Vernon J. Louw

Thrombotic thrombocytopenic purpura directly linked with ADAMTS13 inhibition in the baboon ( Papio ursinus )

Thrombotic thrombocytopenic purpura (TTP) is the prototypical microangiopathy characterized by disseminated microthromboses, hemolytic anemia, and ultimately organ dysfunction. A link with deficiency of the von Willebrand factor-cleaving protease (ADAMTS13) has been demonstrated, but additional genetic and/or environmental triggers are thought to be required to incite acute illness. Here we report that 4 days of ADAMTS13 functional inhibition is sufficient to induce TTP in the baboon (Papio ursinus), in the absence of inciting triggers because injections with an inhibitory monoclonal antibody (mAb) consistently (n = 6) induced severe thrombocytopenia (< 12 × 10(9)/L), microangiopathic hemolytic anemia, and a rapid rise in serum lactate dehydrogenase. Immunohistochemical staining revealed the characteristic disseminated platelet- and von Willebrand factor-rich thrombi in kidney, heart, brain, and spleen but not lungs. Prolonged inhibition (14 days, n = 1) caused myocardial ischemic damage and asplenia but not death. Control animals (n = 5) receiving equal doses of a noninhibitory anti-ADAMTS13 mAb remained unaffected. Our results provide evidence for a direct link between TTP and ADAMTS13 inhibition and for a mild disease onset. Furthermore, we present a reliable animal model of this disease as an opportunity for the development and validation of novel treatment strategies.

Multiple Myeloma Treatment Strategies with Novel Agents in 2011: A European Perspective

The arrival of the novel agents thalidomide, bortezomib, and lenalidomide has significantly changed our approach to the management of multiple myeloma and, importantly, patient outcomes have improved. These agents have been investigated intensively in different treatment settings, providing us with data to make evidence-based decisions regarding the optimal management of patients. This review is an update to a previous summary of European treatment practices that examines new data that have been published or presented at congresses up to the end of 2010 and assesses their impact on treatment practices.

Effect of Cytochrome P450 3A4 Inducers on the Pharmacokinetic, Pharmacodynamic and Safety Profiles of Bortezomib in Patients with Multiple Myeloma or Non-Hodgkin’s Lymphoma

AbstractBackground and Objective: Bortezomib, an antineoplastic agent with proteasome inhibitory activity, is extensively metabolized by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C19. Drugs that affect these enzymes may therefore have an impact on the pharmacological profile of bortezomib. This study evaluated the effects of co-administration of a potent CYP3A4 inducer (rifampicin [rifampin]) and a weak CYP3A4 inducer (dexamethasone) on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib. Patients and Methods: Patients aged ≥18 years with relapsed or refractory multiple myeloma or non-Hodgkin’s lymphoma received intravenous bortezomib 1.3 mg/m2, administered on days 1, 4, 8 and 11 of a 21-day cycle, for 3 cycles. In stage 1, patients were randomized (1:1) to receive bortezomib alone or in combination with oral rifampicin 600 mg once daily on days 4–10 during cycle 3 only. If the mean area under the plasma concentration-time curve (AUC) of bortezomib was reduced by ≥30% during rifampicin co-administration, then stage 2 was initiated, in which patients received bortezomib with dexamethasone 40 mg once daily on days 1–4 and days 9–12 during cycle 3 only. Blood samples were collected on days 11 through 14 of cycles 2 and 3 before and after bortezomib administration, at prespecified time points, for pharmacokinetic and pharmacodynamic (proteasome inhibition) assessments. Results: Twelve patients in the bortezomib-alone arm, six patients in the bortezomib plus rifampicin arm and seven patients in the bortezomib plus dexamethasone arm were included in the pharmacokinetics-evaluable set. Rifampicin reduced the mean AUC from 0 to 72 hours (AUC72h) of bortezomib by approximately 45% (223 ng · h/mL in cycle 2 vs 123 ng · h/mL in cycle 3), while dexamethasone had no effect (mean AUC72h: 179 ng · h/mL in cycle 2 vs 170 ng · h/mL in cycle 3). Proteasome inhibition parameters in peripheral blood were unaffected by rifampicin or dexamethasone. Safety profiles were similar across the treatment arms and consistent with previous experience of bortezomib. Conclusions: In patients with multiple myeloma or non-Hodgkin’s lymphoma, co-administration of rifampicin decreased the exposure to bortezomib but did not affect the proteasome inhibition or safety profiles; co-administration of dexamethasone did not affect the exposure to bortezomib, proteasome inhibition or safety profiles. Concomitant administration of bortezomib with strong CYP3A4 inducers such as rifampicin is not recommended, as it may result in a reduction of the clinical effect, whereas concomitant administration of weak CYP3A4 inducers such as dexamethasone does not affect the pharmacological profile of bortezomib.

Pica and food craving in adults with iron deficiency in Bloemfontein, South Africa

Pica has been defined as the craving or compulsive ingestion of non-food substances, but an enhanced craving for or intake of foodstuffs is sometimes included in this definition.

