Training future haematologists, a privilege or a burden? "A trainer's view".

Recent decades have seen the emergence of new problems in haematology training, relating particularly to an expanding curriculum, less time available for training, staff shortages and the increasing separation of clinical haematology from its laboratory base. We have sought to identify the problems and propose possible solutions.

A novel mutation in exon 2 of FGB caused by c.221G>T † substitution, predicting the replacement of the native Arginine at position 74 with a Leucine (p.Arg74Leu † ) in a proband from a Kurdish family with dysfibrinogenaemia and familial venous and arterial thrombosis.

Dysfibrinogenaemias may present in either congenital or acquired form and are disorders of fibrinogen structure which may or may not be associated with abnormal function. More than 100 point mutations with single amino acid substitutions have been identified in over 400 families. These lead to defective DNA in the translated fibrinogen molecule. Such cases have improved our understanding of the fibrinogen-fibrin structure. Six members of a consanguineous family including a female proband, a female sibling, three male siblings and a daughter, with ages between 29 years and 53 years presented with early onset venous and premature arterial thromboembolic disease were investigated for a pro-thrombotic tendency associated with dysfibrinogenaemia. The family was investigated using standard coagulation assays and DNA sequencing of the genes encoding the FGA, FGB and FGG. All cases have dysfibrinogenaemia with a fibrinogen level 1.4 to 1.5 (1.9-4.3 g/L). Thrombophilia testing (including AT, PS & PC, F5 G1691A (FV Leiden)/F2 (prothombin G20210A) genotypes, homocysteine, antiphosphlipid antibody, paroxysmal nocturnal haemoglobinuria by flow cytometry and Janus Kinase-2 (exon 14)) were normal. PCR amplification and sequencing of exon 2 of FBG revealed a heterozygous mutation for a c.221G> T † substitution, predicting the replacement of the native Arginine at position 74 with a Leucine (p.Arg74Leu † ). In silico analysis of p.Arg74Leu strongly support pathogenicity. A novel mutation was identified in exon 2 of FGB caused by c.221G> T † substitution, predicting the replacement of Arginine at position 74 with a Leucine (p.Arg74Leu † ) in a proband from a Kurdish family with dysfibrinogenaemia and familial venous and arterial thrombosis.

A Novel Homozygous c.800C>G Substitution in GP1BA Exon 2 in a Kuwaiti Family with Bernard-Soulier Syndrome.

BACKGROUND: Bernard-Soulier syndrome (BSS) is a congenital bleeding disorder characterised by thrombocytopenia, giant platelets and decreased platelet adhesion resulting from genetic alterations of the glycoprotein (GP) Ib/IX/V complex. OBJECTIVES: Three sisters with a lifelong bleeding history and a provisional diagnosis of BSS were referred for further characterisation of their bleeding diathesis. The siblings' symptoms varied in severity from skin and gum bleeding to menorrhagia associated with iron-deficiency anaemia requiring regular transfusion of red cells and platelets. The parents were consanguineous but did not demonstrate any bleeding disorder. METHODS: The family were investigated using standard haematological techniques, platelet aggregometry, platelet membrane GP analysis and DNA sequencing of the genes encoding the GPIb/IX complex. RESULTS: All 3 sisters had thrombocytopenia and giant platelets. Platelet aggregation and flow cytometry studies confirmed the lack of aggregation with ristocetin and a markedly reduced GPIb/IX surface expression. Molecular analysis demonstrated a novel homozygous c.800C>G substitution in GP1BA exon 2 leading to a serine 267 Ter stop codon in all 3 siblings. CONCLUSIONS: A novel, nonsense mutation was identified as the cause of the bleeding disorder in this family. This is the first reported BSS mutation identified in a family from Kuwait.

Antiphospholipid syndrome presenting as cerebral venous sinus thrombosis: a case series and a review.

The cerebral venous sinus system is a rare site for venous thrombosis except in patients with antiphospholipid syndrome. We describe three patients presenting with cerebral venous thrombosis in association with other thrombotic sites in two patients and as an only site in one patient. Antiphospholipid syndrome has varied clinical manifestations but the defining feature is the persistent presence of antiphospholipid antibodies. In this report we will review the clinical and laboratory diagnostic criteria and the management of patients with antiphospholipid syndrome.

The impact of the DoH Commissioning for Quality and Innovation incentive on the success of venous thromboembolism risk assessment in hospitalised patients. A single institution experience in a quality outcome improvement over a 4-year cycle.

