Publications by authors named "Jennifer Curnow"

40 Publications

HOW Collaborative position paper on the management of thrombocytopenia in pregnancy.

Aust N Z J Obstet Gynaecol 2021 Jan 12. Epub 2021 Jan 12.

Westmead Hospital, Sydney, New South Wales, Australia.

Thrombocytopenia in pregnancy is a common occurrence, affecting up to 10% of women by the time of birth. These recommendations aim to provide pragmatic guidance on the investigation, diagnosis and management of thrombocytopenia in pregnancy; including safety of neuraxial anaesthesia and precautions required for birth. Management of neonatal thrombocytopenia is also addressed. The authors are clinicians representing haematology, obstetric medicine, maternal-fetal medicine, and anaesthesia. Each author conducted a detailed literature review then worked collaboratively to produce a series of unanimous recommendations. The recommendation strength is limited by the lack of high-quality clinical trial data, and represents level C evidence.
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http://dx.doi.org/10.1111/ajo.13303DOI Listing
January 2021

Clinical consequences of the extremely rare anti-PP1Pk isoantibodies in pregnancy: a case series and review of the literature.

Vox Sang 2020 Dec 16. Epub 2020 Dec 16.

Department of Haematology, Westmead Hospital, Sydney, NSW, Australia.

Background: The absence of the red cell antigens P, P1 and P , known as 'p', represents an extremely rare red cell phenotype. Individuals with this phenotype spontaneously form anti-PP1P isoantibodies, associated with severe haemolytic transfusion reactions, recurrent spontaneous abortion and haemolytic disease of the fetus and newborn (HDFN).

Methods: We report a series of four successful pregnancies in three women with anti-PP1P isoantibodies, one complicated by HDFN, another by intrauterine growth restriction, all managed supportively. We also review the literature regarding the management of pregnancy involving anti-PP1P isoimmunization.

Results: The literature surrounding anti-PP1P in pregnancy is limited to a very small number of case reports. The majority report management with therapeutic plasma exchange (TPE) with or without intravenous immunoglobulin. The relationship between titre and risk of pregnancy loss remains unclear, though a history of recurrent pregnancy loss appears important. Although a positive cord blood direct antiglobulin test is frequently noted, clinically significant HDFN appears uncommon, though possible.

Conclusion: Early initiation of TPE in high risk patients should be strongly considered. If possible, pregnancies should be managed in a high-risk obstetric or maternal fetal medicine service. The fetus should be monitored closely with interval fetal ultrasound and middle cerebral artery peak systolic volume Doppler to screen for fetal anaemia. Timely sourcing of compatible blood products is likely to be highly challenging, and both directed and autologous donation should be contemplated where appropriate. The International Red Cell Donor Panel may also provide access to compatible products.
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http://dx.doi.org/10.1111/vox.13042DOI Listing
December 2020

How we diagnose 2M von Willebrand disease (VWD): Use of a strategic algorithmic approach to distinguish 2M VWD from other VWD types.

Haemophilia 2021 Jan 20;27(1):137-148. Epub 2020 Nov 20.

Sydney Centres for Thrombosis and Haemostasis, Westmead Hospital, Westmead, NSW, Australia.

Introduction: von Willebrand disease (VWD) is the most common inherited bleeding disorder and caused by an absence, deficiency or defect in von Willebrand factor (VWF). VWD is currently classified into six different types: 1, 2A, 2B, 2N, 2M, 3. Notably, 2M VWD is more often misdiagnosed as 2A or type 1 VWD than properly identified as 2M VWD.

Aim: To describe an algorithmic approach to better ensure appropriate identification of 2M VWD, and reduce its misdiagnosis, as supported by sequential laboratory testing.

Methods: Comparative assessment of types 1, 2A, 2B and 2M VWD using various laboratory tests, including VWF antigen and several VWF activity assays, plus DDAVP challenge data, ristocetin-induced platelet agglutination (RIPA) data, multimer analysis and genetic testing.

Results: Types 1, 2A, 2B and 2M VWD give characteristic test patterns that can provisionally classify patients into particular VWD types. Notably, type 1 VWD shows low levels of VWF, but VWF functional concordance (VWF activity/Ag ratios >0.6), with both baseline assessment and post-DDAVP. Types 2A, 2B and 2M VWD show VWF functional discordance (low VWF activity/Ag ratio(s)) dependent on the defect, but type 2M separates from 2A/2B VWD based on specific test patterns, especially with collagen binding vs glycoprotein Ib binding assays. RIPA identifies 2B VWD. Multimers separate 2M from 2A/2B.

Conclusion: We provide strategies to improve correct diagnosis of VWD, especially focussed on 2M VWD, and which can be used by most diagnostic haemostasis laboratories, reserving genetic analysis (if required) for confirmation.
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http://dx.doi.org/10.1111/hae.14204DOI Listing
January 2021

Pregnancy complicated by refractory severe hypercholanaemia from sodium taurocholate co-transporting polypeptide deficiency.

