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Recent initiatives from the RCPA haematology QAP: PFA-100 and FVIII inhibitors
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PATHOLOGY UPDATE 2010 ABSTRACTS
IMMUNE THROMBOCYTOPENIC PURPURA Kenneth Kaushansky University of California, San Diego, United States The disease that was formerly termed idiopathic thrombocytopenia (ITP), is becoming far better understood, so much so that the same acronym has been reworked, to mean immune thrombocytopenia. Recent progress using murine models of the disease has shed new insights into the mechanisms of platelet destruction (both B and T cell mediated), and have lead to a growing appreciation that megakaryopoiesis is impaired in the disease. It is also clear that novel approaches to therapy are upon us. For example, while 1 mg/kg of prednisone was standard of care for decades, high doses of dexamethasone are being appreciated as a potentially disease modifying treatment. While many (or most) patients will respond to glucocorticoid therapy, most relapse once the drug is discontinued. In contrast, while anti-B cell antibody therapy does not yield as high an initial response rate as glucocorticoids, when they do occur remissions tend to be more long-lasting. As such, newer approaches emphasise the combination of high dose glucocorticoids plus anti-B-cell antibodies. With the cloning and characterisation of thrombopoietin, a number of drugs have emerged that bind to and stimulate the thrombopoietin receptor. Two of these drugs have now received US Food and Drug Administration approval for use in patients with chronic refractory ITP. The appropriate use of such agents has not yet been rigorously determined, but it is clear that a subset of patients can benefit from such agents. Finally, in this era of ‘targeted therapy’, the urge to shed old standards is strong. Nevertheless, recent long term follow up studies, and meta-analyses have suggested that splenectomy should remain as an important element in our approach to patients with chronic ITP. The mechanisms of impaired platelet formation and survival, and newer approaches to therapy will be reviewed in this talk.
NOVEL ANTICOAGULANTS: REVERSAL Kate Burbury Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia Thromboembolism (TE), a major contributor to morbidity and mortality, is a preventable disease. With increasing indications, chronic anticoagulation is escalating. Warfarin, the conventional choice, is problematic; concerns surrounding safety and practicalities remain an issue. Heparin derivatives as alternatives are not without complexity, spurring the continuous efforts for the development of novel agents, predominantly targeting FXa and thrombin, which may offer a more reliable and convenient approach. However there are potential obstacles. The balance between ‘anti-thrombosis’ and retaining a haemostatic response to vascular injury is complex, with bleeding an important complication. In situations of clinically relevant or recognised risk of bleeding (surgery or trauma), rapid and reliable reversal is required, ideally with a means to monitor residual antithrombotic activity. Apart from idrabioparinux, none of the newer agents have a specific antidote. Non-specific prohaemostatic agents, such as recombinant FVIIa, and
Pathology (2010), 42(S1)
modalities to assist clearance (e.g., haemodialysis) may have a role. However, there is no robust clinical data demonstrating utility, or validated assays for monitoring. Although there are advantages of these newer agents, he lack of effective antidotes and means of monitoring remains a challenge. As with ‘traditional’ anticoagulants, local guidelines for management need to be considered.
RECENT INITIATIVES FROM THE RCPA HAEMATOLOGY QAP: PFA-100 AND FVIII INHIBITORS Roslyn Bonar RCPA Haematology QAP, Northmead, Sydney, NSW, Australia The PFA-100 is commonly used in haemostasis laboratories for screening and monitoring of both von Willebrand disease (VWD) and platelet dysfunction. Testing requires fresh whole blood, so providing an external quality assurance (EQA) sample is a challenge and no EQA can currently provide such material. The Royal College of Pathologists of Australasia (RCPA) Haematology Quality Assurance Program (QAP) has recently sent two trial surveys to establish the feasibility of providing an EQA program for the PFA-100. The results from the trials were encouraging and will provide the basis for formulating an external EQA program. The factor inhibitors most commonly seen by laboratories are those directed against factor VIII (FVIII), and most usually detected either using Bethesda assays or Nijmegen modified methods. Inter-laboratory evaluations, including those recently conducted by the RCPA Haematology QAP, have consistently shown high variability in laboratory results for inhibitor assays, as well as false positive and negative identification. In brief, we recently conducted two questionnaire-based surveys and two wet-challenge surveys and identified ongoing high inter-laboratory variation, with CVs around 50% not uncommon, and that some 15% of Bethesda testing laboratories fail to detect low-level inhibitors of around 1 BU/mL. In conclusion, our experience indicates that is still much need for standardisation and improvement in factor inhibitor detection and the performance of PFA-100 screening, and we hope that the two new modules offered from 2010 provide a basis for future improvements in these areas.
