Publications by authors named "Harshal Nandurkar"

61 Publications

Global coagulation assays in healthy controls: are there compensatory mechanisms within the coagulation system?

J Thromb Thrombolysis 2021 Feb 24. Epub 2021 Feb 24.

Department of Haematology, Northern Hospital, 185 Cooper St, Epping, VIC, 3076, Australia.

Global coagulation assays (GCAs) may provide a more comprehensive individual hemostatic profiling. We aim to evaluate GCAs (thromboelastography, thrombin generation) in healthy controls, and correlate results with age, gender, lipid status, tissue factor pathway inhibitor (TFPI) and P-selectin. Blood samples were collected from healthy controls (> 18 years of age) not taking anticoagulation or antiplatelet agents and without known cardiovascular disease. Thromboelastography (TEG) was performed on citrated whole blood while calibrated automated thrombogram (CAT), P-selectin (endothelial marker) and TFPI (principle inhibitor of tissue factor-initiated coagulation) were performed on platelet-poor plasma. 153 healthy controls (mean age 42 years, 98 females (64%)) were recruited. Female controls demonstrated more hypercoagulable TEG and CAT parameters while those over 50 years of age demonstrated more hypercoagulable TEG parameters despite comparable thrombin generation. Paradoxically, individuals with "flattened" thrombin curves (lower velocity index (rate of thrombin generation) despite preserved endogenous thrombin potential (amount of thrombin)) were more likely to be male (49% vs 20%, p = 0.003) with increased low-density lipoprotein cholesterol (3.3 vs 2.6 mmol/L, p = 0.003), P-selectin (54.2 vs 47.3 ng/mL, p = 0.038) and TFPI (18.7 vs 8.6 ng/ml, p = 0.001). In addition to reduced velocity index and thrombin peak, controls in the highest TFPI tertile also demonstrated a poorer lipid profile. GCAs can detect subtle changes of the hemostatic profile. Interestingly, reduced thrombin generation was paradoxically associated with increased cardiovascular risk factors, possibly attributable to increased TFPI. This finding may suggest compensation by the coagulation system in response to endothelial activation and represent a biomarker for early cardiovascular disease. A larger prospective study evaluating these assays in the cardiovascular disease population is ongoing.
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http://dx.doi.org/10.1007/s11239-021-02400-yDOI Listing
February 2021

Characterization of a novel model of global forebrain ischaemia-reperfusion injury in mice and comparison with focal ischaemic and haemorrhagic stroke.

Sci Rep 2020 10 23;10(1):18170. Epub 2020 Oct 23.

Australian Centre for Blood Diseases, Central Clinical School, Alfred Hospital, Monash University, Melbourne, VIC, 3004, Australia.

Stroke is caused by obstructed blood flow (ischaemia) or unrestricted bleeding in the brain (haemorrhage). Global brain ischaemia occurs after restricted cerebral blood flow e.g. during cardiac arrest. Following ischaemic injury, restoration of blood flow causes ischaemia-reperfusion (I/R) injury which worsens outcome. Secondary injury mechanisms after any stroke are similar, and encompass inflammation, endothelial dysfunction, blood-brain barrier (BBB) damage and apoptosis. We developed a new model of transient global forebrain I/R injury (dual carotid artery ligation; DCAL) and compared the manifestations of this injury with those in a conventional I/R injury model (middle-cerebral artery occlusion; MCAo) and with intracerebral haemorrhage (ICH; collagenase model). MRI revealed that DCAL produced smaller bilateral lesions predominantly localised to the striatum, whereas MCAo produced larger focal corticostriatal lesions. After global forebrain ischaemia mice had worse overall neurological scores, although quantitative locomotor assessment showed MCAo and ICH had significantly worsened mobility. BBB breakdown was highest in the DCAL model while apoptotic activity was highest after ICH. VCAM-1 upregulation was specific to ischaemic models only. Differential transcriptional upregulation of pro-inflammatory chemokines and cytokines and TLRs was seen in the three models. Our findings offer a unique insight into the similarities and differences in how biological processes are regulated after different types of stroke. They also establish a platform for analysis of therapies such as endothelial protective and anti-inflammatory agents that can be applied to all types of stroke.
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http://dx.doi.org/10.1038/s41598-020-75034-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585423PMC
October 2020

Global Coagulation Assays in Transgender Women on Oral and Transdermal Estradiol Therapy.

J Clin Endocrinol Metab 2020 07;105(7)

Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia.

Context: The thrombotic effects of estradiol therapy in transgender women are unclear. Global coagulation assays (GCA) may be better measures of hemostatic function compared with standard coagulation tests.

Objective: To assess the GCA profiles of transgender women in comparison to cisgender controls and to compare how GCA differ between routes of estradiol therapy in transgender women.

Design: Cross-sectional case-control study.

Setting: General community.

Participants: Transgender women, cisgender male and cisgender female controls.

Main Outcome Measures: Citrated blood samples were analyzed for (i) whole blood thromboelastography (TEG®5000), (ii) platelet-poor plasma thrombin generation (calibrated automated thrombogram); and (iii) platelet-poor plasma fibrin generation (overall hemostatic potential assay). Mean difference (95% confidence intervals) between groups are presented.

Results: Twenty-six transgender women (16 oral estradiol, 10 transdermal estradiol) were compared with 98 cisgender women and 55 cisgender men. There were no differences in serum estradiol concentration (P = 0.929) and duration of therapy (P = 0.496) between formulations. Transgender women demonstrated hypercoagulable parameters on both thromboelastography (maximum amplitude + 6.94 mm (3.55, 10.33); P < 0.001) and thrombin generation (endogenous thrombin potential + 192.62 nM.min (38.33, 326.91); P = 0.009; peak thrombin + 38.10 nM (2.27, 73.94); P = 0.034) but had increased overall fibrinolytic potential (+4.89% (0.52, 9.25); P = 0.024) compared with cisgender men. No significant changes were observed relative to cisgender women. Route of estradiol delivery or duration of use did not influence the GCA parameters.

