Haemophilia

Although the nature of haemophilia has been understood for thousands of years, knowledge of its molecular genetics is recent. These X-linked bleeding disorders have diverse underlying DNA defects and, in 1992, DNA inversion within the X chromosome was found to explain half of the most serious cases of haemophilia A. The life-span and quality of-life for patients with haemophilia had improved steadily throughout the early 1980s but the principal cause of death remained intracranial haemorrhage until the epidemic of HIV infection due to contaminated factor concentrates. Infection with hepatitis C virus is almost universal for patients treated with clotting factors before 1985. No curative treatment is available for hepatitis C at present. Knowledge of the transmission of viruses in concentrates has led to important developments in processing techniques to eliminate them. Recombinant technology has produced factor VIII and, more recently, factor IX concentrate which is likely to be very safe. Development of inhibitors to factor concentrates (especially factor VIII) remains one of the most serious complications of haemophilia. The variety of treatments available testifies to the lack of a single universally efficacious one. The use of prophylactic treatment has been conclusively demonstrated to result in a preservation of joint function in severely affected patients who might otherwise develop significant joint problems. The many facets of the care of patients with severe haemophilia, ranging from dental care to genetic counselling, can be advantageously co-ordinated in a haemophilia comprehensive care centre

Writing to patients: a randomised controlled trial

It has been suggested that consultants should consider writing directly to patients with a summary of their outpatient consultation. In a controlled trial involving consecutive new referrals to a haematology outpatient clinic, we randomised patients to receive either a personal letter from their consultant summarising their consultation (n = 77) or a brief note thanking them for attending the clinic (n = 73). Patients were assessed for recall of and satisfaction with the consultation by a single independent observer, using standardised methods. At the second visit to outpatients, the patients' median percentage recall of items discussed during the consultation was 67% (IQ range 50-80%) in the intervention group, versus 57% (IQ range 43-76%) in the control group (p = 0.3). Strongly positive views on the personal letter were expressed by patients and referring clinicians. The findings suggest that although personal letters do not substantially improve recall of the clinical encounter, they are feasible, highly valued by patients and acceptable to referring clinicians

Writing to patients: 'putting the patient in the picture'

We have explored consultant, general practitioner and patient attitudes towards the proposal that following an outpatient consultation, consultants should consider communicating directly with patients in the form of a summary letter, with a copy to the referring general practitioner or other professionals as appropriate. We conducted in-depth interviews with a purposive sample of 20 consultants, 16 patients and 12 general practitioners. The consultants and general practitioners were both involved in the care of participating patients. Patients highlighted the likely value of summary letters including, increased knowledge, improvement recall of the clinical encounter, and reassurance. Clinicians were concerned that patients would not understand letters from consultants. Additional concerns included the impact of letter on consultant-general practitioner relationship and medico-legal issues. These findings reflect fundamental differences in expectations about the nature and quality of communications between doctors and their patients

CALR-positive essential thrombocythaemia preceded by immune thrombocytopaenia

Presentation: The patient initially presented with gum bleeding and a petechial rash. Diagnosis: The patient was found to be severely thrombocytopaenic and bone marrow biopsy showed a marked excess of megakaryocytes consistent with a diagnosis of immune thrombocytopaenia (ITP). She underwent splenectomy. Seven years following splenectomy, her platelet count began to rise again, and repeat bone marrow sampling revealed an increase in megakaryocytes with evidence of clustering. On further testing the calreticulin (CALR) exon 9 variant was found and a diagnosis of essential thrombocythaemia (ET) was made. Treatment: Thromboprophylaxis and cytoreductive therapy (hydroxyurea) were initiated following ET diagnosis. Discussion: Possible mechanisms of ET (platelet excess) following ITP (platelet deficiency) include the known associations of autoimmune conditions and malignancy and the effects of immunosuppression and splenectomy in tumorigenesis. To our knowledge, this is the first recorded case of ITP preceding later development of CALR- positive ET

