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.

Combined Liver-Kidney Transplant for Juvenile Polycystic Kidney Disease and Concomitant Hereditary Factor V Deficiency.

Factor V deficiency is a congenital bleeding diathesis that, in selected cases, may be managed with liver transplant. In this case, we describe the treatment of an adult patient with kidney failure secondary to juvenile onset polycystic kidney disease who received a combined liver-kidney transplant as a method to manage the risks associated with the need for a kidney transplantin the setting of factorV deficiency and high sensitization.

Building platelet phenotypes: Diaphanous-related formin 1 (DIAPH1)-related disorder.

Variants of the Diaphanous-Related Formin 1 (DIAPH-1) gene have recently been reported causing inherited macrothrombocytopenia. The essential/"diagnostic" characteristics associated with the disorder are emerging; however, robust and complete criteria are not established. Here, we report the first cases of DIAPH1-related disorder in Australia caused by the autosomal dominant gain-of-function DIAPH1 R1213X variant formed by truncation of the protein within the diaphanous auto-regulatory domain (DAD) with loss of regulatory motifs responsible for autoinhibitory interactions within the DIAPH1 protein. We affirm phenotypic changes induced by the DIAPH1 R1213X variant to include macrothrombocytopenia, early-onset progressive sensorineural hearing loss, and mild asymptomatic neutropenia. High-resolution microscopy confirms perturbations of cytoskeletal dynamics caused by the DIAPH1 variant and we extend the repertoire of changes generated by this variant to include alteration of procoagulant platelet formation and possible dental anomalies.

Development and implementation of venous thromboembolism stewardship across a hospital network.

BACKGROUND: Venous thromboembolism (VTE) is a leading cause of preventable death in hospital. Ensuring all hospitalized patients are assessed for VTE risk and given appropriate prophylaxis can reduce the burden of VTE on patients and the healthcare system. This is the first study to explore the effectiveness of a VTE stewardship program using electronic clinical decision support (eCDS) to provide oversight of hospital initiatives to prevent VTE. AIM: To determine if a VTE stewardship program can increase risk-appropriate VTE prophylaxis, VTE risk assessment using eCDS, any documented risk assessment and risk assessment within 24 h of admission, plus reduce the incidence of hospital acquired VTE (HA-VTE). METHODS: Education, daily medication chart auditing, weekly clinician performance feedback, health promotion and gamification were deployed over 6 months by two multidisciplinary VTE stewardship teams across four hospitals. Service impact was assessed through cross-sectional audits of electronic medical records every 3 months and review of HA-VTE events pre- and post-intervention. Implementation costs were calculated. RESULTS: A total of 1622 patients were audited in separate cohorts at baseline, 3, 6 and 9 months. There was significant improvement in the prescription of appropriate prophylaxis (78%, 83%, 84%, and 88%, p = 0.004), VTE risk assessment using the eCDS tool (20%, 50%, 81% and 87%, p < 0.001), any documented risk assessment (71%, 82%, 95% and 93%, p < 0.001) and any documented risk assessment within 24 h of admission (54%, 56%, 65% and 63%, p = 0.001). Use of eCDS was associated with prescription of risk-appropriate VTE prophylaxis (p < 0.001). Annual incidence of HA-VTE decreased from 7.88 to 6.99 events per 10,000 discharges pre- to post-intervention (Odds Ratio (OR) 0.89, 95 %CI 0.66-1.18, p = 0.43). The cost of implementing the program across 133,078 episodes of care during the study period was AUD$108,167 (mean cost of $0.82 per patient).

Primary membranous glomerulonephritis with negative serum PLA2R in haemophilia A successfully managed with rituximab - case report and review of the literature.