Conclusion: Transgender women on estradiol therapy demonstrated hypercoagulable GCA parameters compared with cisgender men with a shift towards cisgender female parameters. Route of estradiol delivery did not influence the GCA parameters.
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http://dx.doi.org/10.1210/clinem/dgaa262DOI Listing
July 2020

Global coagulation assays in patients with multiple myeloma and monoclonal gammopathy of unknown significance.

Thromb Res 2019 Nov 20;183:45-48. Epub 2019 Oct 20.

Department of Haematology, Northern Pathology Victoria, Northern Hospital, Epping, VIC, Australia; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1016/j.thromres.2019.10.017DOI Listing
November 2019

Active Micropump-Mixer for Rapid Antiplatelet Drug Screening in Whole Blood.

Anal Chem 2019 08 6;91(16):10830-10839. Epub 2019 Aug 6.

The Australian Centre for Blood Diseases , Monash University , 99 Commercial Road , Melbourne , Victoria 3004 , Australia.

There is a need for scalable automated lab-on-chip systems incorporating precise hemodynamic control that can be applied to high-content screening of new more efficacious antiplatelet therapies. This paper reports on the development and characterization of a novel active micropump-mixer microfluidic to address this need. Using a novel reciprocating elastomeric micropump design, we take advantage of the flexible structural and actuation properties of this framework to manage the hemodynamics for on-chip platelet thrombosis assay on type 1 fibrillar collagen, using whole blood. By characterizing and harnessing the complex three-dimensional hemodynamics of the micropump operation in conjunction with a microvalve controlled reagent injection system we demonstrate that this prototype can act as a real-time assay of antiplatelet drug pharmacokinetics. In a proof-of-concept preclinical application, we utilize this system to investigate the way in which rapid dosing of human whole blood with isoform selective inhibitors of phosphatidylinositol 3-kinase dose dependently modulate platelet thrombus dynamics. This modular system exhibits utility as an automated multiplexable assay system with applications to high-content chemical library screening of new antiplatelet therapies.
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http://dx.doi.org/10.1021/acs.analchem.9b02486DOI Listing
August 2019

Hepatitis B management during immunosuppression for haematological and solid organ malignancies: an Australian consensus statement.

Med J Aust 2019 06 19;210(10):462-468. Epub 2019 May 19.

University of Melbourne, Melbourne, VIC.

Introduction: Individuals with chronic hepatitis B virus (HBV) infection or past exposure to HBV infection have a substantial risk of reactivation during immunosuppressive cancer therapy. HBV reactivation can lead to liver failure, cancer treatment interruption or death. Clinical concordance with screening and treatment guidelines is inconsistent in practice, and existing international guidelines are not specific to the Australian context. We developed an Australian consensus statement with infectious diseases, hepatology, haematology and oncology specialists to inform hepatitis B screening and antiviral management for immunocompromised patients with haematological and solid organ malignancies in Australia.

Main Recommendations: Recommendations address four key areas of HBV infection management for immunocompromised patients with haematological and solid organ malignancies: who to test for HBV infection, when to start antiviral agents, when to stop antiviral agents, and how to monitor patients during cancer therapy. We recommend testing all patients undergoing cancer treatment for hepatitis B (including HBV surface antigen [HBsAg], HBV core antibody [anti-HBc], and HBV surface antibody) before cancer treatment. Individuals with chronic HBV infection (HBsAg positive) or past exposure (HBsAg negative and anti-HBc positive) receiving higher risk chemotherapy require antiviral prophylaxis using entecavir or tenofovir.

Changes In Management As A Result Of This Statement: This consensus statement will simplify the approach to testing and prophylaxis for HBV infection during cancer therapy, and harmonise approaches to discontinuing and monitoring individuals which have been highly variable in practice. We advocate for broader Medicare Benefits Schedule and Pharmaceutical Benefits Scheme access to HBV testing and treatment for patients undergoing cancer therapy.
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http://dx.doi.org/10.5694/mja2.50160DOI Listing
June 2019

A review of global coagulation assays - Is there a role in thrombosis risk prediction?

Thromb Res 2019 Jul 1;179:45-55. Epub 2019 May 1.

Department of Haematology, Northern Hospital, 185 Cooper St, Epping, VIC 3076, Australia; Australian Centre for Blood Diseases, Monash University, Monash AMREP Building, Level 1 Walkway via the Alfred Centre, 99 Commercial Road, Melbourne, VIC 3004, Australia; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade (corner Genetics Lane), Parkville, VIC 3052, Australia.

Normal haemostasis requires maintenance of a careful equilibrium between the necessity to clot when bleeding and the retention of fluid phase at all other times. Disruption of this equilibrium can result in catastrophic outcomes, e.g. acute myocardial infarction and pulmonary embolism. However, despite the significant therapeutic advances in cardiovascular medicine over recent years, our ability to provide an accurate cardiovascular risk assessment remains an unmet need. Routine coagulation testing is not a useful reflection of haemostasis and cannot be reliably used to predict bleeding and thrombosis risks. Global coagulation assays such as viscoelastic testing, thrombin and fibrin generation have been proposed as better measures of the haemostatic function. These assays, particularly viscoelastic testing, have been increasingly used to assess bleeding risks and guide blood product replacement in trauma and massive transfusion settings. However, the role of these assays in thrombosis is less well-defined but given the complexities of the coagulation system, these global coagulation assays when used in combination may provide a better assessment of cardiovascular and thrombosis risk at an individual level. Hence, we explore the role of some of the currently available global coagulation assays - the viscoelastic, thrombin generation and fibrin generation tests - and provide a review of the literature of the current evidence for these assays specifically in the field of venous thromboembolism and cardiovascular diseases.
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http://dx.doi.org/10.1016/j.thromres.2019.04.033DOI Listing
July 2019

Hemopoietic Cell Kinase amplification with Protein Tyrosine Phosphatase Receptor T depletion leads to polycythemia, aberrant marrow erythoid maturation, and splenomegaly.

Sci Rep 2019 05 7;9(1):7050. Epub 2019 May 7.

Department of Medicine, St Vincent's Hospital, The University of Melbourne, 3065, Fitzroy, Australia.

