Hypertension, haematuria and renal functioning in haemophilia - a cross-sectional study in Europe.

BACKGROUND AND OBJECTIVES: This cross-sectional, epidemiological study sought to assess the prevalence and extent of potential risk factors for hypertension, particularly renal function related to haematuria and their associations in people with haemophilia. METHODOLOGY: Demographic and medical data were collected at a single time-point in patients with haemophilia over 40 years of age from 16 European centres. Associations with diagnosis of hypertension were tested in univariate and multivariate analyses. RESULTS: We enrolled 532 patients (median age 52 years, range 40-98) with haemophilia A (n = 467) or haemophilia B (n = 65). Haemophilia was severe (<0.01 IU mL-1 ) in 313 patients (59%). Hypertension was diagnosed in 239 patients (45%). In multivariate analyses, age and body mass index (BMI) were significantly and independently associated with hypertension (adjusted odds ratio (OR) 18.1, P < 0.001, in elderly patients and OR = 25.1, P < 0.001, in patients with BMI >30 kg m-2 ). Estimated glomerular filtration rate (eGFR) <70 mL min-1 (OR = 2.7, P = 0.047) was significantly associated with hypertension, but mean eGFR was significantly higher for severe than mild haemophilia. Further variables with OR > 2.8 were diabetes (OR = 2.8, P = 0.04), coronary artery disease (OR = 3.3, P = 0.052) and family history of hypertension (OR = 4.4, P < 0.001). Neither severity of haemophilia nor history of haematuria was significantly associated with hypertension in univariate or multivariate analyses. CONCLUSION: As in the general population, age and BMI were major risk factors for hypertension in people with haemophilia. Renal dysfunction was associated with hypertension, but the prevalence of renal dysfunction was not extensive and furthermore not significantly correlated with haematuria. The associations of other variables with hypertension require further studies to confirm causal relationships over time.

How to compare cardiovascular disease and risk factors in elderly patients with haemophilia with the general population.

INTRODUCTION: Studies on the prevalence of cardiovascular disease (CVD) and risk factors in patients with haemophilia (PWH) in comparison to the general population have generated inconsistent results. The ADVANCE Working Group collected data on CV comorbidities in PWH aged ≥40 years (H(3) Study). AIM: Identification of German epidemiological data on CVD for the general population, evaluation for appropriateness, and execution of comparisons with PWH. METHODS: Identification of data sources by structured literature (EMBASE, MEDLINE) searches. INCLUSION CRITERIA: German general population, CVD and risk factors, gender/age stratification, sample size >500 male persons, age groups ≥40 years, current data collection, language English/German. Comparison of data on CVD and risk factors in PWH (H(3)  Study) with published German general population data. RESULTS: Criteria for data source appropriateness were defined. Of five national and three international epidemiological studies, the DEGS1 Study (German Health Interview and Examination Survey for Adults) was identified as the most suitable comparator. Compared with men from DEGS1, hypertension was significantly more prevalent in PWH aged 50-59 years (41.7% [95% CI: 37.3-46.2] vs. 52.0% [95% CI: 43.7-60.1], P = 0.03). Coronary artery/heart disease (CHD) was significantly less prevalent in PWH aged ≥60 years (60-69 years: 19.5% [95% CI: 15.9-23.7] vs. 8.1% [95% CI: 3.3-16.1], P = 0.02; 70-79 years: 30.5% [95% CI: 25.9-35.5] vs. 11.8% [95% CI: 5.2-21.9], P = 0.002). No statistically significant difference for ischaemic cerebrovascular disease/stroke was detected. CONCLUSION: Increased prevalence of hypertension in PWH should trigger regular screening. CHD does occur in PWH aged ≥60 years though apparently with lower prevalence. Given the growing population of elderly PWH, guidelines for prevention and treatment of CVD should be developed.