OBJECTIVES: To i) demonstrate compliance with the Commissioning for Quality and Innovation for venous thromboembolism risk assessment ii) to undertake root cause analysis of Hospital Acquired Thrombosis and to investigate its impact on quality of care. DESIGN: Prospective monitoring of all admissions. SETTING: Imperial College Healthcare Hospitals, London. PARTICIPANTS: All Hospital Provider Spells as defined on the NHS Data Model and Dictionary. MAIN OUTCOME MEASURES: i) Percentage of patients undergoing Venous Thromboembolism Risk Assessment (VTE-RA) at and 24-hours after admission ii) root cause analysis of Hospital Acquired Thrombosis up to 90 days following discharge. RESULTS: Over a 48-month cycle 83% were overall VTE-RA assessed with 36% in the first 12 months but with significant improvement to ≥95% between April 2013 and April 2015, achieving compliance target since April 2012 involving a massive 633, 850 Spells over the 4 year period. We undertook root cause analysis of all VTE episodes from April 2013 to March 2014, to ascertain Hospital Acquired Thrombosis (HAT), we analysed 433, 174 inpatient days and found a HAT rate of 1 per 1000 with 23% and 24% for DVTs and PEs potentially avoidable respectively. We further analysed VTE risk stratification (n = 1000) and found 37.0% at high risk, 44.4% at medium risk and 18.6 % at low risk, indicating the need of thromboprophylaxis in 81.4% (high and medium) of whom 33.6% were excluded. CONCLUSIONS: We achieved 95% RA compliance which has favourably impacted on our daily practice and improved the quality of the clinical care.

Successful aortic aneurysm repair in a woman with severe von Willebrand (type 3) disease.

von Willebrand disease type 3 (VWD3) is a rare but the most severe form of von Willebrand disease; it is due to almost complete lack of von Willebrand factor activity (VWF:RCo). It is inherited as autosomal recessive trait; whilst heterozygote carriers have mild, or no symptoms, patients with VWD3 show severe bleeding symptoms. In the laboratory, this is characterised by undetectable VWF:Ag, VWF:RCo, and reduced levels of factor VIII < 0.02 IU/dL. The bleeding is managed with von Willebrand/FVIII factor concentrate replacement therapy. In this rare but challenging case we report on the successful excision and repair of an ascending aortic aneurysm following adequate VWF/FVIII factor concentrate replacement using Haemate-P.

Intra-Arterial Immunoselected CD34+ Stem Cells for Acute Ischemic Stroke.

Treatment with CD34+ hematopoietic stem/progenitor cells has been shown to improve functional recovery in nonhuman models of ischemic stroke via promotion of angiogenesis and neurogenesis. We aimed to determine the safety and feasibility of treatment with CD34+ cells delivered intra-arterially in patients with acute ischemic stroke. This was the first study in human subjects. We performed a prospective, nonrandomized, open-label, phase I study of autologous, immunoselected CD34+ stem/progenitor cell therapy in patients presenting within 7 days of onset with severe anterior circulation ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score≥8). CD34+ cells were collected from the bone marrow of the subjects before being delivered by catheter angiography into the ipsilesional middle cerebral artery. Eighty-two patients with severe anterior circulation ischemic stroke were screened, of whom five proceeded to treatment. The common reasons for exclusion were age>80 years (n=19); medical instability (n=17), and significant carotid stenosis (n=13). The procedure was well tolerated in all patients, and no significant treatment-related adverse effects occurred. All patients showed improvements in clinical functional scores (Modified Rankin Score and NIHSS score) and reductions in lesion volume during a 6-month follow-up period. Autologous CD34+ selected stem/progenitor cell therapy delivered intra-arterially into the infarct territory can be achieved safely in patients with acute ischemic stroke. Future studies that address eligibility criteria, dosage, delivery site, and timing and that use surrogate imaging markers of outcome are desirable before larger scale clinical trials.

Adverse effects of lupus anticoagulant positive blood sera on placental viability can be prevented by heparin in vitro.

OBJECTIVE: Lupus anticoagulant poses a significant risk factor for obstetric complications, whereas heparin improves live birth rates in those pregnancies. Pathophysiology of antiphospholipid antibodies on placental function involves coagulopathies and thrombosis but also dysregulated trophoblast turnover. STUDY DESIGN: With the use of placental explant cultures, we assessed the effect of lupus anticoagulant positive sera (LA + sera) on apoptosis, mitosis, and invasion of trophoblast and determined the role of unfractionated heparin in regulating these functions. RESULTS: LA + sera were associated with increased placental apoptosis (TUNEL, M30 formation, DNA laddering). LA + sera decreased villous trophoblast proliferation and reduced extravillous trophoblast invasion through matrigel. Heparin attenuated LA + sera-induced apoptosis and facilitated trophoblast invasion. CONCLUSION: Lupus anticoagulant may impair placentation by increasing apoptosis, attenuating mitosis and reducing invasion of the trophoblast. The direct effects on trophoblast viability by heparin demonstrate an alternative biologic function for this anticoagulant and raise the possibility that anomalous trophoblast development may be therapeutically regulated.