Chong Chyn Chua

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

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.

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

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.

The superficial femoral vein – time to change this misnomer

The (superficial) femoral vein is commonly involved in venous thrombosis of the lower limb with up to 22% of all above knee (proximal) deep vein thromboses (DVT) being isolated to this vessel (Fig. 1). In the absence of contraindications, thrombosis in this vein should be managed with therapeutic anticoagulation for at least 3 months to prevent clot extension and embolisation to the lungs, and to reduce the risk of recurrence. However, clots isolated to the (superficial) femoral vein may be suboptimally treated due to the mistaken belief among clinicians that the involved vessel is a superficial vein. A survey among general practitioners (GPs) in the United States in 1995 found that 76% of respondents would not have therapeutically anticoagulated patients when superficial femoral vein thrombosis was noted on radiology reports. To remedy this, the International Interdisciplinary Consensus Committee on Venous Anatomical Terminology in 2001 discarded the term ‘superficial femoral vein’ and replaced it simply with ‘femoral vein’. Despite this, the use of the former term has been shown to persist in up to 17% of all ultrasound scan reports in the investigation of suspected DVT in a centre in the United Kingdom in recent years. The author group operate a Thrombosis Clinic in a tertiary referral centre. Our anecdotal experience suggests that the term ‘superficial femoral vein’ is still used frequently, and some clinicians do not appreciate that the vessel is a deep vein. To test this assumption, we conducted a survey among GPs in Victoria. This survey comprised a short case study followed by two multiplechoice questions. The case was a hypothetical one based on a common clinical scenario encountered by GPs in their daily practice: a 40-year-old woman presenting with 3 days of signs and symptoms suggestive of lower limb venous thrombosis. A lower limb Doppler venous ultrasound assessment was requested. The Doppler ultrasound report used in this exercise was based on an actual radiology report, however, it had been edited and patient-identifying details removed to preserve anonymity (Fig. 2). The report in the survey read:

Passenger lymphocyte syndrome due to anti-B and anti-Jka following combined intestinal and renal transplantation

Passenger lymphocyte syndrome (PLS) is an immune‐mediated haemolysis in which antibodies directed against recipient red‐blood‐cell (RBC) antigens are formed by viable donor B‐lymphocytes found within an allograft, leading to alloimmune destruction of recipient RBC. To our knowledge, this is the first reported case of PLS with anti‐B and anti‐Jka after combined interstitial and renal transplants at the Australian Intestinal Transplant Service.

Peripheral blood stem cell mobilisation with G-CSF alone versus G-CSF and cyclophosphamide after bortezomib, cyclophosphamide and dexamethasone induction in multiple myeloma.

Bortezomib-based induction is often used in transplant-eligible patients with myeloma. The optimal peripheral blood stem cell (PBSC) mobilisation strategy in this context is unclear. We reviewed the efficacy of G-CSF alone (G-alone) vs. G-CSF and cyclophosphamide (G-cyclo: standard dose: 1.5–2u2009g/m2; high dose: 3–4u2009g/m2) PBSC mobilisation strategies in 288 patients who only received bortezomib, cyclophosphamide and dexamethasone (VCD) induction prior to autograft across six apheresis centres from November 2012 to June 2017. ‘Uncomplicated successful mobilisation’ was defined as achieving a PBSC yield of ≥4u2009×u2009106/kg within two aphereses, without plerixafor or mobilisation-associated toxicity (predominantly febrile neutropenia, FN). Success rates were 84% in G-cyclo standard dose (6% FN), 64% in G-cyclo high dose (18% FN) and 69% in G-alone (plerixafor successfully salvaged 8/9 patients). Median total stem cell yield was significantly higher with G-cyclo, but not different between the two cyclophosphamide doses. Age greater than the median of 61 years was associated with higher failure rates (22 vs. 11%, pu2009=u20090.01) and lower PBSC yield, especially in the G-alone group. Prior radiotherapy exposure did not impact on collection success. Our observations suggest that both G-cyclo standard dose and G-alone are reasonable mobilisation strategies. The former may be preferred if salvage plerixafor is unavailable.