Guideline on aspects of cancer-related venous thrombosis

The guideline was drafted by a writing group identified by the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology (BCSH). All the authors are consultants in haematology in the UK. A search was performed of PubMed and Embase using the term 'cancer' combined with 'thrombosis', 'treatment', 'prophylaxis' and 'clinical presentation'. The search covered articles published up until December 2014. Only human studies were included and articles not written in English were excluded. References in recent reviews were also examined. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the BCSH and the BCSH executive. The guideline was then reviewed by the sounding board of the British Society for Haematology (BSH). This comprises 50 or more members of the BSH who have reviewed the guidance and commented on the content and application to the UK setting. The 'GRADE' system was used to quote levels and grades of evidence, details of which can be found at: http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the prevention and management of venous thromboembolism (VTE) in patients with cancer and to advise on an approach to screening for cancer in patients with unprovoked VTE in whom cancer was not initially suspected based on clinical grounds.(AU)

Sex difference in the risk of recurrent venous thrombosis: a detailed analysis in four European cohorts.

BACKGROUND: Previous analyses reported a higher risk of recurrent venous thrombosis in men than women. OBJECTIVES: We aimed to assess the risk of recurrence in men compared with women whilst taking female reproductive risk factors (oral contraception, postmenopausal hormone therapy and pregnancy) into account. In addition, we hypothesized that the sex difference in venous thrombosis was related to F9 Malmö, an X-linked prothrombotic factor. METHODS: In four pooled European cohorts (CARROT study, Glasgow, UK; CVTE study, Cambridge, UK; AUREC study, Vienna, Austria; and LETS follow-up study, Leiden, the Netherlands), the risk of recurrent venous thrombosis was calculated in men, women with reproductive risk factors and women without reproductive risk factors at the time of their first venous thrombosis. F9 Malmö was genotyped and carriers and non-carriers contrasted. RESULTS: In total, 2185 patients with a first venous thrombosis, 1043 men and 1142 women, were included. Overall, men had a 2.8-fold (95% confidence interval [CI], 2.2-3.4) higher risk of recurrent venous thrombosis than women. This risk was 5.2-fold (95% CI, 3.5-7.7) higher in men than in women with reproductive risk factors, and 2.3-fold (95% CI, 1.7-3.2) higher in men than in women without reproductive risk factors. No difference in risk of recurrence was found for carriers vs. non-carriers of F9 Malmö. CONCLUSION: Men experienced a recurrent venous thrombosis twice as often as women without reproductive risk factors. These findings indicate that men have a higher intrinsic risk of venous thrombosis than women, which is partly masked by female reproductive risk factors. The sex difference cannot be explained by F9 Malmö.

Risk of recurrence after a first unprovoked venous thromboembolism: external validation of the Vienna Prediction Model with pooled individual patient data.

BACKGROUND: In order to stratify patients with a first unprovoked venous thromboembolism (VTE) according to their recurrence risk and to identify those who would actually benefit from indefinite anticoagulation, three prediction models have been developed so far; none of them has been yet externally validated. OBJECTIVE: To externally validate the Vienna Prediction Model (VPM), a prediction guide for estimating the recurrence risk after a first unprovoked VTE developed through Cox modeling and including sex, D-dimer and index VTE site as predictors. PATIENTS/METHODS: Nine hundred and four patients pooled from five prospective studies evaluating the prognostic value of D-dimer for VTE recurrence served as the validation cohort. The validity of the VPM in stratifying patients according to their relative recurrence risk (discrimination) and in predicting the absolute recurrence risk (calibration) was tested with survival analysis methods. RESULTS: The ability of the VPM to distinguish patients' risk for recurrent VTE in the validation cohort was at least as good as in the original cohort, with a calibration slope of 1.17 (95% confidence interval 0.71-1.64; P = 0.456 for the hypothesis of a significant difference from 1), and a c-statistic of 0.626 (vs. 0.651 in the original derivation cohort). The VPM absolute predictions in terms of cumulative rates tended to underestimate the observed recurrence rates at 12 months. CONCLUSIONS: By using a pooled individual patient database as a validation cohort, we confirmed the ability of the VPM to stratify patients with a first unprovoked VTE according to their risk of recurrence.

Hepatitis C infection and outcomes in the Scottish haemophilia population.