Warfarin prevalence, indications for use and haemorrhagic events

Warfarin, the standard oral anticoagulant drug used in Ireland, is a widely prescribed medication, particularly in the elderly. A HSE Mid-Western Area wide audit was undertaken over a 12-month period to examine the prevalence and indications for warfarin use and haemorrhagic complications associated with the drug. Every patient receiving warfarin therapy over a 13-week period was included (2564). The age standardised rate varied from 0.09% of 35-39 year olds to 6.1% of 80-84 year olds. Atrial fibrillation was the most common indication (54%) in patients attending the Mid-Western Regional Hospital anticoagulation clinic. The annual cumulative incidence of adverse haemorrhagic events in patients with a recorded INR > or = 5.0 episode was 16.6%. The incidence of major and minor haemorrhagic events per INR > or = 5.0 episode was 1.3% and 15.3% respectively. The most common sites of haemorrhage were genitourinary (39%) and gastrointestinal (27%). No fatal or intracranial haemorrhage relating to episodes of over-anticoagulation were reported during the audit period. The most frequent reason for over-anticoagulation was drug interaction (43%). In 74% of patients, the elevated INR was reversed by omitting or reducing warfarin dose. In 17% of cases, vitamin K was administered. Only 3% of incidents were treated with fresh frozen plasma or prothrombin complex concentrates.Warfarin, the standard oral anticoagulant drug used in Ireland, is a widely prescribed medication, particularly in the elderly. A HSE Mid-Western Area wide audit was undertaken over a 12-month period to examine the prevalence and indications for warfarin use and haemorrhagic complications associated with the drug. Every patient receiving warfarin therapy over a 13-week period was included (2564). The age standardised rate varied from 0.09% of 35-39 year olds to 6.1% of 80-84 year olds. Atrial fibrillation was the most common indication (54%) in patients attending the Mid-Western Regional Hospital anticoagulation clinic. The annual cumulative incidence of adverse haemorrhagic events in patients with a recorded INR > or = 5.0 episode was 16.6%. The incidence of major and minor haemorrhagic events per INR > or = 5.0 episode was 1.3% and 15.3% respectively. The most common sites of haemorrhage were genitourinary (39%) and gastrointestinal (27%). No fatal or intracranial haemorrhage relating to episodes of over-anticoagulation were reported during the audit period. The most frequent reason for over-anticoagulation was drug interaction (43%). In 74% of patients, the elevated INR was reversed by omitting or reducing warfarin dose. In 17% of cases, vitamin K was administered. Only 3% of incidents were treated with fresh frozen plasma or prothrombin complex concentrates

Challenges of providing biochemistry results in a patient with Evans syndrome

Highlights A case report of in vivo hemolysis in patient with Evans syndrome is described Hemolysis disrupts biochemistry analysis, yielding unreliable results A laboratory designed algorithm ensures results with interpretative comments Close communication between the laboratory and the clinical team is essential A case report of in vivo hemolysis in a female patient with Evans syndrome is described. The patient was admitted with anemia and jaundice and, during her 26-day hospital admission, had 83 samples taken for biochemistry analyses. The laboratory hemolytic index (HI) was frequently elevated due to persistent complement-mediated in vivo hemolysis despite multiple lines of therapy. Initially, the release of many biochemical parameters was blocked per the manufacturer´s recommendations and reported as “sample hemolyzed”. The patient developed severe acute kidney injury, ultimately requiring dialysis. Automated and timely reporting of indicative creatinine and other biochemical results in the context of ongoing hemolysis, therefore, became essential to patient care. Following a review of literature from various sources, a laboratory algorithm was designed to ensure the timely release of numerical biochemical values, where possible, with appropriate interpretative comments appended. Biochemistry, hematology, and nephrology teams were in regular communication to ensure patient samples were rapidly identified, analyzed and validated according to the algorithm, informing timely, safe and appropriate patient care. Ultimately, the patient died due to multiple disease- and treatment-related complications. In conjunction with clinical users, laboratories should plan for situations, such as in vivo hemolysis, where significant unavoidable interferences in biochemistry methodologies may occur in an ongoing manner for certain patients. Reporting categorical or best-estimate biochemistry results in such cases can be safer for patients than failing to report any results. Interpretation of these results by clinical teams requires input from appropriately trained and qualified laboratory personnel

Sickle cell trait and risk of cognitive impairment in African-Americans: The REGARDS cohort