J Obstet Gynaecol Res 2021 Feb 10;47(2):822-826. Epub 2020 Nov 10.

Westmead Institute for Maternal and Fetal Medicine, Westmead Hospital, Sydney, New South Wales, Australia.

Sodium taurocholate co-transporting polypeptide deficiency is a rare metabolic autosomal recessive condition resulting in critically elevated plasma bile acid levels. Hypercholanaemia in similar conditions such as intrahepatic cholestasis of pregnancy has been associated with an increased risk of adverse obstetric outcomes including stillbirth. We present the first case of Sodium taurocholate co-transporting polypeptide deficiency in a current pregnancy in a patient with one previous stillbirth in the context of severe hypercholanaemia, where conventional treatments for cholestasis including ursodeoxycholic acid, rifampicin and cholestyramine were ineffective. Therapeutic plasma exchange and novel treatment with elobixibat were trialed with mixed results. The pregnancy resulted in an iatrogenic preterm delivery of a live infant at 32 weeks gestation.
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http://dx.doi.org/10.1111/jog.14568DOI Listing
February 2021

Immune-Mediated Thrombotic Thrombocytopenic Purpura: A Narrative Review of Diagnosis and Treatment in Adults.

Semin Thromb Hemost 2020 Apr 7;46(3):289-301. Epub 2020 Apr 7.

Sydney Medical School, University of Sydney, Sydney, Australia.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and potentially lethal disease characterized by fragmentary hemolysis, moderate-to-severe thrombocytopenia, end-organ dysfunction, and severely reduced ADAMTS13 levels (< 10%). Survival in iTTP has improved significantly since the introduction of plasma exchange as standard therapy combined with immune suppression to address the underlying pathophysiology. A host of challenges remain including prompt recognition of the disease, treatment of the end-organ effects of the disease, improving the early mortality rate, significantly reducing the relapse rate as well as addressing refractory disease. Discussed in this narrative review of iTTP are the recent measures aimed at addressing these issues, including improvements in clinical prediction models, postremission maintenance approaches with early retreatment as well as the development of novel therapies.
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http://dx.doi.org/10.1055/s-0040-1708541DOI Listing
April 2020

Dental extractions on direct oral anticoagulants vs. warfarin: The DENTST study.

Res Pract Thromb Haemost 2020 Feb 11;4(2):278-284. Epub 2020 Feb 11.

Department of Haematology Westmead Hospital Sydney NSW Australia.

Background: Conflicting recommendations exist addressing the management of direct oral anticoagulants (DOACs) for invasive dental procedures.

Objectives: To determine the safety of DOAC continuation compared to warfarin continuation for dental extractions with regards to bleeding outcomes.

Methods: A single-center, prospective, cohort study was performed to compare 7-day bleeding outcomes between patients who continued their DOAC, and patients on warfarin with an International Normalized Ratio (INR) between 2.0 and 4.0. Blood tests including oral anticoagulant drug levels were measured immediately prior to extraction. The gauze used to apply pressure to the socket was weighed before and after extraction to estimate blood loss. Patients were contacted by phone 2 and 7 days after extraction.

Results: Eighty-six patients on a DOAC had a total of 145 teeth extracted, and 21 patients on warfarin had 50 teeth extracted. There were no major bleeding events. The rate of minor plus clinically relevant nonmajor bleeding was comparable between the DOAC and warfarin cohorts (36% and 43%, respectively; odds ratio, 0.75; 95% confidence interval, 0.29-1.98). Preextraction apixaban and dabigatran levels were comparable between bleeders and nonbleeders, while rivaroxaban levels were higher in those who bled. The weight change of gauze used to tamponade the socket was similar between the 2 cohorts.

Conclusion: Dental extractions on patients continuing DOACs led to bleeding rates similar to patients on warfarin with an INR between 2.0 and 4.0. There is no need to adjust DOAC dosing prior to dental extractions.
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http://dx.doi.org/10.1002/rth2.12307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040537PMC
February 2020

B cell depletion therapy resulting in sustained remission of severe autoimmune complications following Alemtuzumab treatment of Multiple Sclerosis.

Mult Scler Relat Disord 2019 Oct 20;35:100-103. Epub 2019 Jul 20.

Department of Neurology, St Vincent's Hospital, Sydney, NSW, Australia.

Secondary autoimmune disorders (AID) are a recognised complication of alemtuzumab treatment for multiple sclerosis. We have previously reported two female multiple sclerosis patients treated with alemtuzumab who developed rare but severe secondary AID; acquired haemophilia A and autoimmune encephalitis with seizures. Both cases proved to be refractory to treatment with conventional immuno-therapy. However, treatment of the patients with anti-CD20 therapy resulted in sustained remission. This observation validates anti-CD20 therapy as a potential treatment option in patients with autoimmune complications of alemtuzumab that are postulated to arise as a result of B cell hyperpopulation.
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http://dx.doi.org/10.1016/j.msard.2019.07.016DOI Listing
October 2019

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

Med J Aust 2019 04 29;210(7):326-332. Epub 2019 Mar 29.