Patients with bleeding disorders previously frequently became infected with hepatitis C virus. We identified the number of patients infected in Scotland and assessed several aspects of the outcomes of HCV infection and its treatment comparing these with cohorts infected for other reasons. We calculated the number of individuals infected in Scotland (cohort A) starting with the total number of patients treated in Scottish haemophilia centres registered on the UKHCDO database between 1970 and 1989. Cases were then removed or added based on additional information from centre records. A second cohort B, consisted of 255 patients from cohort A and 47 patients HCV infected outside Scotland, but with follow-up data from Scottish centres around their HCV infection. We estimate that 455 patients with bleeding disorders became infected by coagulation factor provided by NHS Scotland. In 302 individuals with documented HCV infection, rates of natural clearance (17.4%), genotype spread (64% genotype 1) and responses to antiviral therapy (14.5% with monotherapy; 38.8% with combination therapy) were similar to those in other cohorts. Thirty-four liver biopsies were performed without adverse event and liver transplantation has been performed in 11 patients, seven for liver failure, four for hepatocellular carcinoma. Around 455 patients with bleeding disorders became HCV infected in Scotland before 1989. The natural history of HCV infection and responses to treatment are similar to those in other HCV-infected cohorts. Liver transplantation has been used successfully for the treatment of end-stage liver failure and hepatocellular carcinoma.

Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH).

BACKGROUND: In patients with unprovoked venous thromboembolism (VTE), the optimal duration of anticoagulation is anchored on estimating the risk of disease recurrence. OBJECTIVES: We aimed to develop a score that could predict the recurrence risk following a first episode of unprovoked VTE, pooling individual patient data from seven prospective studies. METHODS: One thousand eight hundred and eighteen cases with unprovoked VTE treated for at least 3 months with a vitamin K antagonist were available for analysis. Optimism-corrected Cox regression coefficients were used to develop a recurrence score that was subsequently internally validated by bootstrap analysis. RESULTS: Abnormal D-dimer after stopping anticoagulation, age <50 years, male sex and VTE not associated with hormonal therapy (in women) were the main predictors of recurrence and were used to derive a prognostic recurrence score (DASH, D-dimer, Age, Sex, Hormonal therapy) showing a satisfactory predictive capability (ROC area =0.71). The annualized recurrence risk was 3.1% (95% confidence interval [CI], 2.3-3.9) for a score ≤ 1, 6.4% (95% CI, 4.8-7.9) for a score=2 and 12.3% (95% CI, 9.9-14.7) for a score ≥ 3. By considering at low recurrence risk those patients with a score ≤ 1, life-long anticoagulation might be avoided in about half of patients with unprovoked VTE. CONCLUSIONS: The DASH prediction rule appears to predict recurrence risk in patients with a first unprovoked VTE and may be useful to decide whether anticoagulant therapy should be continued indefinitely or stopped after an initial treatment period of at least 3 months.

F8 and F9 mutations fail to co-segregate in a family with co-incident haemophilia A and B.

Haemophilia A and B in one individual may arise from co-incident inheritance of independent mutations in the F8 and F9 genes. However, this association is rare and has been studied poorly at a genetic level. We report a male patient with abnormal bleeding and reduced factor VIII:C (26 IU dL(-1)) and factor IX:C (35 IU dL(-1)). This index case harboured a F8 c.979C>G transversion (predictive of p.Leu327Val) and a F9 c.845A>G transition (predictive of p.His282Arg) which have been previously associated with mild haemophilia A and B, respectively. Identical F8 and F9 mutations were identified in the mother and maternal grandmother. However, an affected maternal uncle showed only the F8 c.979C>G mutation, indicating haemophilia A alone. The sister of the index case was heterozygous only for F9 c.845A>G, indicating carriership of haemophilia B alone. The non-Mendelian inheritance of F8 c.979C>G and F9 c.845A>G in this kindred is consistent with recombination between F8 and F9 and illustrates the large recombination distance between these loci. Recognition of this phenomenon was essential for accurate genetic counselling in this kindred.

Does the clinical presentation and extent of venous thrombosis predict likelihood and type of recurrence? A patient-level meta-analysis.