A physician targeted intervention improves prescribing in chronic heart failure in general medical units

BackgroundDespite strong evidence for beta-blockers and angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in chronic heart failure (CHF), they have been under-utilised especially in general medical units. We aim to evaluate the effectiveness and feasibility of a physician-targeted quality improvement intervention with education and feedback on the prescription of beta-blockers and ACEI/ARB for CHF management in an inpatient setting.MethodsWe conducted an interrupted time series study between January 2009 and February 2012. A two-stage intervention was implemented. Between November 2009 and January 2011, a structured physician-oriented education program was undertaken. From February 2011, quarterly performance feedback was provided to each medical unit by a senior clinician. Medical notes of patients admitted with CHF under general medical units before and during the intervention were prospectively audited. Main outcomes were beta-blockers and ACEI/ARB prescription rates, and 180-day readmission rates for CHF.ResultsFour hundred and sixty-eight patients were included in this study. Structured education program was associated with a significant rise in beta-blockers prescription rates from a baseline of 60 to 92% (pxa0=u20090.003), but a non-sustained rise in ACEI/ARB prescription. Regular performance feedback resulted in a further sustained increase in ACEI/ARB prescription rates from 62 to 93% (pxa0=u20090.028) and a positive trend for beta-blockers with rates maintained at 89%. There was a reduction in 180-day readmission rates that correlated with the improvements in beta-blocker (pxa0=u20090.030) and ACEI/ARB (pxa0=u20090.035) prescription.ConclusionImplementation of a structured education program with regular performance feedback was durable and was associated with improvements in appropriate prescribing and an observed decrease in CHF-related readmissions.

Mutational analysis aids the diagnosis of primary myelofibrosis with atypical morphology

Dear Editor, The diagnosis of primary myelofibrosis (PMF) is multifaceted. It requires the presence of characteristic megakaryocyte proliferation, atypia, significant reticulin and/or collagen fibrosis and either the identification of myeloproliferative neoplasm (MPN) driver mutations (JAK2, CALR or MPL) or presence of another clonal marker (e.g. ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2 or SF3B1) or the lack of reactive myelofibrosis. [1] In addition, at least one minor criterion has to be demonstrated twice, including anaemia, leucocytosis, elevated lactate dehydrogenase (LDH), palpable splenomegaly or leucoerythroblastosis. We describe an interesting case where the morphological findings did not fulfil the diagnostic criteria and mutational analysis was helpful in reaching the diagnosis of PMF. A 47-year-old man with a history of epilepsy, unprovoked pulmonary embolism and peripheral vascular disease presented with a 3-month history of constitutional symptoms. Complete blood count (CBC) showed haemoglobin 61 g/L with an MCVof 86 fL, leucocyte count 4.6 × 10/L and platelet count 77 × 10/L. LDH was elevated at 259 IU/L. Nonpalpable mild splenomegaly was identified on imaging. The blood film was leucoerythroblastic with tear drop cells, 2% blasts and giant platelets (Fig. 1a). Of note, the only abnormality on CBC 3 months prior to presentation was haemoglobin of 90 g/L. Bone marrow aspirate was dry tap and non-diagnostic. The trephine was markedly hypocellular with almost absent trilineage haematopoiesis and scattered scant atypical megakaryocytes (Fig. 1f). Haematopoietic space was completely replaced by collagenous tissue, fibroblasts, increase in reticulin (MF 1–2) and collagen fibrosis (grade 2) with normal bone trabeculae (Fig. 1b–e). [2] No non-haematological cells were observed. Secondary causes of fibrosis were not identified. Cytogenetic analysis was unsuccessful. The lack of characteristic features made it difficult to ascertain a diagnosis based on morphological and clinical findings. Subsequent molecular testing on peripheral blood nucleated cells using a targeted NGS amplicon panel detected five mutations: MPL (W515L), U2AF1 (Q157H), ASXL1 (G646Wfs*12), EZH2 (Y731S) and TP53 (S215G). MPL is a driver MPN mutation resulting primarily in megakaryocyte proliferation, and is seen in 5–10% of PMF and 2– 3% of essential thrombocythaemia. [3] Complex mutational profiles are often seen in PMF and the latter four clonal markers have been described with frequencies of 16, 13, 7 and 4% respectively. [3] U2AF1 mutations are reported to correlate with significant anaemia and thrombocytopenia in PMF as observed in this case. [4] ASXL1 and EZH2 have been found to be associated with an adverse prognosis independent of current prognostic scoring systems. [5] TP53 mutation is associated with increase progression to acute myeloid leukaemia. [6] Considering the clinical, morphological and genetic findings, we established a diagnosis of PMF. The complex mutations heralded a grim prognosis. The patient was commenced on low-dose melphalan and a regular transfusion schedule but unfortunately passed away 9 months post-diagnosis from mesenteric ischemia. It was unclear if these mutations contributed to such unusual bone marrow morphology. This is an atypical case of PMF that demonstrated the utility of mutational analysis in aiding the diagnosis of difficult morphology, especially when morphology findings do not completely fulfil the WHO classification of tumours. * Chong Chyn Chua cchyn.chua@gmail.com

Fanconi anemia in 55-year-old identical twins first presenting as fatal post-chemotherapy pancytopenia.

