction analysis, incorporating more leukemia specific markers and identifying leukemic stem cells. This review will discuss current methods together with new and emerging techniques to determine the role of MFC MRD analysis.