Haemophilia Treatment Centre, Westmead Hospital, Sydney, NSW.

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.
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http://dx.doi.org/10.5694/mja2.50123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850504PMC
April 2019

To Maintain or Cease Non-Vitamin K Antagonist Oral Anticoagulants Prior to Minimal Bleeding Risk Procedures: A Review of Evidence and Recommendations.

Semin Thromb Hemost 2019 Mar 11;45(2):171-179. Epub 2019 Feb 11.

Department of Haematology, Westmead Hospital, Sydney, Australia.

For procedures associated with minimal bleeding risk, there are data and experience to support the practice of continuing vitamin K antagonists rather than interrupting therapy, to prevent exposing patients to the undue risk of developing thromboembolism during anticoagulation cessation. Despite the increasing use of non-vitamin K oral anticoagulants (NOACs), there is little evidence to guide the management of these drugs around minimal bleeding risk procedures. This review examines and discusses the major society guidelines and recommendations addressing the management of NOACs around minimal bleeding risk procedures. Additionally, it summarizes the existing evidence, and highlights the gaps in knowledge where evidence is not yet available. Finally, recommendations are made to assist the proceduralist deal with this area of limited evidence.
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http://dx.doi.org/10.1055/s-0039-1678719DOI Listing
March 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

Laboratory testing for lupus anticoagulant (LA) in patients taking direct oral anticoagulants (DOACs): potential for false positives and false negatives.

Pathology 2019 Apr 18;51(3):292-300. Epub 2019 Jan 18.

Department of Laboratory Haematology, Institute of Clinical Pathology and Medical Research, NSW Health Pathology, Westmead Hospital, Westmead, NSW, Australia; Sydney Centres for Thrombosis and Haemostasis, Sydney, NSW, Australia.

We and others have previously highlighted the potential problems with testing of lupus anticoagulants (LA) in patients on anticoagulant therapy, including most recently as related to the direct oral anticoagulants (DOACs). Thus, current DOACs in use (e.g., dabigatran, a direct thrombin inhibitor, and apixaban and rivaroxaban, both direct Xa inhibitors), affect a wide variety of coagulation assays, including those used in LA investigation. The Russell viper venom time (RVVT) assay in particular, key to the investigation of LA, is highly sensitive to DOACs. LA is a marker of thrombophilia, and patients who have had a thrombosis may be placed on a DOAC. Thus, there is a high likelihood that LA testing will be requested on patients whilst they are on DOACs. In the current report, we have assessed data from our facility for the past two and a half years for all LA tests performed by RVVT testing, and have evaluated this data with respect to patient anticoagulant status. In total, there were 7170 test requests for RVVT associated testing during the period of data capture. Most LA-RVVT screen results (5008; ∼70%) were within normal limits, thereby excluding LA by RVVT method in most of the patient cohort. All DOACs led to a prolongation in both RVVT screen and confirm assays. However, rivaroxaban affected the screen more than the confirm, leading to higher RVVT ratios, whereas apixaban affected the confirm more than the screen, leading to lower RVVT ratios. LA testing in the presence of DOACs also led to lower intra-patient consistency in LA test results. We conclude that ex-vivo data appears to confirm the potential for false positive (with rivaroxaban) and potential for false negative (with apixaban) identification of LA in patients on DOAC treatment. We also make some recommendations in regards to such testing.
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http://dx.doi.org/10.1016/j.pathol.2018.11.008DOI Listing
April 2019

Variation in the incidence and timing of diagnosis of hospital-associated venous thromboembolism using linked administrative data.

Intern Med J 2018 09;48(9):1137-1141

Epidemiology and Health Analytics, Western Sydney Local Health District, Westmead, New South Wales, Australia.

Venous thromboembolism (VTE) is a potentially preventable adverse effect of hospitalisation. Inter-hospital variation in the incidence of hospital-associated VTE (HA-VTE) and timing of diagnosis (in-hospital or post-discharge) in New South Wales public hospitals were examined. Large variations in incidence (22% risk difference) and post-discharge diagnosis (115% odds difference) were evident after adjustment for case mix, which only explained 59% and 32% of inter-hospital variation respectively. The need for improved compliance with best practice guidelines is reinforced.
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http://dx.doi.org/10.1111/imj.14019DOI Listing
September 2018

Anticoagulation at the extremes of body weight: choices and dosing.

Expert Rev Hematol 2018 10 25;11(10):817-828. Epub 2018 Sep 25.

d Department of Clinical Haematology , Westmead Hospital , Westmead , Australia.