Deletion of long arm of chromosome 20 [del(20q)] is the second most frequent recurrent chromosomal abnormality in hematological malignancies. It is detected in 10% of myeloproliferative neoplasms, 4-5% of myelodysplastic syndromes, and 1-2% of acute myeloid leukaemia. Recurrent, non-random occurrence of del(20q) indicates that it is a pathogenic driver in myeloid malignancies. Genetic mapping of patient samples has identified two regions of interest on 20q - the "Common Deleted Region" (CDR) and "Common Retained Region" (CRR), which was often amplified. We proposed that the CDR contained tumor suppressor gene(s) (TSG) and the CRR harbored oncogene(s); loss of a TSG together with over-expression of an oncogene favored development of myeloid malignancies. Protein Tyrosine Phosphatase Receptor T (PTPRT) and Hemopoietic cell kinase (HCK) were identified to be the likely candidate TSG and oncogene respectively. Retroviral transduction of HCK into PTPRT-null murine LKS+ stem and progenitor cells resulted in hyperproliferation in colony forming assays and hyperphosphorylation of intracellular STAT3. Furthermore, over half of the murine recipients of these transduced cells developed erythroid hyperplasia, polycythemia and splenomegaly at 12 months, although no leukemic phenotype was observed. The findings suggested that HCK amplification coupled with PTPRT loss in del(20q) leads to development of a myeloproliferative phenotype.
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http://dx.doi.org/10.1038/s41598-019-43373-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505535PMC
May 2019

The mode of anesthesia influences outcome in mouse models of arterial thrombosis.

Res Pract Thromb Haemost 2019 Apr 15;3(2):197-206. Epub 2019 Feb 15.

Australian Centre for Blood Diseases Central Clinical School Monash University Alfred Hospital Melbourne Vic. Australia.

Background: Arterial thrombosis models are important for preclinical evaluation of antithrombotics but how anesthetic protocol can influence experimental results is not studied.

Objectives: We studied how three most commonly used rodent anesthetics affect the induction of thrombosis and thrombus resolution with antiplatelet agent integrilin (Eptifibatide).

Methods: The Folts, electrolytic, and FeCl models of carotid artery thrombosis were evaluated. The extent of blood flow reduction required to elicit cyclic flow reductions (CFR) was examined in the Folts model. The occlusion time and stability following electrolytic or FeCl injury was assessed. The efficacy of Eptifibatide was studied in each cohort and clot composition following FeCl application was assessed histologically.

Results: Isoflurane and ketamine-xylazine (ket-x) elicited higher basal blood flow velocities. For reliable CFR in the Folts model, a higher degree of blood flow reduction was required under ket-x and isoflurane. For the FeCl and electrolytic models, injury severity had to be increased in mice under ket-x anesthesia to achieve rapid occlusion. FeCl-injured artery sections from ket-x and isoflurane-treated mice showed vessel dilatation and clots that were more fibrin/red-cell rich compared to pentobarbitone. Integrilin led to cycle abolishment for all three Folts-injury cohorts but for the electrolytic model a 2.5-fold higher dose was required to restore blood flow under pentobarbitone. Integrilin after FeCl arterial injury was partially ineffective in isoflurane-treated mice.

Conclusions: Anesthesia impacts rodent carotid artery occlusion experiments and alters integrilin efficacy. It is important to consider anesthetic protocols in animal experiments involving pharmacological agents for treatment of atherothrombosis.
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http://dx.doi.org/10.1002/rth2.12184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462741PMC
April 2019

New guidelines from the Thrombosis and Haemostasis Society of Australia and New Zealand for the diagnosis and management of venous thromboembolism.

Med J Aust 2019 03 10;210(5):227-235. Epub 2019 Feb 10.

Monash University, Melbourne, VIC.

Introduction: Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cardiovascular disease and, globally, more than an estimated 10 million people have it yearly. It is a chronic and recurrent disease. The symptoms of VTE are non-specific and the diagnosis should actively be sought once considered. The mainstay of VTE treatment is anticoagulation, with few patients requiring additional intervention. A working group of experts in the area recently completed an evidence-based guideline for the diagnosis and management of DVT and PE on behalf of the Thrombosis and Haemostasis Society of Australia and New Zealand (www.thanz.org.au/resources/thanz-guidelines).

Main Recommendations: The diagnosis of VTE should be established with imaging; it may be excluded by the use of clinical prediction rules combined with D-dimer testing. Proximal DVT or PE caused by a major surgery or trauma that is no longer present should be treated with anticoagulant therapy for 3 months. Proximal DVT or PE that is unprovoked or associated with a transient risk factor (non-surgical) should be treated with anticoagulant therapy for 3-6 months. Proximal DVT or PE that is recurrent (two or more) and provoked by active cancer or antiphospholipid syndrome should receive extended anticoagulation. Distal DVT caused by a major provoking factor that is no longer present should be treated with anticoagulant therapy for 6 weeks. For patients continuing with extended anticoagulant therapy, either therapeutic or low dose direct oral anticoagulants can be prescribed and is preferred over warfarin in the absence of contraindications. Routine thrombophilia testing is not indicated. Thrombolysis or a suitable alternative is indicated for massive (haemodynamically unstable) PE.

Changes In Management As A Result Of The Guideline: Most patients with acute VTE should be treated with a factor Xa inhibitor and be assessed for extended anticoagulation.
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http://dx.doi.org/10.5694/mja2.50004DOI Listing
March 2019

Targeting CD39 Toward Activated Platelets Reduces Systemic Inflammation and Improves Survival in Sepsis: A Preclinical Pilot Study.

Crit Care Med 2019 05;47(5):e420-e427

Department of Anesthesiology and Intensive Care Medicine, University of Tübingen, Tübingen, Germany.

Objectives: Sepsis is associated with a systemic inflammatory reaction, which can result in a life-endangering organ dysfunction. Pro-inflammatory responses during sepsis are characterized by increased activation of leukocytes and platelets, formation of platelet-neutrophil aggregates, and cytokine production. Sequestration of platelet-neutrophil aggregates in the microvasculature contributes to tissue damage during sepsis. At present no effective therapeutic strategy to ameliorate these events is available. In this preclinical pilot study, a novel anti-inflammatory approach was evaluated, which targets nucleoside triphosphate hydrolase activity toward activated platelets via a recombinant fusion protein combining a single-chain antibody against activated glycoprotein IIb/IIIa and the extracellular domain of CD39 (targ-CD39).