A 55-year-old male presented with a two-day history of fevers and rigors. He reported mild nausea but otherwise no focal infective symptoms. Ten days previously he had received transarterial chemoembolization (TACE) for hepatocellular carcinoma. The chemotherapy consisted of mitomycin C 10 mg, cisplatin 50 mg, doxorubicin 50 mg, and lipiodol 10 mg. The patient had clinical features of sepsis without localizing signs and was urgently commenced on empirical broad-spectrum intravenous antibiotics with piperacillin-tazobactam. The diagnosis of hepatocellular carcinoma (HCC) was made 6 months earlier on a background of biopsy-proven nonalcoholic noninfective steatohepatitis without cirrhosis. Other past medical history included an asymptomatic horseshoe kidney noted since childhood and diet-controlled diabetes mellitus. The patient was of Italian descent, born to parents who were non-consanguineous and had a monozygotic twin brother. The temporal association with chemoembolization raised a high suspicion of a TACE related complication. TACE is one of the major treatment modalities for patients with unresectable but localized HCC with preserved liver function. It involves targeted delivery of chemotherapy into a branch of the hepatic artery supplying the tumor, followed by embolization of the artery to ensure intratumoral drug retention and minimal systemic adverse effects. Favorable tumor responses range from 35 to 60% [1]. Complications of TACE can be divided into vascular and nonvascular events [2]. Vascular complications include puncture site issues, hepatic artery damage (arterial perforation or ulceration) and inadvertent systemic embolization. Nonvascular complications include postembolization syndrome (fevers, nausea, right upper quadrant pain, transient elevation of liver transaminases) which may occur in up to 90% of patients, both localized and systemic infections, hepatic decompensation, and pulmonary embolization through arteriovenous or portovenous shunting resulting in pneumonitis [2]. The main differential diagnoses for this patient were sepsis either from a primary hepatic or alternate source, or post-embolization syndrome, although typically this syndrome occurs much earlier postprocedure. Investigations including full blood examination (FBE), biochemistry, liver enzymes, blood cultures, and imaging of the abdomen would be of utmost importance. Pre and post TACE blood investigation results are summarized in Table I. FBE examination revealed profound pancytopenia, on a background of a mild pre-existing pancytopenia. The blood film did not demonstrate dysplastic features, circulating blasts, fragments, spherocytes, or platelet clumping. Computed tomography with contrast angiogram of the abdomen only revealed changes consistent with recent chemoembolization; there was no portal hypertension or splenomegaly. Cytopenias following TACE are uncommon with occurrence in less than 3% [3], but severe pancytopenia has not been described previously. Hypothetically this may occur as a result of substantial systemic absorption of the chemotherapeutic agents and their subsequent myelosuppressive effects or modest systemic exposure in patients with preexisting marrow pathology. Systemic absorption can theoretically occur if a nontarget artery is selected for delivery of chemotherapy, an arterial shunt is present or embolization of the target artery is unsuccessful. Primary and secondary causes of severe pancytopenia need to be excluded in this patient, most commonly drug-induced or immunerelated aplastic anemia or, less likely given the time course, marrow infiltration due to malignancy. In the absence of diagnostic features on the peripheral blood smear a bone marrow biopsy was warranted. The marrow biopsy day 24 post TACE demonstrated marked hypocellularity. There was no evidence of dysplasia, nor a clonal population on flow cytometry and conventional cytogenetics did not reveal any abnormality. On review, mild pancytopenia was first noted during a preoperative work-up for a hip arthroplasty 5 years prior to the current presentation. At the time, investigations including viral hepatitis serology, anti-nuclear antibody, and paroxysmal nocturnal hemoglobinuria screen were negative. Vitamin B12 and folate levels were normal. No culprit medications were identified. A marrow biopsy demonstrated a hypoplastic marrow (20% cellularity), with no evidence of dysplasia or megaloblastosis and conventional cytogenetic analysis was normal. A single dose of granulocyte colonystimulating factor (G-CSF) 300 lg was administered with appropriate transient increase in neutrophil count from 0.9 3 10/L to 6.9 3 10/L. The pancytopenia remained stable over the following 5 years and did not require any further G-CSF or blood product support.