Introduction: The landscape of therapeutic anticoagulation has changed dramatically over the past decade, with availability of direct oral anticoagulants (DOACs), which inhibit factor Xa or thrombin. However, the optimal anticoagulant agent and dosing strategy for patients at both extremes of body weight has not been established for any anticoagulant, including DOACs, vitamin K antagonists (VKA), and the various heparin options. Areas covered: This paper reviews available evidence to assist clinicians in prescribing of anticoagulation therapy at the extremes of body weight. Expert commentary: There are limited data to guide prescribing of all available anticoagulants at the extremes of weight and further research regarding efficacy and safety outcomes in these groups is required. Laboratory monitoring to guide dosing of traditional anticoagulants provides reassurance of 'predictable' efficacy. In contrast agents that are not routinely monitored by laboratory testing provide greater challenges. For example, underweight patients are at risk of receiving higher drug exposures of DOACs, whereas the use of fixed dose DOACs in obese patients may be associated with lower drug exposures.
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http://dx.doi.org/10.1080/17474086.2018.1517040DOI Listing
October 2018

Lessons learnt from local real-life experience with idarucizumab for the reversal of dabigatran.

Intern Med J 2019 Jan;49(1):59-65

Department of Haematology, Westmead Hospital, Sydney, New South Wales, Australia.

Background: Idarucizumab is a specific antidote for the direct thrombin inhibitor oral anticoagulant dabigatran etexilate. It has been used with increasing frequency in Australia since it was granted Therapeutic Goods Administration approval in October 2016.

Aims: To assess idarucizumab usage, effect on coagulation parameters and clinical outcomes in patients who received idarucizumab in Western Sydney Local Health District (WSLHD).

Methods: A retrospective audit was conducted of all patients who received idarucizumab in WSLHD between September 2015 and December 2017.

Results: Of the 23 patients who received idarucizumab, 17 (74%) had bleeding, and 6 (26%) required urgent surgery/procedure. Thrombin time (TT) or activated partial thromboplastin time (APTT, when TT not available) remained prolonged at 24 h post-idarucizumab infusion in 10 of 20 (50%) patients. Renal impairment at admission was associated with prolonged TT/APTT at 24 h (P = 0.02). Of the six (26%) patients who died during hospital admission, five had raised TT/APTT at 24 h (P = 0.05). Two deaths were due to continued bleeding despite idarucizumab. Only 17% of patients received prohaemostatic treatments, and none received plasma derivatives. Despite assay availability, dabigatran drug level was only measured in eight patients.

Conclusion: Idarucizumab helped achieve haemostasis in 15 bleeding patients and allowed 6 patients to undergo urgent surgery. Half the patients had prolonged TT/APTT at 24 h post-idarucizumab, which was more likely to occur in patients with impaired renal function.
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http://dx.doi.org/10.1111/imj.13995DOI Listing
January 2019

Procoagulant Effects of Low-Level Platelet Activation and Its Inhibition by Colchicine.

Thromb Haemost 2018 04 19;118(4):723-733. Epub 2018 Mar 19.

ANZAC Research Institute, Concord Repatriation General Hospital, University of Sydney, Concord, New South Wales, Australia.

Platelets play an important role in diseases such as cardiovascular disease and cancer, especially through their release of extracellular vesicles (EVs) and role in thrombosis. The effects of the anti-inflammatory drug colchicine on platelets are not well understood. We investigated the effect of colchicine on the release of pro-coagulant EVs from platelets under low-level activation. Citrated platelet-rich plasma (PRP) from healthy donors was incubated with 2 mM colchicine or vehicle at 37°C for 30 minutes with gentle rotation. The incubation conditions caused mild platelet activation (expression of CD62P and increased surface lactadherin binding) and release of EVs expressing phosphatidylserine (PS, measured by binding of lactadherin), CD61 and CD62P, both of which were attenuated by colchicine. The incubation conditions shortened the delay to fibrin generation and this correlated with elevated levels of PS+/CD61+ EVs. Removal of EVs from plasma abrogated clot formation in the overall haemostatic potential (OHP) assay. Colchicine decreased levels of both PS+/CD61+ and CD62P+ EVs and abrogated the shortened delay to fibrin generation achieved by platelet activation. Similar results were observed after incubation of PRP with 200 µM vinblastine, suggesting a microtubular effect. An alternative method of platelet activation using platelet agonists 20 µM ADP or 10 µM epinephrine also increased CD62P+ EV levels, and this too was attenuated by prior incubation with colchicine. Our novel findings demonstrate procoagulant effects of low-level platelet activation and EV formation which are inhibited by colchicine.
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http://dx.doi.org/10.1055/s-0038-1636915DOI Listing
April 2018

Intravenous iron vs blood for acute post-partum anaemia (IIBAPPA): a prospective randomised trial.

BMC Pregnancy Childbirth 2017 Dec 19;17(1):424. Epub 2017 Dec 19.

Department of Obstetrics and Gynaecology, Westmead Hospital, Westmead, NSW, 2145, Australia.