BACKGROUND: Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause a wide range of glomerular pathologies. In people with haemophilia, transfusion-associated infections with these viruses are common and definitive pathological diagnosis in this population is complicated by the difficulty of safely obtaining a renal biopsy. Membranous nephropathy (MN) is a common cause of adult onset nephrotic syndrome occurring in both primary and secondary forms. Primary MN is associated with podocyte autoantibodies, predominantly against phospholipase A2 receptor (PLA2R). Secondary disease is often associated with viral infection; however, infrequently with HIV or HCV. Distinguishing these entities from each other and other viral glomerular disease is vital as treatment strategies are disparate. CASE PRESENTATION: We present the case of a 48-year-old man with moderate haemophilia A and well-controlled transfusion-associated HCV and HIV coinfection who presented with sudden onset nephrotic range proteinuria. Renal biopsy demonstrated grade two membranous nephropathy with associated negative serum PLA2R testing. Light and electron microscopic appearances were indeterminant of a primary or secondary cause. Given his extremely stable co-morbidities, treatment with rituximab and subsequent angiotensin receptor blockade was initiated for suspected primary MN and the patient had sustained resolution in proteinuria over the following 18 months. Subsequent testing demonstrated PLA2R positive glomerular immunohistochemistry despite multiple negative serum results. CONCLUSIONS: Pursuing histological diagnosis is important in complex cases of MN as the treatment strategies between primary and secondary vary significantly. Serum PLA2R testing alone may be insufficient in the presence of multiple potential causes of secondary MN.

Hemostasis, coagulation and thrombin in venoarterial and venovenous extracorporeal membrane oxygenation: the HECTIC study.

Extracorporeal membrane oxygenation (ECMO) support has a high incidence of both bleeding and thrombotic complications. Despite clear differences in patient characteristics and pathologies between veno-venous (VV) and veno-arterial (VA) ECMO support, anticoagulation practices are often the same across modalities. Moreover, there is very little data on their respective coagulation profiles and comparisons of thrombin generation in these patients. This study compares the coagulation profile and thrombin generation between patients supported with either VV and VA ECMO. A prospective cohort study of patients undergoing VA and VV ECMO at an Intensive care department of a university hospital and ECMO referral centre. In addition to routine coagulation testing and heparin monitoring per unit protocol, thromboelastography (TEG), multiplate aggregometry (MEA), calibrated automated thrombinography (CAT) and von-Willebrand's activity (antigen and activity ratio) were sampled second-daily for 1 week, then weekly thereafter. VA patients had significantly lower platelets counts, fibrinogen, anti-thrombin and clot strength with higher d-dimer levels than VV patients, consistent with a more pronounced consumptive coagulopathy. Thrombin generation was higher in VA than VV patients, and the heparin dose required to suppress thrombin generation was lower in VA patients. There were no significant differences in total bleeding or thrombotic event rates between VV and VA patients when adjusted for days on extracorporeal support. VA patients received a lower median daily heparin dose 8500 IU [IQR 2500-24000] versus VV 28,800 IU [IQR 17,300-40,800.00]; < 0.001. Twenty-eight patients (72%) survived to hospital discharge; comprising 53% of VA patients and 77% of VV patients. Significant differences between the coagulation profiles of VA and VV patients exist, and anticoagulation strategies for patients of these modalities should be different. Further research into the development of tailored anticoagulation strategies that include the mode of ECMO support need to be completed.

The case for extended thromboprophylaxis in medically hospitalised patients - not yet made.

BACKGROUND: The role of extended thromboprophylaxis is established for surgical patients, but not yet for hospitalised medical patients. DESIGN: This systematic review and meta-analysis sought to explore the role of extended thromboprophylaxis for medically ill hospitalised patients. METHODS: Medline, EMBASE and Cochrane Libraries were searched and five randomised controlled trials were identified, comprising 20,046 extended and 20,078 standard duration thromboprophylaxis patients. RESULTS: Allocation to extended treatment, compared with standard duration therapy, significantly reduced the risk of symptomatic deep vein thrombosis (relative risk (RR) 0.47, 95% confidence interval (CI) 0.29-0.78, P = 0.003) and non-fatal pulmonary embolism (RR 0.59, 95% CI 0.39-0.91, P = 0.02). The risk of venous thromboembolism-related death was comparable between the extended and standard duration treatment groups (RR 0.81, 95% CI 0.6-1.09, P = 0.16). Extended treatment also doubled the risk of major bleeding (RR 2.04, 95% CI 1.42-2.91, P < 0.001), without significantly affecting the risk of intracranial bleeding or bleeding-associated death. The cost of preventing one symptomatic deep vein thrombosis and non-fatal pulmonary embolism was found to be £24,972 (€27,969) and £45,148 (€50,566), respectively, which outweigh the direct cost of managing established venous thromboembolism as previously reported. CONCLUSIONS: Extended duration thromboprophylaxis caused a reduction in the risk of venous thromboembolic events, but also a numerically comparable increase in major bleeding. Further trials are required in high-risk subpopulations who may derive mortality benefits from treatment. Only then could a change in current policy and practice be supported.