Design: Experimental animal study and cell culture study.

Setting: University-based experimental laboratory.

Subjects: Human dermal microvascular endothelial cells 1, human platelets and neutrophils, and C57BL/6NCrl mice.

Interventions: Platelet-leukocyte-endothelium interactions were evaluated under inflammatory conditions in vitro and in a murine lipopolysaccharide-induced sepsis model in vivo. The outcome of polymicrobial sepsis was evaluated in a murine cecal ligation and puncture model. To evaluate the anti-inflammatory potential of activated platelet targeted nucleoside triphosphate hydrolase activity, we employed a potato apyrase in vitro and in vivo, as well as targ-CD39 and as a control, nontarg-CD39 in vivo.

Measurements And Main Results: Under conditions of sepsis, agents with nucleoside triphosphate hydrolase activity decreased platelet-leukocyte-endothelium interaction, transcription of pro-inflammatory cytokines, microvascular platelet-neutrophil aggregate sequestration, activation marker expression on platelets and neutrophils contained in these aggregates, leukocyte extravasation, and organ damage. Targ-CD39 had the strongest effect on these variables and retained hemostasis in contrast to nontarg-CD39 and potato apyrase. Most importantly, targ-CD39 improved survival in the cecal ligation and puncture model to a stronger extent then nontarg-CD39 and potato apyrase.

Conclusions: Targeting nucleoside triphosphate hydrolase activity (CD39) toward activated platelets is a promising new treatment concept to decrease systemic inflammation and mortality of sepsis. This innovative therapeutic approach warrants further development toward clinical application.
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http://dx.doi.org/10.1097/CCM.0000000000003682DOI Listing
May 2019

The PI 3-kinase PI3KC2α regulates mouse platelet membrane structure and function independently of membrane lipid composition.

FEBS Lett 2019 01 24;593(1):88-96. Epub 2018 Nov 24.

Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.

PI3KC2α is a phosphoinositide 3-kinase with a recently reported function in platelets; PI3KC2α-deficient mouse platelets have altered membrane structure and impaired function. Yet, how these membrane changes cause platelet dysfunction remains unknown. Here, focused ion beam-scanning electron microscopy of PI3KC2α-deficient platelet ultrastructure reveals a specific effect on the internal membrane structure, while liquid chromatography-tandem mass spectrometry profiling of 294 lipid species shows unaltered lipid composition. Functionally, PI3KC2α-deficient platelets exhibit impaired thrombosis specifically under conditions involving membrane tethering. These studies indicate that the structural changes in PI3KC2α-deficient platelets are limited to the membrane, occur without major changes in lipid composition, and selectively impair cell function during thrombus formation. These findings illustrate a unique mechanism that may be targetable for anti-thrombotic benefit.
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http://dx.doi.org/10.1002/1873-3468.13295DOI Listing
January 2019

A comparison of global coagulation assays between normal controls and patients with thrombocytopenia.

Int J Lab Hematol 2019 Apr 26;41(2):184-191. Epub 2018 Oct 26.

Department of Haematology, Northern Hospital, Epping, Victoria, Australia.

Introduction: Some patients with thrombocytopenia may be at risk of bleeding although quantitative platelet count is not always a sufficient predictive factor. Global coagulation assays such as thromboelastography (TEG ), calibrated automated thrombogram (CAT) and overall haemostatic potential (OHP) may provide a better assessment of an individual's haemostatic profile.

Methods: Blood samples were collected from thrombocytopenic patients. TEG was performed on citrated whole blood, while CAT and OHP were performed on platelet-poor plasma. Results were compared to our previously collected normal controls.

Results: Fifty-eight participants (24 immune thrombocytopenia, 34 chemotherapy/malignancy-related) with mean age of 57.5 years were recruited. Compared to normal controls, thrombocytopenic participants had comparable maximum amplitude but reduced clot lysis (0.0% vs 0.6%; P < 0.001) on TEG with reduced endogenous thrombin potential on CAT (1252.2 vs 1353.0 nmol/L/min; P = 0.040). No differences were seen in the OHP parameters. TEG showed significant difference between marked and mild thrombocytopenia groups with minimal differences seen on CAT and OHP. Those with marked thrombocytopenia showed reduced maximum amplitude (47.2 vs 57.8 mm; P = 0.002) as expected while participants with mild thrombocytopenia (platelet count 100-150 × 10 /L) paradoxically demonstrated increased maximum amplitude (66.4 vs 57.8 mm; P < 0.001).

Conclusion: Global coagulation assays, particularly TEG , can detect subtle differences in coagulation in thrombocytopenic patients. While patients with marked thrombocytopenia showed reduced maximum amplitude, patients with mild thrombocytopenia appear to paradoxically show increased maximum amplitude, suggesting compensatory activity within the coagulation pathway which may in part explain why not all thrombocytopenic patients have bleeding complications.
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http://dx.doi.org/10.1111/ijlh.12941DOI Listing
April 2019

Elastomeric microvalve geometry affects haemocompatibility.

Lab Chip 2018 06;18(12):1778-1792

School of Engineering, RMIT University, 124 La Trobe Street, Melbourne, Victoria 3000, Australia.

This paper reports on the parameters that determine the haemocompatibility of elastomeric microvalves for blood handling in microfluidic systems. Using a comprehensive investigation of blood function, we describe a hierarchy of haemocompatibility as a function of microvalve geometry and identify a "normally-closed" v-gate pneumatic microvalve design that minimally affects blood plasma fibrinogen and von Willebrand factor composition, minimises effects on erythrocyte structure and function, and limits effects on platelet activation and aggregation, while facilitating rapid switching control for blood sample delivery. We propose that the haemodynamic profile of valve gate geometries is a significant determinant of platelet-dependent biofouling and haemocompatibility. Overall our findings suggest that modification of microvalve gate geometry and consequently haemodynamic profile can improve haemocompatibility, while minimising the requirement for chemical or protein modification of microfluidic surfaces. This biological insight and approach may be harnessed to inform future haemocompatible microfluidic valve and component design, and is an advance towards lab-on-chip automation for blood based diagnostic systems.
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http://dx.doi.org/10.1039/c7lc01320eDOI Listing
June 2018

Direct Oral Anticoagulants and the Paradigm Shift in the Management of Venous Thromboembolism.