Background: Acute post-partum anaemia can be associated with significant morbidity including a predisposition for postnatal depression. Lack of clear practice guidelines means a number of women are treated with multiple blood transfusions. Intravenous iron has the potential to limit the need for multiple blood transfusions but its role in the post-partum setting is unclear.

Methods/design: IIBAPPA is a multi-centre randomised non-inferiority trial. Women with a primary post-partum haemorrhage (PPH) >1000 mL and resultant haemoglobin (Hb) 5.5-8.0 g/dL after resuscitation with ongoing symptomatic anaemia who are otherwise stable (no active bleeding) are eligible to participate. Patients with sepsis or conditions necessitating rapid Hb restoration are excluded. Eligible participants are randomised to receive a blood transfusion or a single dose of intravenous iron polymaltose calculated using the Ganzoni formula. Primary outcome measures include Hb, Ferritin and C-Reactive Protein levels on Day 7. Secondary outcomes evaluate (i) Hb, Ferritin and CRP levels on Day 14, 28, (ii) anaemia symptoms on Day 0, 7, 14 and 28 using structured health related quality of life questionnaires, (iii) treatment safety by assessing adverse reactions and infection endpoints and (iv) the quantitative impact of anaemia on breast feeding quality using a hospital designed questionnaire.

Discussion: If equivalence in Hb and ferritin levels, symptom scores and safety endpoints is demonstrated, intravenous iron may become the preferred treatment for women with acute post-partum anaemia to minimise transfusion reactions and costs.

Trial Registration: Australian and New Zealand Clinical Trials Registry: ACTRN12615001370594 on 16th December, 2015 (prospective approval).
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http://dx.doi.org/10.1186/s12884-017-1596-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735511PMC
December 2017

Acquired haemophilia A complicating alemtuzumab therapy for multiple sclerosis.

BMJ Case Rep 2017 Dec 5;2017. Epub 2017 Dec 5.

Haematology Department, Westmead Hospital, Sydney, New South Wales, Australia.

Alemtuzumab is a highly efficacious therapy used in the treatment of multiple sclerosis (MS), but uncoupling of T and B cell repopulation during immune reconstitution associates with an increasing range of secondary B cell-mediated autoimmune complications. A 34-year-old woman developed Graves' disease 11 months following an initial course of alemtuzumab treatment for MS. Nine months following the second treatment with alemtuzumab, the patient presented with spontaneous intramuscular and subcutaneous haemorrhage due to development of an inhibitory autoantibody to coagulation factor VIII. Acquired haemophilia A (AHA) is an extremely rare complication in patients treated with alemtuzumab. Treatment with rituximab may induce a rapid remission of AHA; however, the patient's high John Cunningham virus (JCV) antibody index and alemtuzumab-induced T cell lymphopenia may lead to an increased risk of progressive multifocal leucoencephalopathy, a potential complication which was unacceptable to the patient.
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http://dx.doi.org/10.1136/bcr-2017-223016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728240PMC
December 2017

Trenonacog alfa for prophylaxis, on-demand and perioperative management of hemophilia B.

Expert Opin Biol Ther 2018 01 26;18(1):95-100. Epub 2017 Nov 26.

c Sydney Centres for Thrombosis and Haemostasis , Westmead , Sydney , Australia.

Introduction: Current treatment for hemophilia B involves replacing the missing coagulation factor IX (FIX) with either plasma-derived or recombinant (r) FIX. Trenonacog alfa is the third normal half-life rFIX that has been granted FDA approval. Area covered: In this review, the authors examine trenonacog alfa for the treatment of hemophilia B including prophylaxis, on-demand and perioperative hemostasis. They compare the PK profile to nonacog alfa and evaluate the drug's efficacy and safety from published studies. Expert opinion: Trenonacog alfa appears to be an effective and safe treatment option for patients with hemophilia B with a PK profile similar to that of nonacog alfa. Despite the advent of extended half-life rFIX and other novel therapeutic approaches, normal half-life rFIX products, including trenonacog alfa, are likely to continue to have a place in hemophilia B treatment for at least the immediate future while the new landscape takes shape, particularly in countries that cannot afford the newer treatments.
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http://dx.doi.org/10.1080/14712598.2018.1407311DOI Listing
January 2018

Incidence of in-hospital and post-discharge diagnosed hospital-associated venous thromboembolism using linked administrative data.

Intern Med J 2018 02;48(2):157-165

Epidemiology and Health Analytics, Western Sydney Local Health District, Westmead, New South Wales, Australia.

Background: Hospital-associated venous thromboembolism (HA-VTE) is a serious adverse event, preventable with appropriate care during and post-admission. Accurate measurement of in-hospital and post-discharge incidences is essential for implementation and evaluation of prevention strategies and monitoring.

Aims: To estimate in-hospital and post-discharge diagnosed VTE, trends and risk factors.

Methods: This was a population-based study in New South Wales, Australia, using linked hospital admission and emergency department data for 2010-2013 of adult patients with a minimum stay of 48 h. HA-VTE were diagnosed in-hospital or post-discharge (within 90 days). Multi-level modelling schemes produced adjusted rates and ratios for patient, admission and hospital-related characteristics.