Inverse relationship between oligoclonal expanded CD69- TTE and CD69+ TTE cells in bone marrow of multiple myeloma patients.

CD8+CD57+ terminal effector T (TTE) cells are a component of marrow-infiltrating lymphocytes and may contribute to the altered immune responses in multiple myeloma (MM) patients. We analyzed TTE cells in the bone marrow (BM) and peripheral blood (PB) of age-matched controls and patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and newly diagnosed (ND) MM using flow cytometry, mass cytometry, and FlowSOM clustering. TTE cells are heterogeneous in all subjects, with BM containing both CD69- and CD69+ subsets, while only CD69- cells are found in PB. Within the BM-TTE compartment, CD69- and CD69+ cells are found in comparable proportions in controls, while CD69- cells are dominant in MGUS and SMM and predominantly either CD69- or CD69+ cells in NDMM. A positive relationship between CD69+TTE and CD69-TTE cells is observed in the BM of controls, lost in MGUS, and converted to an inverse relationship in NDMM. CD69-TTE cells include multiple oligoclonal expansions of T-cell receptor/Vß families shared between BM and PB of NDMM. Oligoclonal expanded CD69-TTE cells from the PB include myeloma-reactive cells capable of killing autologous CD38hi plasma cells in vitro, involving degranulation and high expression of perforin and granzyme. In contrast to CD69-TTE cells, oligoclonal expansions are not evident within CD69+TTE cells, which possess low perforin and granzyme expression and high inhibitory checkpoint expression and resemble T resident memory cells. Both CD69-TTE and CD69+TTE cells from the BM of NDMM produce large amounts of the inflammatory cytokines interferon-γ and tumor necrosis factor α. The balance between CD69- and CD69+ cells within the BM-TTE compartment may regulate immune responses in NDMM and contribute to the clinical heterogeneity of the disease.

Updated Australian consensus statement on management of inherited bleeding disorders in pregnancy.

INTRODUCTION: There have been significant advances in the understanding of the management of inherited bleeding disorders in pregnancy since the last Australian Haemophilia Centre Directors' Organisation (AHCDO) consensus statement was published in 2009. This updated consensus statement provides practical information for clinicians managing pregnant women who have, or carry a gene for, inherited bleeding disorders, and their potentially affected infants. It represents the consensus opinion of all AHCDO members; where evidence was lacking, recommendations have been based on clinical experience and consensus opinion. MAIN RECOMMENDATIONS: During pregnancy and delivery, women with inherited bleeding disorders may be exposed to haemostatic challenges. Women with inherited bleeding disorders, and their potentially affected infants, need specialised care during pregnancy, delivery, and postpartum, and should be managed by a multidisciplinary team that includes at a minimum an obstetrician, anaesthetist, paediatrician or neonatologist, and haematologist. Recommendations on management of pregnancy, labour, delivery, obstetric anaesthesia and postpartum care, including reducing and treating postpartum haemorrhage, are included. The management of infants known to have or be at risk of an inherited bleeding disorder is also covered. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: Key changes in this update include the addition of a summary of the expected physiological changes in coagulation factors and phenotypic severity of bleeding disorders in pregnancy; a flow chart for the recommended clinical management during pregnancy and delivery; guidance for the use of regional anaesthetic; and prophylactic treatment recommendations including concomitant tranexamic acid.

Anti-glycoprotein VI mediated immune thrombocytopenia: An under-recognized and significant entity?

Idiopathic immune thrombocytopenia (ITP) is an autoimmune disorder characterized by relapsing/ remitting thrombocytopenia. Bleeding complications are infrequent with platelet counts above 30×109/L, and this level is commonly used as a threshold for treatment. The question of another/ co-existent diagnosis or an alternate mechanism of platelet destruction arises when bleeding is experienced with platelet counts above this threshold. We report a case of anti-GPVI mediated ITP that was diagnosed following investigations performed to address this key clinical question. A patient with ITP experienced exaggerated bruising symptoms despite a platelet count of 91×109/L. Platelet functional testing showed an isolated platelet defect of collagen-induced aggregation. Next generation sequencing excluded a pathogenic variant of GP6, and anti-GPVI antibodies that curtailed GPVI function were confirmed by extended platelet phenotyping. We propose that anti-GPVI mediated ITP may be under-recognized, and that inclusion of GPVI in antibody detection assays may improve their diagnostic utility and in turn, facilitate a better understanding of ITP pathophysiology and aid individualized treatment approaches.