Background: Sickle cell anemia may be associated with cognitive dysfunction, and some complications of sickle cell anemia might affect those with sickle cell trait (SCT), so we hypothesized that SCT is a risk factor for cognitive impairment. Methods: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study enrolled a national cohort of 30,239 white and black Americans from 2003 to 7, who are followed every 6 months. Baseline and annual global cognitive function testing used the Six-Item Screener (SIS), a validated instrument (scores range 0-6; ≤ 4 indicates cognitive impairment). Participants with baseline cognitive impairment and whites were excluded. Logistic regression was used to calculate the association of SCT with incident cognitive impairment, adjusted for risk factors. Linear mixed models assessed multivariable-adjusted change in test scores on a biennially administered 3-test battery measuring learning, memory, and semantic and phonemic fluency. Findings: Among 7743 participants followed for a median of 7·1 years, 85 of 583 participants with SCT (14·6%) developed incident cognitive impairment compared to 902 of 7160 (12·6%) without SCT. In univariate analysis, the odds ratio (OR) of incident cognitive impairment was 1·18 (95% CI: 0·93, 1·51) for those with SCT vs. those without. Adjustment did not impact the OR. There was no difference in change on 3-test battery scores by SCT status (all p > 0·11). Interpretation: In this prospective cohort study of black Americans, SCT was not associated with incident cognitive impairment or decline in test scores of learning, memory and executive function. Funding: National Institutes of Health, American Society of Hematology

All-trans retinoic acid (ATRA)-induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL)

© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: In acute promyelocytic leukemia (APL), normal retinoid signaling is disrupted by an abnormal PML-RARα fusion oncoprotein, leading to a block in cell differentiation. Therapeutic concentrations of all-trans-retinoic acid (ATRA) can restore retinoid-induced transcription and promote degradation of the PML-RARα protein. Autophagy is a catabolic pathway that utilizes lysosomal machinery to degrade intracellular material and facilitate cellular re-modeling. Recent studies have identified autophagy as an integral component of ATRA-induced myeloid differentiation. Methods: As the molecular communication between retinoid signaling and the autophagy pathway is not defined, we performed RNA sequencing of NB4 APL cells treated with ATRA and examined autophagy-related transcripts. Results: ATRA altered the expression of >80 known autophagy-related transcripts, including the key transcriptional regulator of autophagy and lysosomal biogenesis, TFEB (11.5-fold increase). Induction of TFEB and its transcriptional target, sequestosome 1 (SQSTM1, p62), is reduced in ATRA-resistant NB4R cells compared to NB4 cells. TFEB knockdown in NB4 cells alters the expression of transcriptional targets of TFEB and reduces CD11b transcript levels in response to ATRA. Conclusions: We show for the first time that TFEB plays an important role in ATRA-induced autophagy during myeloid differentiation and that autophagy induction potentiates leukemic cell differentiation (Note: this study includes data obtained from NCT00195156, https://clinicaltrials.gov/show/NCT00195156)

All-Trans-Retinoic Acid Combined With Valproic Acid Can Promote Differentiation in Myeloid Leukemia Cells by an Autophagy Dependent Mechanism

Acute myeloid leukemia (AML) is an aggressive blood cancer with an overall survival of 30%. One form of AML, acute promyelocytic leukemia (APL) has become more than 90% curable with differentiation therapy, consisting of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Application of differentiation therapy to other AML subtypes would be a major treatment advance. Recent studies have indicated that autophagy plays a key role in the differentiation of ATRA-responsive APL cells. In this study, we have investigated whether differentiation could be enhanced in ATRA resistant cells by promoting autophagy induction with valproic acid (VPA). ATRA sensitive (NB4) and resistant leukemia cells (NB4R and THP-1) were co-treated with ATRA and valproic acid, followed by assessment of autophagy and differentiation. The combination of VPA and ATRA induced autophagic flux and promoted differentiation in ATRA-sensitive and -resistant cell lines. shRNA knockdown of ATG7 and TFEB autophagy regulators impaired both autophagy and differentiation, demonstrating the importance of autophagy in the combination treatment. These data suggest that ATRA combined with valproic acid can promote differentiation in myeloid leukemia cells by mechanism involving autophagy