Results: From 1 865 059 admissions, the HA-VTE incidence rate was 9.7 per 1000 admissions; 71% were diagnosed post-discharge, and 4.3% died with a greater risk for VTE diagnosed in hospital compared to post-discharge (8.4% vs 2.6%, P < 0.001). Compared with surgical patients, medical patients developed fewer HA-VTE (IRR = 0.60, 95% CI: 0.58-0.63) but were more likely to be diagnosed post-discharge (OR = 2.19; 95% CI: 2.00-2.40). HA-VTE increased 6.5% over the period, driven by the 44% increase in in-hospital diagnoses and not by the 9% decrease in post-discharge diagnoses.

Conclusions: HA-VTE is a continuing burden, and diagnosis after recent hospital discharge is notably high. Incidence varies across patients and facilities, highlighting the need for individual VTE risk assessment. Inclusive measures and routine monitoring of HA-VTE incidence and mortality are essential for implementing best practice and assessing effectiveness of prevention strategies.
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http://dx.doi.org/10.1111/imj.13679DOI Listing
February 2018

Managing and Supporting Surgery in Patients with Bleeding Disorders.

Authors:
Jennifer Curnow

Semin Thromb Hemost 2017 Oct 13;43(7):653-671. Epub 2017 Sep 13.

Department of Clinical and Laboratory Hematology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney Centers for Thrombosis and Haemostasis, Westmead, New South Wales, Australia.

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http://dx.doi.org/10.1055/s-0037-1605568DOI Listing
October 2017

The Overall Hemostatic Potential (OHP) Assay.

Authors:
Jennifer Curnow

Methods Mol Biol 2017 ;1646:523-531

Departments of Clinical and Laboratory Haematology, Sydney Centres for Thrombosis and Haemostasis, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, NSW, Australia.

The principle of the overall hemostatic potential (OHP) assay is the generation of a fibrin time curve by optical density readings, which represent the balance between fibrin generation, triggered by thrombin or tissue factor, and fibrinolysis, triggered by tissue plasminogen activator (tPA). OHP measures the integrated effect of procoagulant, anticoagulant, and fibrinolytic factors, and OHP assay parameters provide a means of quantifying both the coagulation and fibrinolytic potential of platelet poor plasma. In particular, the OHP assay can be used to evaluate hypercoagulable states and abnormalities of fibrinolysis which are not well defined by assays which are routinely available in the coagulation laboratory. OHP is a technically simple assay, with potential for application in the routine laboratory at minimal cost.
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http://dx.doi.org/10.1007/978-1-4939-7196-1_38DOI Listing
May 2018

Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes.

Cell Rep 2017 07;20(3):572-585

Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia; Prince of Wales Clinical School, UNSW, Sydney, NSW 2052, Australia; Haematology Department, South Eastern Area Laboratory Services, Prince of Wales Hospital, Randwick, NSW 2031, Australia. Electronic address:

Myelodysplastic syndromes and chronic myelomonocytic leukemia are blood disorders characterized by ineffective hematopoiesis and progressive marrow failure that can transform into acute leukemia. The DNA methyltransferase inhibitor 5-azacytidine (AZA) is the most effective pharmacological option, but only ∼50% of patients respond. A response only manifests after many months of treatment and is transient. The reasons underlying AZA resistance are unknown, and few alternatives exist for non-responders. Here, we show that AZA responders have more hematopoietic progenitor cells (HPCs) in the cell cycle. Non-responder HPC quiescence is mediated by integrin α5 (ITGA5) signaling and their hematopoietic potential improved by combining AZA with an ITGA5 inhibitor. AZA response is associated with the induction of an inflammatory response in HPCs in vivo. By molecular bar coding and tracking individual clones, we found that, although AZA alters the sub-clonal contribution to different lineages, founder clones are not eliminated and continue to drive hematopoiesis even in complete responders.
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http://dx.doi.org/10.1016/j.celrep.2017.06.067DOI Listing
July 2017

Laboratory Monitoring or Measurement of Direct Oral Anticoagulants (DOACs): Advantages, Limitations and Future Challenges.

Curr Drug Metab 2017 ;18(7):598-608

Pathology West, NSW Health Pathology. Australia.

Background: The Direct Oral Anticoagulants (DOACs) represent a new generation of antithrombotic agents, providing direct inhibition of either thrombin (factor IIa; FIIa) or activated factor X (FXa). Around the globe, their use is progressively rising, as these new agents replace the historical anticoagulants (heparin and vitamin K antagonists including warfarin) for various clinical conditions in medical practice. Other acronyms used to designate DOACs include TSOAC (target specific oral anticoagulants) and NOAC (novel; or non-vitamin K antagonist oral anticoagulants). Currently available DOACS include dabigatran (FIIa inhibitor), along with rivaroxaban, apixaban, edoxaban and betrixaban (FXa inhibitors).