Human plasma-derived FVIII/VWD concentrate (Biostate): a review of experimental and clinical pharmacokinetic, efficacy and safety data.

Human plasma-derived factor VIII/von Willebrand factor complex concentrates are used to control bleeding in patients with von Willebrand disease (VWD) or haemophilia A (HA). The properties of these haemostatic factor concentrates vary widely, which can have significant clinical implications. This review provides an extensive overview of the molecular properties, in addition to pharmacokinetic, efficacy and safety data, and case studies of clinical experience of one such concentrate, Biostate. These data are discussed in the context of various therapeutic applications and compared with other factor concentrate products. Data are presented from data on file from the manufacturer; product information and published experimental and clinical pharmacokinetic, safety and efficacy study data; and example case studies of clinical experience. The data discussed herein demonstrate that Biostate has well-established efficacy profiles in the treatment of patients with VWD or HA, with the control of bleeding rated as 'excellent', 'good' or 'moderate' in >90% of patients. In an immune-tolerance induction setting, 73% of patients achieved a complete response following treatment with Biostate. Biostate was generally well tolerated in patients with HA or VWD, with infrequent minor adverse events reported and no reported cases of clinically relevant thrombosis.

The Australian and New Zealand Haemostasis Registry: ten years of data on off-licence use of recombinant activated factor VII.

BACKGROUND: Recombinant activated factor VII (rFVIIa) has been widely used as an off-licence pan-haemostatic agent in patients with critical bleeding. However, outside the trauma setting, there is relatively little high quality evidence on the risks and benefits of this agent. The Haemostasis Registry was established to investigate the extent of use, dosing, safety and outcomes of patients after off-licence rFVIIa treatment of critical bleeding. MATERIALS AND METHODS: The Registry recruited non-haemophiliac patients treated with rFVIIa from 2000-2009 (inclusive) in Australia and New Zealand. Detailed information was gathered on patients' demographics, context of bleeding, rFVIIa administration, laboratory results, blood component and other therapies, and outcomes. Outcome measures included subjectively assessed effect of rFVIIa on bleeding (response), adverse events (thromboembolic and other) and 28-day mortality. RESULTS: The registry included 3,446 cases in 3,322 patients (median [IQR] age 56 [33-70] years, 65% (n=2,147) male). Clinical indications included cardiac surgery (45%), other surgery (18%), trauma (13%), medical bleeding (6%), liver disease (6%), and obstetric haemorrhage (5%). The median [IQR] dose was 91 [72-103] µg/kg and 77% received a single dose. Reduction or cessation of bleeding was reported in 74% and 28-day survival was 71% but outcomes varied depending on clinical context. pH strongly correlated with outcome measures; 81% of patients with pH <7.1 died. Approximately 11% of patients had thromboembolic adverse events. In multivariate analysis, pH prior to administration and bleeding context were independently associated with reported response to rFVIIa and 28-day mortality. DISCUSSION: The Haemostasis Registry is the largest dataset of its kind and provides observational data on the off-licence use of rFVIIa over a 10-year period. It has been an invaluable resource for rigorously tracking adverse events and helping to inform clinical practice.

Immune tolerance induction using a factor VIII/von Willebrand factor concentrate (BIOSTATE), with or without immunosuppression, in Australian paediatric severe haemophilia A patients with high titre inhibitors: a multicentre, retrospective study.

INTRODUCTION: It has been postulated that factor VIII (FVIII) products containing von Willebrand factor (VWF) may improve immune tolerance induction (ITI) success rate in patients with haemophilia A and poor prognostic factors. MATERIALS AND METHODS: We conducted a retrospective cohort analysis of a FVIII/VWF concentrate (BIOSTATE) for ITI in paediatric patients with severe haemophilia A (SHA) and inhibitors, from January 2003 to December 2011 at 3 paediatric-only Haemophilia Treatment Centres in Australia. Response to ITI was assessed at or before 33 months and at completion of ITI. Fifteen male patients with SHA were included in the analysis. RESULTS: BIOSTATE was used for primary ITI in 8 patients (2 years, range 1.1-11.5 years) and for salvage ITI in 7 patients (9.9 years, range 1.1-15.4). At the end of the observation period there were 11 patients who achieved a complete response with BIOSTATE after a median duration of 21 months (range 5-85 months); a partial response was achieved in 2 patients in whom ITI is ongoing. Therefore, the overall response rate was 86.6%. Two patients were deemed treatment failures: one due to non-compliance after 18 months of ITI and another in whom a partial response had not been achieved after 22 months of ITI. CONCLUSION: BIOSTATE was well-tolerated and effective when used for primary or salvage ITI in this cohort of paediatric patients with SHA and a high-level inhibitor.

