Scott Dunkley

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.

Platelet glycoprotein VI‐related clinical defects

Human patients with defects associated with the platelet collagen receptor, glycoprotein (GP)VI, are rare and usually described as having a mild bleeding disorder. However, here we review clinical profiles of patients with familial or acquired GPVI defects, revealing the bleeding defect is often severe and associated with immune dysfunction. GPVI is a member of the immunoreceptor family, and co‐expressed on platelets with Fc receptor γ‐chain (FcRγ). Ligand binding to GPVI leads to activation of platelet integrins, in particular αIIbβ3 that mediates platelet aggregation; and activation of endogenous platelet metalloproteinases resulting in ectodomain shedding and release of a soluble GPVI fragment. Increasing evidence supports the functional importance of GPVI/FcRγ in thrombus formation at arterial shear rates, and expression levels of platelet GPVI may be a marker of thrombotic risk. Over the past 20 years, patients have been reported with GPVI‐related defects involving: (i) an acquired deficiency, resulting from (a) anti‐GPVI autoantibodies or (b) other causes; or (ii) a congenital deficiency, where (c) GPVI is not expressed or (d) is expressed in a dysfunctional form with defective signalling to αIIbβ3. Clinical consequences of GPVI‐related defects may be uniquely informative about the role of platelet GPVI in health and disease.

The use of FEIBA ® in the correction of coagulation abnormalities induced by dabigatran

Studies have shown dabigatran to be an effective anticoagulant with an acceptable bleeding profile. None the less, these patients do suffer from bleeding complications. Unfortunately, there are currently no direct reversal agents to dabigatran or established guidelines on the management of bleeding in these circumstances.

Recombinant activated factor VII in critical bleeding: experience from the Australian and New Zealand Haemostasis Register

Background:  There has been increasing off‐label use of recombinant activated factor VII (rFVIIa/NovoSeven; Novo Nordisk, Bagsvaerd, Denmark) for patients with critical bleeding. Given the lack of high‐level evidence, the clinical indications, observed response and adverse events are important to capture.

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.

Elucidating the clinical characteristics of patients captured using different definitions of massive transfusion

The type and clinical characteristics of patients identified with commonly used definitions of massive transfusion (MT) are largely unknown. The objective of this study was to define the clinical characteristics of patients meeting different definitions of MT for the purpose of patient recruitment in observational studies.

Clinical efficacy and safety of the factor VIII/von Willebrand factor concentrate BIOSTATE® in patients with von Willebrand’s disease: a prospective multi-centre study

Summary.  von Willebrand’s disease (VWD) is an inherited bleeding disorder characterized by deficient levels of or dysfunctional von Willebrand factor (VWF). This phase II/III open‐label, multicentre study evaluated the efficacy and safety of BIOSTATE®, a high purity plasma‐derived double‐virus inactivated FVIII/VWF concentrate, when used in non‐surgical bleeds, surgical procedures and prophylactic therapy in VWD patients for whom desmopressin treatment was deemed ineffective, inadequate or contraindicated. Twenty three patients (7 type 1, 9 type 2 and 7 type 3; 12 male, 11 female), who received FVIII/VWF concentrate as part of their VWD management, were recruited prospectively between December 2004 and May 2007 from eight centres in Australia and New Zealand. BIOSTATE dosing was based on pre‐treatment FVIII:C and/or VWF:RCo plasma levels and a predetermined dosing guide. Haemostatic efficacy of BIOSTATE was rated as excellent or good for all major and minor surgery events, long‐term prophylaxis, and for four of the six assessable non‐surgical bleeding events. Blood transfusions were required by two major surgery patients as well as one patient with a non‐surgical bleed. The median overall exposure to BIOSTATE across all groups was 8 days, greater in the prophylactic group (range 53–197) compared with major surgery (3–24), minor surgery (1–8) and non‐surgical bleeds (1–10). BIOSTATE was shown to be efficacious and well tolerated when treating patients with VWD. This study also provides important insights into dosing regimens with BIOSTATE and the role of monitoring therapy with FVIII:C and VWF:RCo.

Rituximab treatment of mild haemophilia A with inhibitors: a proposed treatment protocol

Summary.  Inhibitors are an uncommon complication of mild haemophilia A but represent a severe disease, typically with high titre inhibitors and an associated high rate of bleeding. We present data from three patients with MHAI who were successfully treated with Rituximab alone and unequivocally prove that such inhibitors respond to this agent. A treatment protocol is suggested.

A familial platelet function disorder associated with abnormal signalling through the glycoprotein VI pathway

The platelet collagen receptor, glycoprotein (GP)VI, of the immunoreceptor family forms a complex with the von Willebrand factor (VWF) receptor, GPIb‐IX‐V, critical for initiating thrombus formation. GPVI is co‐associated with Fc receptor γ‐chain (FcRγ), which contains a cytoplasmic immunoreceptor tyrosine‐based activation motif domain, involved in activation of Syk, and a signalling cascade leading to (i) activation of αIIbβ3, which binds VWF and fibrinogen and mediates platelet aggregation, and (ii) metalloproteinase‐mediated shedding of the GPVI ectodomain (blocked by Syk inhibitors), a key mechanism for regulating GPVI surface expression. In this study, we report a familial case of abnormal platelet aggregation with dysfunctional signalling through GPVI that uniquely demonstrates divergent αIIbβ3‐activating and GPVI‐shedding pathways. The patient is a 60‐year‐old female with a history of immune disorders, excessive bleeding from childhood and a life‐threatening haemorrhage post‐trauma. Platelet aggregation to ADP, thrombin receptor‐agonist peptide or ristocetin/VWF was normal (indicating normal expression and function of αIIbβ3), but platelet aggregation to GPVI agonists, collagen, collagen‐related peptide, or convulxin, was defective. Both GPVI/FcRγ expression and ligand‐induced GPVI ectodomain shedding were normal, confirming expression of functional GPVI/FcRγ, but suggesting a signalling defect downstream of Syk. A genetic defect in GPVI/Fcγ signalling compromising platelet function is hypothesised in this family.

Efficacy and safety of a high purity, double virus inactivated factor VIII/von Willebrand factor concentrate (Biostate®) in patients with von Willebrand disorder requiring invasive or surgical procedures

Summary.  Biostate® is a double virally inactivated, plasma derived coagulation factor VIII (FVIII)/von Willebrand factor (VWF) concentrate registered and used in Australia, New Zealand and Asia for the treatment of patients with haemophilia A. Although Biostate® has been well characterized for FVIII and VWF (ratio 1:2 respectively) and shows a similar VWF multimeric pattern to normal plasma, limited published data is available on its clinical efficacy and safety in patients with von Willebrand disorder (VWD) who require surgical procedures. We retrospectively assessed the efficacy and safety of Biostate® in all VWD patients treated at three Australian haemophilia treatment centres undergoing invasive procedures or surgery over a 29‐month period between April 2003 and September 2005. A chart review of 43 VWD patients (26 VWD type 1, 12 VWD type 2, 5 VWD type 3; 21 male, 22 female; mean age 52 years, range 19–80 years) undergoing 58 surgical procedures (24 major, 34 minor) was performed. For each procedure, data were collected on Biostate® dosage and administration, adverse reactions, haemostatic efficacy and bleeding events. Haemostatic efficacy of Biostate® was assessed as excellent in 78% or good in 22% of procedures. There were no bleeding events attributable to lack of efficacy in any patients. No adverse reactions related to the administration of Biostate® were observed. These results suggest that Biostate® is both safe and efficacious for the prevention of excessive bleeding in VWD patients undergoing surgery or invasive procedures.