Semin Thromb Hemost 2018 Apr 20;44(3):261-266. Epub 2018 Mar 20.

Department of Haematology, Northern Health, Epping, Victoria, Australia.

The advent of direct oral anticoagulants (DOACs) has revolutionized anticoagulation management in both stroke prevention and venous thromboembolism (VTE) treatment/prevention. Clinical trials and secondary real-world data have shown that DOACs have similar efficacy and, in some cases, improved bleeding safety profiles compared with vitamin K antagonists. Together with benefits of patient convenience, this has shifted the risk-benefit ratio toward long-term anticoagulation. However, current VTE risk assessment models are based on vitamin K antagonists and do not take into account the new paradigm of DOACs. Therefore, challenges to the thrombosis community remain to determine patients who would benefit from long-term anticoagulation in the DOAC era. Here, the authors review the current literature on risks and benefits of DOACs and their potential role in long-term VTE thromboprophylaxis as well as in current risk assessment models. The increasing use of DOACs, led by their convenience of use and generally lower bleeding rates, calls for a reevaluation of the current models as the benefits of long-term anticoagulation may begin to outweigh risks and inconvenience associated with their predecessors.
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http://dx.doi.org/10.1055/s-0038-1637750DOI Listing
April 2018

An evaluation of global coagulation assays in myeloproliferative neoplasm.

Blood Coagul Fibrinolysis 2018 Apr;29(3):300-306

Department of Haematology, Northern Hospital.

: Myeloproliferative neoplasms (MPN) are independent risks for thrombotic events. Routine laboratory tests are inadequate to evaluate the underlying procoagulant state. Global coagulation assays such as thromboelastography, thrombin and fibrin generation may provide better assessment of coagulation activation and thereby of thrombosis risk. Participants with MPN were recruited. Thromboelastography was performed on citrated whole blood while thrombin generation using calibrated automated thrombogram, fibrin generation using overall haemostatic potential assays and P-selectin were quantified on platelet-poor plasma. Thirty-eight MPN patients (median age: 65 years) were recruited. There were 26 patients with essential thrombocythemia (68.4%), eight polycythemia vera (20.5%), three primary myelofibrosis and one MPN, unclassifiable. Compared with normal controls, there was no difference in maximum amplitude although lysis time (LY30) was significantly higher (2.9 vs. 0.6%, adjusted P < 0.01) using thromboelastography. Calibrated automated thrombogram showed higher thrombin peak (260.8 vs. 222.6 nmol/l; P < 0.01) and velocity index (91.1 vs. 65.0 nmol/l/min; P < 0.01) with comparable endogenous thrombin potential. Fibrin generation parameters were significantly reduced with preserved overall fibrinolytic potential, whereas P-selectin was markedly increased (108.9 vs. 49.3 ng/ml, P < 0.01). This study demonstrated unique differences between MPN population and normal controls using a combination of global coagulation assays. The presence of high lysis time (LY30) and reduced fibrin generation in MPN patients were contradictory to the prothrombotic nature and may represent a compensatory effort to achieve equilibrium within the Virchow's triad. Both markers may be important prognostic indicators of thrombosis in MPN and further prospective studies to confirm these findings are proposed.
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http://dx.doi.org/10.1097/MBC.0000000000000724DOI Listing
April 2018

Thrombin generation estimates the anticoagulation effect of direct oral anticoagulants with significant interindividual variability observed.

Blood Coagul Fibrinolysis 2018 Mar;29(2):148-154

Department of Clinical Haematology, Northern Health, Epping.

: Direct oral anticoagulants (DOACs) are increasingly being used, primarily due to their drug stability and patient convenience. Although these drugs have been evaluated to be well tolerated in numerous clinical trials, their impact on in-vivo anticoagulation effect, variability and therapeutic drug level remains unknown. Hence, we aim to study the effect and variability of DOACs on thrombin generation via the calibrated automated thrombogram. Anonymized coagulation specimens from outpatients on warfarin were collected. Pooled normal plasma samples were spiked with increasing concentrations of dabigatran, rivaroxaban and apixaban. Similarly, plasma samples with normal coagulation profiles were spiked with two concentrations each of dabigatran, rivaroxaban and apixaban. Thrombin generation via calibrated automated thrombogram was run using the above samples and compared with a dataset of normal controls. Increasing international normalized ratio was associated with a reduction of endogenous thrombin potential (ETP) and thrombin peak and increasing lag time. Factor Xa inhibitors produced a flattened thrombin generation curve with a reduction of thrombin peak and relative preservation of ETP. Direct thrombin inhibitors produced a reduction of both ETP and thrombin peak and increasing lag time. Seventy-one citrated plasma samples (26 dabigatran, 21 rivaroxaban and 24 apixaban) were evaluated. The two concentrations produced a reduction of thrombin generation parameters with significant interindividual variability compared with neat plasma of 35-93, 13-31 and 18-71% and for dabigatran, rivaroxaban and apixaban, respectively. Thrombin generation can measure the anticoagulation effect of commonly used DOACs, with each drug having a unique thrombin generation profile. The variability noted using the same concentration suggests significant interindividual pharmacodynamic differences, which maybe relevant with respect to efficacy as well as bleeding side effects. Further delineation of the modifiers of interindividual differences is required in the in-vivo setting.
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http://dx.doi.org/10.1097/MBC.0000000000000678DOI Listing
March 2018

CD39 and CD73 activity are protective in a mouse model of antiphospholipid antibody-induced miscarriages.

J Autoimmun 2018 03 3;88:131-138. Epub 2017 Nov 3.

Australian Centre for Blood Diseases, Central Clinical School, Monash University, Alfred Hospital, Melbourne, Australia. Electronic address:

Objective: Antiphospholipid syndrome (APS) is a systemic autoimmune disorder of young adults associated with devastating pregnancy complications (recurrent miscarriages, preeclampsia and low birth weight) and vascular complications including thrombosis. The key components implicated in pathogenesis of APS are the complement cascade and tissue factor (TF) activity causing inflammation and coagulation. Purinergic signalling involving catabolism of ATP to adenosine by cell-surface enzymes CD39 and CD73 has anti-inflammatory and anti-thrombotic effects. We studied whether activities of CD39 and CD73 are important in preventing the development of miscarriages in APS.