Validation of 4% albumin as a diluent in the Bethesda Assay for FVIII inhibitors.

INTRODUCTION: External quality assurance programs show the Nijmegen Bethesda Assay for FVIII inhibitors improves test specificity compared to the Classic Bethesda Assay but its uptake has been slow possibly due to the cost of using FVIII deficient plasma as diluent. This study was conducted to determine if modifying the Nijmegen Bethesda assay by replacement of FVIII deficient plasma with 4% as a diluent would be suitable for for measuring FVIII inhibitors. MATERIALS AND METHODS: The titres of 59 samples from 35 patients with FVIII inhibitors were determined in parallel tests by the Nijmegen Bethesda Assay and and the modified Nijmegen assay. Method reproducibility was assessed on inhibitor-containing samples from seven individuals covering a range of titres from 1-200 Bethesda units/mL. RESULTS: The all-sample geometric mean titre was 6.73 Bethesda units/mL for the Nijmegen Bethesda Assay and 7.54 Bethesda units/mL for the modified Nijmegen assay. No sample was found where a difference in measured titre between methods would have altered clinical management. Agreement was very close in samples with titres less than 2BU/mL. Both assays gave inhibitor titres in external quality assurance samples of close to consensus values. The average between-run coefficients of variation were 8.6% for the Nijmegen Bethesda Assay and 7.9% for the modified Nijmegen assay. CONCLUSIONS: The modified Nijmegen assay using 4% albumin as the sample diluent showed good overall comparability to our existing Nijmegen Bethesda Assay and is substantially more cost-effective, making it a reasonable alternative for measuring FVIII inhibitors.

Effects of FEIBA on platelet and leucocyte activation in severe haemophilia patients with inhibitors.

Factor eight inhibitory bypassing agent (FEIBA) is used as a therapeutic option in haemophilia patients who have developed inhibitors. The measurement of thrombin generation has been applied to monitor the efficacy of FEIBA. However, a major concern about the clinical use of FEIBA is whether or not an increase in thrombin activity causes subsequent platelet activation and risk of thrombosis. Our aim is to evaluate whether FEIBA causes platelet and leucocyte activation in haemophilia patients with inhibitors. We evaluated the effects of FEIBA on platelet and leucocyte activity in correlation with thrombin generation. Initially, an in vitro study was conducted to evaluate the effects of FEIBA on platelet and leucocyte activity (using flow cytometry) using peripheral blood from normal volunteers. We then performed an ex vivo study looking at the effect of FEIBA on the above parameters in two haemophiliacs with high-titre inhibitors. A parallel study was also carried out ex vivo to evaluate thrombin generation using a thrombinoscope. FEIBA did not cause platelet or leucocyte activation in either the in vitro or ex vivo studies but showed a predictable increase in thrombin generation. Our study is the first one to address the effect of FEIBA on platelet and leucocyte function. We found no evidence of 'systemic' platelet activation. The findings suggest that whilst FEIBA improves global haemostasis, platelet activation is likely to be contained to the site of injury and systemic platelet activation, a previously feared consequence of FEIBA infusion that that may have contributed to thrombotic risk is absent.

Recombinant activated factor VII in liver patients: a retrospective cohort study from Australia and New Zealand.