Postgraduate education in transfusion medicine in the absence of formal residency training: Assessment of factors needed to develop and sustain a postgraduate diploma program

BACKGROUND Quality education in transfusion medicine is key to delivering a safe and cost-effective blood service, yet postgraduate residency programs are lacking in many resource-limited countries and regions. The first formal, accredited, postgraduate training program in transfusion medicine aimed at medical doctors was developed and implemented at the University of the Free State in Bloemfontein, South Africa, in 2008. In the context of high demand and limited resources, ensuring sustainability of postgraduate training programs is essential. STUDY DESIGN AND METHODS A formal qualitative and semi-quantitative research approach was followed to determine and test the factors considered important in program sustainability, and consisted of a literature survey, followed by semi-structured interviews and a Delphi survey. RESULTS Fifty-five factors were identified from the semi-structured interviews. During the Delphi survey, consensus was reached on 41 and stability declared on a further 13. These factors formed the basis of a structured model informing the sustainability aspects of a postgraduate program in transfusion medicine. CONCLUSION Literature on program sustainability in the field of transfusion medicine is very limited. This study identified the key factors essential to the long-term viability of a postgraduate program in transfusion medicine and should find broad applicability in other resource-limited countries and regions. It is envisaged that this will enable such programs to reach a state of self-sufficiency while not being overly reliant on external funding and support.

Factors affecting the current status of transfusion medicine education in South Africa

Education in transfusion medicine, aimed at clinical transfusion practice, is limited in most South African pre- and postgraduate medical training programs. A number of local and global factors impact on the need for and provision of transfusion medicine education programs in South Africa, which are discussed in this paper. A perspective is provided on the effects of issues such as global versus local training need, blood safety, appropriate use of blood in resource-restrained environments, the presence or absence of national blood policies, standardization of training, medical migration and workforce diversity. Harnessing support for the development of training programs for medical doctors and new opportunities for developing a career in transfusion medicine are discussed. Commentary is also provided on online learning, social networking and integration of modern paradigms of learning, such as screencasting and online learning, into teaching programs. This article should provide anyone in medical education or program development, in particular in the field of transfusion medicine, with an indication of the factors that should be considered when embarking on such an endeavor.

Chronic myeloid leukaemia in South Africa

Abstract Despite the challenges of a resource-limited environment, the outcome of chronic myeloid leukaemia (CML) patients in South Africa is similar to that in developed countries, thanks to access to tyrosine kinase inhibitors through patient assistance programmes and clinical trials. A number of challenges are faced in terms of reimbursement of drugs, simultaneous co-infection with human immunodeficiency virus, access to allogeneic stem cell transplantation and, until recently, a lack of local recommendations appropriate for our setting. It is hoped that the newly published recommendations for the management of CML in South Africa will close many of the gaps in knowledge and practice and thus translate into better patient outcomes. Epidemiological data are limited and there is a need for more collaborative studies locally to elucidate issues such as incidence, prevalence and response to treatment. The challenges experienced in the management of CML and other cancers in the developing world are often economical and political in nature and require a comprehensive approach by clinicians, pathologists, health economists, medical insurers and policy makers if we are to find sustainable solutions.

An audit of the use of platelet transfusions at Universitas Academic Hospital, Bloemfontein, South Africa

An audit was performed at a tertiary hospital in Bloemfontein, South Africa, to establish whether clinicians adhered to local platelet transfusion guidelines. The audit showed poor compliance with local guidelines, with 34% of platelet transfusions not aligned with guidelines and 29.9% of transfusions administered to patients with platelet counts of ≥ 150 × 10(9)/L. When compared to medical disciplines, surgical disciplines tended significantly more to transfuse platelets inappropriately (17.1% and 53.7%, respectively; p < 0.0001). Documentation was poor and in 48.4% of orders for platelets, the indication for the platelet transfusion was not clearly stated. Considerable cost could be avoided with improved adherence to guidelines. This study emphasises the need for improving education in transfusion medicine amongst medical doctors. It is hoped that the information gleaned from this study would assist in the design of educational programmes in transfusion medicine as we attempt to close the existing gaps in knowledge and skills in the field, while ensuring that blood is transfused in a cost-effective and appropriate manner.

The utilization of red cell concentrates at Kimberley Hospital Complex, Northern Cape Province, South Africa

This prospective clinical audit of the utilization of red cell concentrates assesses 55 consecutive transfusion episodes in chronically anaemic adult patients. It examines the appropriateness and outcome of the transfusion episodes; over-transfusion and wastage rates, assessment of anaemia, the informed consent process, and if teaching influenced these parameters when compared to an earlier retrospective audit. The audit revealed several strengths and weaknesses relating to our institutions transfusion practices. Training sessions led to clinically and economically important improvements in transfusion decisions, the investigation of anaemia and the obtainment of informed consent prior to transfusions.

HIV-associated Thrombotic Thrombocytopenic Purpura - What We Know So Far

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterised by microvascular platelet deposition and thrombus formation in selected organs, resulting in microangiopathic haemolytic anaemia, thrombocytopenia, neurological symptoms and renal failure. Typically a very rare disorder, TTP is being seen with increased frequency in patients infected with the human immunodeficiency virus (HIV). Deficiency of the von Willebrand factor cleavage protease, ADAMTS13, has been implicated as the cause of TTP. However, the pathophysiology of HIV-associated TTP and the thrombotic potential in these patients are not known. This article provides not only an overview of the literature regarding HIV-associated TTP, but also presents new data on this disease. We propose a mechanism for the initial onset of HIV-associated TTP that includes the release of extreme amounts of von Willebrand factor and the downregulation of ADAMTS13 and/or the production of autoantibodies to ADAMTS13.