AIM: To determine if the mode of presentation of venous thromboembolism (VTE), as deep vein thrombosis (DVT) or pulmonary embolism (PE), predicts the likelihood and type of recurrence. METHODS: We carried out a patient-level meta-analysis of seven prospective studies in patients with a first VTE who were followed after anticoagulation was stopped. We used Kaplan-Meier analysis to determine the cumulative incidence of recurrent VTE according to mode of presentation, and multivariable Cox regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for mode of and extent of DVT as potential risk factors for recurrence. RESULTS: The 5-year cumulative rate of recurrent VTE in 2554 patients was 22.6%. In 869 (36.1%) patients with PE, the 5-year rate of any recurrence (DVT or PE) was 22.0%, and recurrence as PE was 10.6%. In 1365 patients with proximal DVT, the 5-year recurrence rate was 26.4%, and recurrence with PE was 3.6%. The risk of recurrence as PE was 3.1-fold greater in patients presenting with symptomatic PE than in patients with proximal DVT (HR, 3.1; 95% CI, 1.9-5.1). Patients with proximal DVT had a 4.8-fold higher cumulative recurrence rate than those with distal DVT (HR, 4.8; 95% CI, 2.1-11.0). CONCLUSION: Whilst DVT and PE are manifestations of the same disease, the phenotypic expression is predetermined. Patients presenting with PE are three times more likely to suffer recurrence as PE than patients presenting with DVT. Patients presenting with calf DVT are at low risk of recurrence and at low risk of recurrence as PE.

Molecular characterization of 11 novel mutations in patients with heterozygous and homozygous FV deficiency.

Coagulation factor V (FV) has an important role in the blood coagulation cascade, in both the pro- and anticoagulant pathways. FV deficiency is a rare bleeding disorder with variable phenotypic expression. We report a cohort of 10 patients with mild-severe FV deficiency in whom a total of 11 novel mutations were identified. Three patients were compound heterozygous for two mutations, whereas each of the remaining patients had a single heterozygous variant. FV levels did not correlate with either the type of mutation identified or the bleeding diathesis exhibited by the patients. Although considered to have an autosomal recessive mode of inheritance, patients with a single missense mutation may present with a significant bleeding history. The addition of a significant number of previously unidentified mutations to the public domain will contribute to the knowledge and understanding of the molecular pathology of this rare disorder.

Changing patterns of bleeding in patients with severe haemophilia A.

Previous studies on the pattern of joint bleeding in patients with haemophilia have reported that the knee joint is most frequently affected. Home treatment data reporting bleeding frequency and location collected from 100 patients registered at six haemophilia centres in the UK have been analysed to determine current patterns of bleeding. Bleeding frequency has markedly decreased although bleeding into joints remains the main characteristic of haemophilia. However, the ankle joint has replaced the knee joint as the most common joint affected. Furthermore, it seems that the frequency of knee joint bleeding is also less than the elbow joint suggesting that the traditional pattern of joint bleeding in haemophilia has now changed significantly.

Vitamin B12 deficiency following restorative proctocolectomy.

OBJECTIVE: Restorative proctocolectomy (RP) involves terminal ileal resection and formation of a small bowel reservoir that predisposes to bacterial overgrowth. It was anticipated that these patients would be at risk of vitamin B12 deficiency. METHOD: Vitamin B12 levels were measured sequentially in 171 patients who underwent RP. Prospective results were obtained from all 20 patients undergoing pouch formation after the commencement of the study. Further results were obtained retrospectively from case notes and computerized laboratory records of the 151 patients who underwent RP prior to the commencement of the study and these were correlated with the results of follow-up samples taken prospectively from the same patients after the commencement of the study. The median age of the patients was 40 years (range: 13-67) and the median duration of follow up was 5.4 years (range: 1-12). Patients with an abnormally low serum B12 level underwent both a Schilling and a hydrogen breath test. Eight of these patients were then treated with oral vitamin B12. RESULTS: Abnormally low serum B12 levels were found in 25% of patients. Forty per cent of our patient group had three or more sequential B12 measurements and of these, 66% showed steadily declining B12 levels. Ninety-four per cent of patients with low B12 had a normal Schilling test and were negative for bacterial overgrowth. CONCLUSION: Subnormal vitamin B12 levels develop in almost one-quarter of patients after pouch surgery. The exact mechanism for B12 deficiency in these patients is uncertain. In the majority of patients undergoing RP, vitamin B12 levels fall on sequential measurement. Serum B12 levels should be measured during follow up and pouch patients with subnormal B12 levels, should see them successfully restored to a normal value after treatment with oral B12 replacement therapy.

Are atrial fibrillation guidelines altering management? A community based study.