Objective: This narrative review aims to briefly summarise the evidence concerning utility of different laboratory assays for qualitative or quantitative assessment of DOACs, emphasizing the difference between 'drug monitoring' and 'drug measurement' and ultimately discussing advantages and limitations of these processes.

Results And Conclusion: Recently, the dogma that these innovative anticoagulant agents will not necessitate laboratory testing has been challenged with the recognition that assessment of drug concentration or activity may be required in some circumstances, although this does not immediately translate to the concept of 'drug monitoring'.
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http://dx.doi.org/10.2174/1389200218666170417124035DOI Listing
September 2018

2B or not 2B? A prothrombotic tendency masquerading as a bleeding disorder.

Am J Hematol 2017 Jun;92(6):584-590

Sydney Centres for Thrombosis and Haemostasis, Sydney, Australia.

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http://dx.doi.org/10.1002/ajh.24724DOI Listing
June 2017

Formalising multidisciplinary peer review: developing a haematological malignancy-specific electronic proforma and standard operating procedure to facilitate procedural efficiency and evidence-based clinical practice.

Intern Med J 2017 May;47(5):542-548

Departments of Haematology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia.

Background: Multidisciplinary team (MDT) meetings aimed at facilitating peer review have become standard practice in oncology. However, there is scant literature on the optimal structure and conduct of such meetings.

Aims: To develop a process for formal peer review of patients with haematological malignancies and to audit any resulting changes made to the management recommendations of the treating physician.

Methods: A standard operating procedure (SOP) for MDT meetings was developed essentially to integrate clinical peer review with weekly pathology and radiology meetings. The centrepiece is the electronic submission of a patient-specific proforma (Microsoft InfoPath) prior to the meeting. It serves as the template for presentation, discussion and recording of recommendations and conclusions. The final verified document is stored in the electronic patient record, and a copy is sent to the general practitioner. The proposed management plans were compared to the consensus recommendations of the meeting for the first 4 years since inception.

Results: Both SOP and proforma underwent continual improvements. These provided the framework for the conduct of a robust weekly MDT meeting for peer review of the management of patients with haematological malignancies. On 20% of occasions, patient management plans were altered to optimise patient care as a direct consequence on peer review at the MDT.

Conclusion: Our streamlined process, in its ultimate format, has provided a mature and efficient forum for formal peer review in a genuine multidisciplinary environment. Both initial data and informal feedback support its ongoing activity as an integral component of delivering quality patient care.
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http://dx.doi.org/10.1111/imj.13302DOI Listing
May 2017

Monitoring Therapy during Treatment of von Willebrand Disease.

Semin Thromb Hemost 2017 Apr 29;43(3):338-354. Epub 2016 Jul 29.

Sydney Centres for Thrombosis and Haemostasis, Departments of Clinical and Laboratory Haematology, Institute of Clinical Pathology and Medical Research and Westmead Hospital, Westmead, New South Wales Australia.

von Willebrand factor (VWF) is an adhesive plasma protein that primarily acts to bridge platelets to sites of vascular injury and thus prevent bleeding. von Willebrand disease (VWD) is the most common inherited bleeding disorder and is caused by deficiency and/or defects of VWF, leading to low levels of plasma VWF or dysfunctional VWF. Factor VIII (FVIII) is also reduced in many patients with VWD, since VWF stabilizes and protects FVIII from degradation. Treatment of VWD primarily entails replacement of VWF, and sometimes FVIII, to protect against bleeding. This may entail use of VWF/FVIII concentrates, and/or desmopressin (1-deamino-8-d-arginine vasopressin) to release endogenous VWF in some patients. Adjunct therapies include antifibrinolytics and hormonal therapies in women. Optimal treatment of VWD entails measuring the effects of treatment, either as a trial before surgery or during therapeutic management. This is usually accomplished by performance of the same tests that are used to help diagnose VWD, although additional monitoring (clinically and/or by laboratory testing) may also be performed. The current review provides an overview of the treatment of VWD but is primarily focused on the monitoring of such therapy.
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http://dx.doi.org/10.1055/s-0036-1585080DOI Listing
April 2017

Type 2M and Type 2A von Willebrand Disease: Similar but Different.

Semin Thromb Hemost 2016 Jul 5;42(5):483-97. Epub 2016 May 5.

Departments of Clinical and Laboratory Haematology, Institute of Clinical Pathology and Medical Research and Westmead Hospital, Sydney Centres for Thrombosis and Haemostasis, Westmead, New South Wales, Australia.