Methods: We studied frequency of miscarriages and decidual pathology following passive transfer of human aPL-ab to pregnant wildtype mice, and mice deficient in CD39 and CD73, and also transgenic mice exhibiting 2-3X higher CD39 activity.

Results: aPL-ab infusion in pregnant CD39-or CD73-knockout mice triggers an increase in miscarriages, associated with increased TF expression and complement deposition as well as elevated oxidative stress and pro-inflammatory TNF-α and IL-10 expression within the placental decidua. In contrast, aPL-ab induced miscarriages are prevented in mice over-expressing CD39, with reduced decidual TF expression and C3d deposition, diminished lipid peroxidation (4-hydroxynonenal or 4-HNE positive lipid adducts), and reduced TNF-α expression.

Conclusion: We demonstrate a protective role for CD39 in APS and provide rationale for both the development of endothelial cell-targeted soluble CD39 as a novel therapeutic for APS and analysis of perturbations in the purinergic pathway to explain human disease.
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http://dx.doi.org/10.1016/j.jaut.2017.10.009DOI Listing
March 2018

Thrombotic microangiopathy associated with intravenous injection of extended-release oxycodone.

BMJ Case Rep 2017 Jul 17;2017. Epub 2017 Jul 17.

Clinical Haematology & Australian Centre for Blood Diseases, Alfred Health, Melbourne, Australia.

We describe the case of a 35-year-old man presenting with thrombotic microangiopathy (TMA) and renal impairment following, as he later disclosed, intravenous injection of oral formulation tamper-resistant extended-release oxycodone hydrochloride (Oxycontin). Recurrent misuse of this agent was associated with relapsing TMA despite treatment with terminal complement inhibitor eculizumab. Cases of TMA have been reported in the USA in association with intravenous misuse of extended-release oxymorphone (Opana ER) after the introduction of a new non-crushable formulation in 2012. There are two reported accounts of TMA associated with tamper-resistant Oxycontin, which became available in Australia in 2014. This is the first documented case in which eculizumab was used. This case illustrates the practical diagnostic challenges in identifying TMA disorders, and the importance of a detailed drug history. It also highlights the need to clarify what role, if any, eculizumab therapy has in cases of drug-associated TMA.
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http://dx.doi.org/10.1136/bcr-2017-220977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535099PMC
July 2017

Application of a strain rate gradient microfluidic device to von Willebrand's disease screening.

Lab Chip 2017 07;17(15):2595-2608

The Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Educational Precinct, Melbourne, Victoria, Australia.

Von Willebrand's disease (VWD) is the most common inherited bleeding disorder caused by either quantitative or qualitative defects of von Willebrand factor (VWF). Current tests for VWD require relatively large blood volumes, have low throughput, are time-consuming, and do not incorporate the physiologically relevant effects of haemodynamic forces. We developed a microfluidic device incorporating micro-contractions that harnesses well-defined haemodynamic strain gradients to initiate platelet aggregation in citrated whole blood. The microchannel architecture has been specifically designed to allow for continuous real-time imaging of platelet aggregation dynamics. Subjects aged ≥18 years with previously diagnosed VWD or who presented for evaluation of a bleeding disorder, where the possible diagnosis included VWD, were tested. Samples were obtained for device characterization as well as for pathology-based testing. Platelet aggregation in the microfluidic device is independent of platelet amplification loops but dependent on low-level platelet activation, GPIb/IX/V and integrin αβ engagement. Microfluidic output directly correlates with VWF antigen levels and is able to sensitively detect aggregation defects associated with VWD subtypes. Testing demonstrated a strong correlation with standard clinical laboratory-based tests. Head-to-head comparison with PFA100® demonstrated equivalent, if not improved, sensitivity for screening aggregation defects associated with VWD. This strain rate gradient microfluidic prototype has the potential to be a clinically useful, rapid and high throughput-screening tool for VWD as well as other strain-dependent platelet disorders. In addition, the microfluidic device represents a novel approach to examine the effects of high magnitude/short duration (ms) strain rate gradients on platelet function.
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http://dx.doi.org/10.1039/c7lc00498bDOI Listing
July 2017

Venous thromboembolism management in Northeast Melbourne: how does it compare to international guidelines and data?

Intern Med J 2017 Sep;47(9):1034-1042

Department of Haematology, Northern Health, Melbourne, Victoria, Australia.

Background: Venous thromboembolism (VTE) is a major cause of morbidity and mortality with significant heterogeneity in its management, both within our local practice and in international guidelines.

Aims: To provide a holistic evaluation of 'real-world' Australian experience in the warfarin era, including how we compare to international guidelines.

Methods: Retrospective evaluation of VTE from July 2011 to December 2012 at two major hospitals in Melbourne, Australia. These results were compared to recommendations in the international guidelines.

Results: A total of 752 episodes involving 742 patients was identified. Contrary to international guidelines, an unwarranted heritable thrombophilia screen was performed in 22.0% of patients, amounting to a cost of AU$29 000. The duration of anticoagulation was longer compared to international recommendations, although the overall recurrence (3.2/100 person-years) and clinically significant bleeding rates (2.4/100 person-years) were comparable to 'real-world' data. Unprovoked VTE (hazard ratio 2.06; P = 0.01) was a risk factor for recurrence, and there was no difference in recurrence between major VTE (proximal deep vein thrombosis (DVT) and/or pulmonary embolism) and isolated distal DVT (3.02 vs 3.94/100 person-years; P = 0.25). Fourteen patients were subsequently diagnosed with malignancy, and patients with recurrent VTE had increased risk of prospective cancer diagnosis (relative risk 6.68; P < 0.001).

Conclusions: While our 'real-world' VTE experience during the warfarin era largely correlates with international guidelines, there remains heterogeneity in the management strategies, including excessive thrombophilia screening and longer duration of anticoagulation. This audit highlights the need for national VTE guidelines, as well as prospective auditing of VTE management, in the direct oral anticoagulant era for future comparison.
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http://dx.doi.org/10.1111/imj.13525DOI Listing
September 2017

A single-chain antibody-CD39 fusion protein targeting activated platelets protects from cardiac ischaemia/reperfusion injury.