BACKGROUND AND AIMS: We wanted to determine the prevalence of atrial fibrillation (AF) in a community based cross sectional study in greater Glasgow and how current anti-thrombotic management compares to published guidelines. METHODS: 1466 patients with AF were identified in General Practices in our community and 1008 consented to take part. Their demographic details and medical history were recorded. RESULTS: 1466 patients (mean age 73.4; 55% female) with AF were identified, in our community, giving a prevalence of 1%. 53% of patients were on warfarin therapy. Of those not receiving warfarin, only one third had a putative contra-indication. The proportion ofAF patients on warfarin increased with increasing stroke risk, and over the period of the study. CONCLUSIONS: Prevalence of AF was in keeping with previous estimates. The proportion of patients with AF receiving warfarin therapy appears to be increasing. In the moderate risk group, there was a tendency to use more warfarin in the younger age groups compared to the elderly. It was in the moderate and low risk groups that there was still evidence of deviation from published guidelines.

Dementia in subjects with atrial fibrillation: hemostatic function and the role of anticoagulation.

BACKGROUND: Atrial fibrillation (AF) is associated with cognitive impairment and dementia, perhaps through encouraging a prothrombotic state and cardioembolism. OBJECTIVES: We wished to test the hypotheses that hemostatic function is altered in subjects with AF who develop dementia, and that long-term warfarin anticoagulation is protective against this complication. PATIENTS AND METHODS: Recruitment was from an observational cohort study of AF. Baseline assessment included measurement of plasma fibrinogen, fibrin D-dimer, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complexes (TAT), von Willebrand factor and tissue plasminogen activator. We assessed cognitive function after 3 years' follow-up using the 13-item modified Telephone Interview for Cognitive Status (TICSm) and the short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). RESULTS: Of the 218 subjects assessed, 145 (66%) were prescribed warfarin. Forty-nine (22%) met TICSm/IQCODE criteria for dementia. D-dimer, F1+2 and TAT levels were higher in AF subjects with dementia compared with those without (medians 81 vs. 60 ng mL(-1), P = 0.008; 0.76 vs. 0.49 nmol L(-1), P = 0.006; and 1.78 vs. 1.44 microg L(-1), P = 0.003, respectively). These associations became of borderline statistical significance following adjustment for age. Logistic regression showed a trend towards warfarin use being independently associated with reduced prevalence of dementia (odds ratio 0.52, P = 0.08). CONCLUSIONS: We found evidence of increased thrombin generation and fibrin turnover in subjects with AF and dementia compared with those without dementia. Long-term warfarin use may be protective against the development of dementia in subjects with AF.

Immediate haemostasis with recombinant factor VIIa for haemorrhage following Hickman line insertion in acute myeloid leukaemia.

Bleeding following Hickman line insertion is not uncommon but can be life threatening, especially in the presence of coagulopathy and thrombocytopenia following chemotherapy. Treatment to control the bleeding can be challenging and treatment options are limited. We present our experience of a patient who had persisting haemorrhage immediately following Hickman line insertion for administration of chemotherapy for relapsed acute myeloid leukaemia. Haemostasis could not be achieved after FFP and platelet administration. A single dose of recombinant factor VIIa (rhFVIIa) stopped the bleeding immediately, avoiding the need for surgical intervention or line removal. Our experience indicates rhFVIIa may be an effective option for bleeding related to Hickman line insertion.

'Last-ditch' use of recombinant factor VIIa in patients with massive haemorrhage is ineffective.

BACKGROUND AND OBJECTIVES: The aim of this retrospective study was to assess the effect of activated recombinant factor VII (rFVIIa) on the natural history of massive transfusion episodes. MATERIALS AND METHODS: During 2002, outcome parameters were assessed in 50 patients transfused with more than 10 units of packed red cells. The effect of the addition of rFVIIa in 10 patients, with intractable bleeding, was then observed. RESULTS: Overall mortality was 20% at 24 h and 34% at 7 days. Severe coagulopathy was confirmed as a serious negative prognostic factor and occurred in 42% of patients overall, but in 70% of rFVIIa-treated patients. Transient cessation or reduction of bleeding was noted in 60% of patients following rFVIIa infusion. However, 24-h and 7-day mortality rates were 40% and 70%, respectively, in this group. CONCLUSIONS: Last-ditch rFVIIa therapy in patients resistant to conventional treatment did not rescue these patients or significantly alter outcomes.