Recombinant factor VIIa (rFVIIa) is used in the treatment of life-threatening haemorrhage that is refractory to conventional treatment. The evidence supporting this practice in patients with liver disease is very limited. It has been used as a salvage therapy in end-stage liver disease (ESLD), in orthotopic liver transplant (OLT), other surgery, and upper gastrointestinal bleeding (UGIB) subpopulations. It has also been used prior to procedures in patients with ESLD. Data were collected by the Australia and New Zealand Haemostasis Registry (ANZHR) to perform a retrospective cohort study on the different subgroups of liver patients. This included 115 cases of use of rFVIIa in liver patients from 20 hospitals. A retrospective cohort study on the different subgroups of liver patients was performed. Main outcome measures were reduction or cessation of bleeding and 28-day mortality. Variables previously shown to predict response to bleeding after administration of rFVIIa were examined to determine whether correlations exist. Salvage therapy with rFVIIa was associated with reduction or cessation in bleeding in 24 of 36 OLT patients, 24 of 36 UGIB patients and 15 of 26 of other surgery patients. Clinical response to rFVIIa in OLT patients and other surgery patients was associated with a significantly lower mortality compared to nonresponders (P = 0.003 and 0.022, respectively). There was no relationship between mortality and bleeding response in patients with UGIB. Variables including acidosis, hypothermia, hypofibrinogenaemia, thrombocytopenia and Model of End-Stage Liver Disease (MELD) score were not associated with clinical response to rFVIIa. Five cases of use prior to procedures are described. Recombinant FVIIa is used as rescue therapy in surgical patients with ESLD and refractory haemorrhage in Australia and New Zealand. Traditional haemostasis variables were not associated with clinical response to rFVIIa in this cohort. Response to rFVIIa is associated with decreased mortality in ESLD patients undergoing OLT and other surgery, but not in UGIB.

A consensus statement on the management of pregnancy and delivery in women who are carriers of or have bleeding disorders.

Pregnancy and delivery are critical times for women with bleeding disorders, with mothers, and possibly their affected infants, being exposed to a variety of haemostatic challenges. Management of women with bleeding disorders during pregnancy involves a multidisciplinary team including, but not limited to, an obstetrician, an anaesthetist and a haematologist. This consensus document from the Australian Haemophilia Centre Directors' Organisation (AHCDO) provides practical information for clinicians managing women with bleeding disorders during pregnancy. Included are: the expected physiological response in pregnancy in such women; management of pregnancy, labour and delivery, as well as obstetric anaesthesia issues, postpartum care, and reducing and treating postpartum haemorrhage; and management of infants at risk of a bleeding disorder and of bleeding in neonates. The guidelines were developed after extensive consultation, face-to-face meetings and revisions. The final document represents a consensus opinion of all AHCDO members. Where evidence is lacking, recommendations are based on clinical experience and consensus opinion.

Laboratory identification of factor inhibitors: the perspective of a large tertiary hemophilia center.

Coagulation factor inhibitors are antibodies that bind and neutralize specific procoagulant plasma proteins. The identification of coagulation factor inhibitors by the hemostasis laboratory requires a careful and systematic approach that excludes other possible causes of prolonged screening tests such as the activated partial thromboplastin time and prothrombin time. Once the laboratory is confident that a specific coagulation factor inhibitor is present in a sample, its strength or titer must be measured. The clinician will use this information as a treatment guide. The most frequently occurring factor inhibitors encountered in the hemostasis laboratory are those directed against factor VIII (FVIII), which can arise in individuals with inherited hemophilia A as an immune response to factor replacement therapy or as an autoantibody leading to the condition of acquired hemophilia A. The Bethesda assay is the most widely used test for measuring the FVIII inhibitor titer. The Bethesda assay has several components that must be carefully controlled to achieve consistent results. This overview examines the behavior of various coagulation inhibitors and laboratory tests with an emphasis on the Bethesda assay for factor inhibitors.

Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy.

We conducted a trial in 103 patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) using imatinib 600 mg/day, with dose escalation to 800 mg/day for suboptimal response. The estimated cumulative incidences of complete cytogenetic response (CCR) by 12 and 24 months were 88% and 90%, and major molecular responses (MMRs) were 47% and 73%. In patients who maintained a daily average of 600 mg of imatinib for the first 6 months (n = 60), MMR rates by 12 and 24 months were 55% and 77% compared with 32% and 53% in patients averaging less than 600 mg (P = .037 and .016, respectively). Dose escalation was indicated for 17 patients before 12 months for failure to achieve, or maintain, major cytogenetic response at 6 months or CCR at 9 months but was only possible in 8 patients (47%). Dose escalation was indicated for 73 patients after 12 months because their BCR-ABL level remained more than 0.01% (international scale) and was possible in 45 of 73 (62%). Superior responses achieved in patients able to tolerate imatinib at 600 mg suggests that early dose intensity may be critical to optimize response in CP-CML. The trial was registered at www.ANZCTR.org.au as #ACTRN12607000614493.