Eur Heart J 2018 01;39(2):111-116

Atherothrombosis and Vascular Biology, Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC 3004, Australia.

Aims: CD39 is a cell membrane NTPase with anti-inflammatory and anti-platelet effects. However, its clinical use is limited by its bleeding side effect. With the goal of harnessing its therapeutic potential while avoiding haemostatic problems, we designed a fusion protein consisting of the extracellular domain of CD39 and a single-chain antibody (Targ-CD39) that specifically binds to activated glycoprotein (GP)IIb/IIIa and thus to activated platelets. Through this enrichment at activated platelets, the required systemic dose is below the dose impairing haemostasis.

Methods And Results: Using an ischaemia/reperfusion mouse model (left anterior descending artery ligated for 1 h) we achieved remarkable protection of the reperfused tissue with Targ-CD39 compared with Non-targ-CD39 (mutated, non-binding version of Targ-CD39) and PBS control. Targ-CD39 restored ejection fraction and fractional shortening to a level indistinguishable from pre-injury status, while controls showed functional deterioration. Employing advanced clinically relevant methods of ultrasound analysis, we observed that both radial and longitudinal strain and strain rate showed infarct-typical changes of myocardial deformation in controls, but not in Targ-CD39 treated mice. Histological assessment confirmed strong reduction of infarct size and increase in neovascularization. Furthermore, attenuation of post-ischaemic inflammation was seen in cytokine profiling.

Conclusion: Overall, we demonstrate that Targ-CD39 holds promise for treatment of myocardial infarction.
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http://dx.doi.org/10.1093/eurheartj/ehx218DOI Listing
January 2018

Significant age, race and gender differences in global coagulation assays parameters in the normal population.

Thromb Res 2017 06 12;154:80-83. Epub 2017 Apr 12.

Haematology Unit, Northern Health, 185 Cooper Street, Epping, VIC, Australia; Monash University, Clayton, VIC, Australia; Alfred Health, Prahran, VIC, Australia.

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http://dx.doi.org/10.1016/j.thromres.2017.04.009DOI Listing
June 2017

Development of a novel strategy to target CD39 antithrombotic activity to the endothelial-platelet microenvironment in kidney ischemia-reperfusion injury.

Purinergic Signal 2017 06 25;13(2):259-265. Epub 2017 Mar 25.

Australian Centre for Blood Diseases, Central Clinical School, Alfred Hospital, Monash University, Monash AMREP building, Level 1, Walkway, via The Alfred Centre, 99 Commercial Road, Melbourne, VIC, 3004, Australia.

Kidney ischemia-reperfusion injury (IRI) is common during transplantation. IRI is characterised by inflammation and thrombosis and associated with acute and chronic graft dysfunction. P-selectin and its ligand PSGL-1 are cell adhesion molecules that control leukocyte-endothelial and leukocyte-platelet interactions under inflammatory conditions. CD39 is the dominant vascular nucleotidase that facilitates adenosine generation via extracellular ATP/ADP-phosphohydrolysis. Adenosine signalling is protective in renal IRI, but CD39 catalytic activity is lost with exposure to oxidant stress. We designed a P-selectin targeted CD39 molecule (rsol.CD39-PSGL-1) consisting of recombinant soluble CD39 that incorporates 20 residues of PSGL-1 that bind P-selectin. We hypothesised that rsol.CD39-PSGL-1 would maintain endothelial integrity by focusing the ectonucleotidase platelet-inhibitory activity and reducing leukocyte adhesion at the injury site. The rsol.CD39-PSGL-1 displayed ADPase activity and inhibited platelet aggregation ex vivo, as well as bound with high specificity to soluble P-selectin and platelet surface P-selectin. Importantly, mice injected with rsol.CD39-PSGL-1 and subjected to renal IRI showed significantly less kidney damage both biochemically and histologically, compared to those injected with solCD39. Furthermore, the equivalent dose of rsol.CD39-PSGL-1 had no effect on tail template bleeding times. Hence, targeting recombinant CD39 to the injured vessel wall via PSGL-1 binding resulted in substantial preservation of renal function and morphology after IRI without toxicity. These studies indicate potential translational importance to clinical transplantation and nephrology.
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http://dx.doi.org/10.1007/s11302-017-9558-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432485PMC
June 2017

Retrospective evaluation of venous thromboembolism: Are all transient provoking events the same?

Eur J Haematol 2017 Jul 24;99(1):18-26. Epub 2017 May 24.

Austin Health, Heidelberg, Melbourne, Vic., Australia.

Objectives: Venous thromboembolism (VTE) provoked by transient risk factors has traditionally been classified as a single entity with lower risk of recurrence. We evaluated the association between different categories of transient provoking factors and the relative risk of recurrence.

Methods: Retrospective evaluation of VTE events in non-cancer patients from July 2011 to December 2012 at two tertiary institutions in Australia with a minimum follow-up of 24 months.

Results: A total of 747 VTE cases were identified, and following exclusion of cases with mortality within 30 days of presentation (n=26), unprovoked cases (40.2%) had a higher risk of recurrence (4.6 vs 2.3/100 event-years, P=.01). Provoking factors included surgery (40.4%), injury (16.7%), medical-related factors including non-surgical hospitalisation or active infection (22.0%), travel (13.2%) and oestrogen related (6.5%). Air travel had the highest recurrence rate of 5.9/100 event-years, comparable to unprovoked VTE. VTE provoked by surgery showed lower recurrence rate at 1.8/100 event-years (P=.03). 62.5% of patients with provoked VTE recurred with an unprovoked event.

Conclusion: Transient provoking factors for VTE are heterogeneous with varying potency and should not be considered a single entity. The high recurrence rate after travel-provoked VTE suggests that it is a "minor," if not negligible provoking factor with higher thrombotic predisposition.
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http://dx.doi.org/10.1111/ejh.12884DOI Listing
July 2017

Multicentre randomised placebo-controlled trial of oral anticoagulation with apixaban in systemic sclerosis-related pulmonary arterial hypertension: the SPHInX study protocol.