Analogous to the differentiation between hemophilia A and B, respectively, reflecting deficiency in factor VIII (FVIII) and FIX, and increasing being recognized as reflecting clinically different disorders, types 2A and 2M von Willebrand disease (VWD) can also be shown to express both similarities and differences in their prevalence, genetic defects, laboratory test results, clinical features, and treatment responses. In this narrative review, we explore these two "subtypes" of type 2 VWD, identifying parallels and dissimilarities in various aspects of their presentation to clinicians and to scientists/laboratories. This differential will become increasingly important as we strive to provide personalized approaches to future management of patients with VWD, particularly in the emerging landscape of recombinant von Willebrand factor.
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http://dx.doi.org/10.1055/s-0036-1579641DOI Listing
July 2016

Laboratory tests used to help diagnose von Willebrand disease: an update.

Pathology 2016 Jun 4;48(4):303-18. Epub 2016 May 4.

Departments of Clinical and Laboratory Haematology, Institute of Clinical Pathology and Medical Research and Westmead Hospital, Sydney Centres for Thrombosis and Haemostasis, Westmead, Australia.

von Willebrand disease (VWD) is due to quantitative deficiencies and/or qualitative defects in von Willebrand factor (VWF), and is reportedly the most common inherited bleeding disorder. However, diagnosis of VWD is problematic, and is subject to over-, under-, and misdiagnosis. This is due to many factors, including limitations in current test procedures and an over-reliance on these imperfect test systems for clinical diagnosis. VWF is a complex plasma protein with multiple functions, but essentially acts to assist in the formation of a platelet thrombus to stop blood loss from sites of injury. VWF achieves this by several activities, including binding to platelets [primarily through the glycoprotein Ib (GPIb) receptor], binding to subendothelial matrix components (primarily collagen), and binding to factor VIII (FVIII), thus protecting FVIII from degradation and enabling its delivery to sites of vascular injury. Laboratory assessment of VWD entails performance of a battery of tests, some of which aim to mimic in vivo VWF activity. VWD is classified into six separate types, based on quantitative deficiencies [types 1 (partial deficiency) and 3 (total deficiency)] of VWF, or qualitative defects (type 2 VWD), which comprise four 'subtypes'. The current report briefly overviews the diagnosis of VWD, describing the currently available armamentarium of laboratory tests, as well as emerging options for laboratory-assisted diagnostics. Although some methodologies suffer from significant limitations that challenge the accurate diagnosis of VWD, newer methodologies and specific approaches can improve detection of this common bleeding disorder, and the appropriate characterisation and typing of patients.
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http://dx.doi.org/10.1016/j.pathol.2016.03.001DOI Listing
June 2016

Why Do Patients Bleed?

Surg J (N Y) 2016 Mar 24;2(1):e29-e43. Epub 2016 Feb 24.

Department of Clinical and Laboratory Hematology, Institute of Clinical Pathology and Medical Research and Westmead Hospital, Sydney Centres for Thrombosis and Hemostasis, Westmead, Australia.

Patients undergoing surgical procedures can bleed for a variety of reasons. Assuming that the surgical procedure has progressed well and that the surgeon can exclude surgical reasons for the unexpected bleeding, then the bleeding may be due to structural (anatomical) anomalies or disorders, recent drug intake, or disorders of hemostasis, which may be acquired or congenital. The current review aims to provide an overview of reasons that patients bleed in the perioperative setting, and it also provides guidance on how to screen for these conditions, through consideration of appropriate patient history and examination prior to surgical intervention, as well as guidance on investigating and managing the cause of unexpected bleeding.
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http://dx.doi.org/10.1055/s-0036-1579657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553458PMC
March 2016

Treatment of von Willebrand Disease.

Semin Thromb Hemost 2016 Mar 2;42(2):133-46. Epub 2016 Feb 2.

Departments of Clinical and Laboratory Haematology, Institute of Clinical Pathology and Medical Research and Westmead Hospital, Sydney Centres for Thrombosis and Haemostasis, Westmead, NSW Australia.

Congenital von Willebrand disease (VWD) and acquired von Willebrand syndrome (AVWS) reflect conditions caused by von Willebrand factor (VWF) deficiency and/or defects. VWD is the most common inherited bleeding disorder and AVWS arises from a variety of causes. Since VWF stabilizes and protects factor VIII (FVIII) in the circulation, this is also reduced in many patients with VWD. The treatment of VWD and AVWS therefore primarily entails replacement of VWF, and sometimes FVIII, to protect against bleeding. This may entail the use of VWF concentrates (currently plasma-derived) and/or FVIII concentrates (currently plasma-derived or more increasingly recombinant forms), and/or desmopressin to release endogenous VWF in subgroups of patients. For AVWS additional treatment of the underlying condition is also required. Adjunct therapies include antifibrinolytics. Globally, various formulations exist for both VWF and FVIII concentrates and are differentially available based on manufacturer marketing or regulatory approvals/clearances in different geographies. Also, guidelines for treatment of VWD vary for different localities and recombinant VWF is undergoing clinical trials. The current review provides an overview of the treatment of VWD as currently practiced in developed countries, and also provides a glimpse towards the future.
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http://dx.doi.org/10.1055/s-0035-1569070DOI Listing
March 2016