FUTURE DEVELOPMENTS IN THE RCPA HAEMATOLOGY QAP John Sioufi RCPA Haematology QAP, Northmead, Sydney, NSW, Australia The Royal College of Pathologists of Australasia Quality Assurance Program (RCPA QAP) for Haematology Morphology was introduced in 1965. In these surveys participants submitted morphological findings and diagnoses on unknown blood and bone marrow films as free text. QAP staff then reviewed each response for key words or themes and recorded them manually. Responses were
PATHOLOGY UPDATE 2010 ABSTRACTS
IMMUNE THROMBOCYTOPENIC PURPURA Kenneth Kaushansky University of California, San Diego, United States The disease that was formerly termed idiopathic thrombocytopenia (ITP), is becoming far better understood, so much so that the same acronym has been reworked, to mean immune thrombocytopenia. Recent progress using murine models of the disease has shed new insights into the mechanisms of platelet destruction (both B and T cell mediated), and have lead to a growing appreciation that megakaryopoiesis is impaired in the disease. It is also clear that novel approaches to therapy are upon us. For example, while 1 mg/kg of prednisone was standard of care for decades, high doses of dexamethasone are being appreciated as a potentially disease modifying treatment. While many (or most) patients will respond to glucocorticoid therapy, most relapse once the drug is discontinued. In contrast, while anti-B cell antibody therapy does not yield as high an initial response rate as glucocorticoids, when they do occur remissions tend to be more long-lasting. As such, newer approaches emphasise the combination of high dose glucocorticoids plus anti-B-cell antibodies. With the cloning and characterisation of thrombopoietin, a number of drugs have emerged that bind to and stimulate the thrombopoietin receptor. Two of these drugs have now received US Food and Drug Administration approval for use in patients with chronic refractory ITP. The appropriate use of such agents has not yet been rigorously determined, but it is clear that a subset of patients can benefit from such agents. Finally, in this era of ‘targeted therapy’, the urge to shed old standards is strong. Nevertheless, recent long term follow up studies, and meta-analyses have suggested that splenectomy should remain as an important element in our approach to patients with chronic ITP. The mechanisms of impaired platelet formation and survival, and newer approaches to therapy will be reviewed in this talk.
NOVEL ANTICOAGULANTS: REVERSAL Kate Burbury Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia Thromboembolism (TE), a major contributor to morbidity and mortality, is a preventable disease. With increasing indications, chronic anticoagulation is escalating. Warfarin, the conventional choice, is problematic; concerns surrounding safety and practicalities remain an issue. Heparin derivatives as alternatives are not without complexity, spurring the continuous efforts for the development of novel agents, predominantly targeting FXa and thrombin, which may offer a more reliable and convenient approach. However there are potential obstacles. The balance between ‘anti-thrombosis’ and retaining a haemostatic response to vascular injury is complex, with bleeding an important complication. In situations of clinically relevant or recognised risk of bleeding (surgery or trauma), rapid and reliable reversal is required, ideally with a means to monitor residual antithrombotic activity. Apart from idrabioparinux, none of the newer agents have a specific antidote. Non-specific prohaemostatic agents, such as recombinant FVIIa, and
Pathology (2010), 42(S1)
modalities to assist clearance (e.g., haemodialysis) may have a role. However, there is no robust clinical data demonstrating utility, or validated assays for monitoring. Although there are advantages of these newer agents, he lack of effective antidotes and means of monitoring remains a challenge. As with ‘traditional’ anticoagulants, local guidelines for management need to be considered.
RECENT INITIATIVES FROM THE RCPA HAEMATOLOGY QAP: PFA-100 AND FVIII INHIBITORS Roslyn Bonar RCPA Haematology QAP, Northmead, Sydney, NSW, Australia The PFA-100 is commonly used in haemostasis laboratories for screening and monitoring of both von Willebrand disease (VWD) and platelet dysfunction. Testing requires fresh whole blood, so providing an external quality assurance (EQA) sample is a challenge and no EQA can currently provide such material. The Royal College of Pathologists of Australasia (RCPA) Haematology Quality Assurance Program (QAP) has recently sent two trial surveys to establish the feasibility of providing an EQA program for the PFA-100. The results from the trials were encouraging and will provide the basis for formulating an external EQA program. The factor inhibitors most commonly seen by laboratories are those directed against factor VIII (FVIII), and most usually detected either using Bethesda assays or Nijmegen modified methods. Inter-laboratory evaluations, including those recently conducted by the RCPA Haematology QAP, have consistently shown high variability in laboratory results for inhibitor assays, as well as false positive and negative identification. In brief, we recently conducted two questionnaire-based surveys and two wet-challenge surveys and identified ongoing high inter-laboratory variation, with CVs around 50% not uncommon, and that some 15% of Bethesda testing laboratories fail to detect low-level inhibitors of around 1 BU/mL. In conclusion, our experience indicates that is still much need for standardisation and improvement in factor inhibitor detection and the performance of PFA-100 screening, and we hope that the two new modules offered from 2010 provide a basis for future improvements in these areas.
FUTURE DEVELOPMENTS IN THE RCPA HAEMATOLOGY QAP John Sioufi RCPA Haematology QAP, Northmead, Sydney, NSW, Australia The Royal College of Pathologists of Australasia Quality Assurance Program (RCPA QAP) for Haematology Morphology was introduced in 1965. In these surveys participants submitted morphological findings and diagnoses on unknown blood and bone marrow films as free text. QAP staff then reviewed each response for key words or themes and recorded them manually. Responses were