BMJ Open 2016 12 8;6(12):e011028. Epub 2016 Dec 8.

Department of Rheumatology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.

Introduction: Systemic sclerosis (SSc) is a severe and costly multiorgan autoimmune connective tissue disease characterised by vasculopathy and fibrosis. One of the major causes of SSc-related death is pulmonary arterial hypertension (PAH), which develops in 12-15% of patients with SSc and accounts for 30-40% of deaths. In situ thrombosis in the small calibre peripheral pulmonary vessels resulting from endothelial dysfunction and an imbalance of anticoagulant and prothrombotic mediators has been implicated in the complex pathophysiology of SSc-related PAH (SSc-PAH), with international clinical guidelines recommending the use of anticoagulants for some types of PAH, such as idiopathic PAH. However, anticoagulation has not become part of standard clinical care for patients with SSc-PAH as only observational evidence exists to support its use. Therefore, we present the rationale and methodology of a phase III randomised controlled trial (RCT) to evaluate the efficacy, safety and cost-effectiveness of anticoagulation in SSc-PAH.

Methods And Analysis: This Australian multicentre RCT will compare 2.5 mg apixaban with placebo, in parallel treatment groups randomised in a 1:1 ratio, both administered twice daily for 3 years as adjunct therapy to stable oral PAH therapy. The composite primary outcome measure will be the time to death or clinical worsening of PAH. Secondary outcomes will include functional capacity, health-related quality of life measures and adverse events. A cost-effectiveness analysis of anticoagulation versus placebo will also be undertaken.

Ethics And Dissemination: Ethical approval for this RCT has been granted by the Human Research Ethics Committees of all participating centres. An independent data safety monitoring board will review safety and tolerability data for the duration of the trial. The findings of this RCT are to be published in open access journals.

Trial Registration Number: ACTRN12614000418673, Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2016-011028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5168661PMC
December 2016

Retrospective review on isolated distal deep vein thrombosis (IDDVT) - A benign entity or not?

Thromb Res 2016 Jun 7;142:11-6. Epub 2016 Apr 7.

Australian Centre for Blood Diseases, Prahran, VIC, Australia; Monash University, Clayton, VIC, Australia.

Introduction: Isolated distal deep venous thrombosis (IDDVT) is traditionally associated with less severe clinical sequelae, with ongoing debate on multiple aspects of its management. Despite numerous studies evaluating its acute management, there remains a paucity of data evaluating long-term complications such as recurrence and subsequent malignancy. We aim to evaluate the characteristics of IDDVT in institutions that routinely perform whole leg ultrasonography, and the risks of recurrence and complications in comparison to major venous thromboembolism (major VTE; defined as above-knee or proximal DVT and pulmonary embolism (PE)).

Methods: Retrospective evaluation of consecutive IDDVT and major VTE from July 2011 to December 2012 in a hospital network in Melbourne, Australia. Patients were followed up for a minimum of 24months. Patients with active malignancy were excluded.

Results: Of 1024 VTE cases, there were 164 non-cancer patients (92 males, 72 females, median age of 61years) with IDDVT. Compared to major VTE, IDDVT was more likely to be provoked (73% vs 59%, p<0.01), has shorter duration of anticoagulation (median 3.5months vs 6.0months, p<0.01) and less clinically significant bleeding (2.4% vs 6.7%, p=0.05), independent of duration of therapy. Recurrence was non-inferior compared to major VTE (10% vs 7%, p=0.36) and 60% recurred with major VTE. Three (1.8%) were subsequently diagnosed with cancer (vs 1.9% in major VTE, p=0.97).

Conclusions: IDDVT has non-inferior rates of recurrence and subsequent cancer detection compared to major VTE and hence, its clinical significance should not differ from major VTE. Further studies are required to determine the adequate length of anticoagulation.
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http://dx.doi.org/10.1016/j.thromres.2016.04.003DOI Listing
June 2016

Imatinib-induced gastric antral vascular ectasia in three patients with chronic myeloid leukaemia.

Int J Hematol 2015 Nov 2;102(5):639-42. Epub 2015 Jul 2.

Department of Haematology, St Vincent's Hospital, 41 Victoria Parade, Fitzroy, VIC, 3065, Australia.

Imatinib is generally well tolerated, but gastric antral vascular ectasia (GAVE) remains a rare but significant complication of imatinib therapy. Whilst this complication has been described in other disease settings, only one other case of GAVE has been reported in a chronic myeloid leukaemia (CML) patient receiving imatinib. Herein, we present three CML patients with GAVE complicating imatinib therapy. In all cases, GAVE resolved only with cessation of imatinib. This confirms a causal relationship between GAVE and imatinib. GAVE should be considered as a possible cause of anaemia and upper gastrointestinal bleeding in patients receiving imatinib therapy.
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http://dx.doi.org/10.1007/s12185-015-1824-yDOI Listing
November 2015

Thrombotic microangiopathy complicating bortezomib-based therapy for multiple myeloma.

Leuk Lymphoma 2015 Jul 7;56(7):2185-6. Epub 2015 Feb 7.

Department of Haematology, St Vincent's Hospital , Melbourne , Australia.

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http://dx.doi.org/10.3109/10428194.2014.977887DOI Listing
July 2015

Src family kinases and their role in hematological malignancies.

Leuk Lymphoma 2015 Mar 21;56(3):577-86. Epub 2015 Jan 21.

Haematology Department and Victorian Cancer Cytogenetics Service, St Vincent's Hospital , Fitzroy , Australia.

The Src family protein tyrosine kinases (SFKs) are non-receptor intracellular kinases that have important roles in both hematopoiesis and leukemogenesis. The derangement of their expression or activation has been demonstrated to contribute to hematological malignancies. This review first examines the mechanisms of SFK overexpression and hyperactivation, emphasizing the dysregulation of the upstream modulators. Subsequently, the role of SFK up-regulation in the initiation, progression and therapy resistance of many hematological malignancies is also analyzed. The presented evidence endeavors to highlight the influence of SFK up-regulation on an extensive number of hematological malignancies and the need to consider them as candidates in targeted anticancer therapy.
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http://dx.doi.org/10.3109/10428194.2014.907897DOI Listing
March 2015