Prophylaxis for severe hemophilia: experience from Europe and the United States

Since the late 1950s, prophylactic therapy has been used in patients with severe hemophilia in order to convert their phenotype into the phenotype of moderate hemophilia. In the early years, prophylaxis was mostly started after the development of arthropathy. This secondary prophylaxis decreased the number of bleeds but did not halt the development of arthropathy. With the start of primary prophylaxis, however, it was shown that both joint bleeds and arthropathy could be prevented. Although its benefits have been proved, prophylaxis has been used as standard treatment for children in only few countries. There are now favorable results with prophylaxis on bleeding and arthropathy with more than 25 years of follow-up. In general, the strategies used for prophylaxis can be divided into those that are targeted at preinfusion clotting factor levels of > 1% and those that are guided by clinical bleeding patterns of individual patients. In both types of strategies, treatment should be started early, before the start of joint damage. However, clotting factor consumption in the first group of strategies is expected to be higher, whereas bleeding frequencies are expected to be slightly lower. The differences in long-term outcome between both strategies may only become apparent after more than two decades. In addition, some patients may be able to stop taking prophylaxis in adulthood while maintaining a low bleeding frequency. In conclusion, although the optimal prophylactic regimen is still under debate, it is well established that prophylaxis reduces or even prevents joint bleeds and hemophilic arthropathy. Therefore, prophylaxis should be offered to all children with severe hemophilia, at least until adulthood.     

Bleeding manifestations in severely thrombocytopenic children with immune thrombocytopenic purpura

OBJECTIVE: To report the observations on various bleeding manifestations in children with immune thrombocytopenic purpura (ITP) having severe thrombocytopenia (platelet count (PC) < 20,000/microl) and to compare the differences in bleeding manifestations at levels of PC at < 10,000/microl compared with between 10,000 and 20,000/microl. STUDY DESIGN: It is a retrospective analysis of bleeding manifestations in children with ITP (n = 58) having severe thrombocytopenia recorded between July 1999 and June 2002. A total of 164 episodes of severe thrombocytopenia were observed. During 31 episodes (18.9%), no bleeding manifestations were observed. When bleeding was observed cutaneous bleeds were the commonest manifestations occurring in 124 episodes. Of these 124 instances, in 82 (66.1%) episodes only cutaneous bleeding was observed while in remaining 42 (33.9%) episodes cutaneous bleeding was associated with other bleeding sites. Other common bleeds observed included epistaxis 22 (13.4%), oral bleeding 21 (12.8%) and gastro-intestinal bleeding 5 (3.04%). Comparison of the bleeding manifestations during episodes when the PC was < 10,000/microl and those between 10,000 and 20,000/microl showed that in 76.6% episodes with the count at > 10,000/microl no or only cutaneous bleeds were observed (clinically mild disease) compared to 59.45% episodes with episodes having PC < 10,000/microl (z score 2.37, p < 0.05). There was no statistically significant difference in proportion of patients having clinically mild disease during acute or chronic phase of the disease. CONCLUSION: During episodes of severe thrombocytopenia, most children have clinically mild disease. When the PC is < 10,000/microl clinically mild disease is observed less often compared to episodes with PC 10,000-20,000/microl. Based on these observations, it can be recommended that during severe thrombocytopenia, particularly when the PC is between 10,000-20,22,000/microl, patients can be safely managed with watchful waiting without any specific therapeutic intervention.     

Decline of factor VIII and factor IX inhibitors during long-term treatment with NovoSeven.

Recombinant factor VIIa (rFVIIa) (NovoSeveng) is used to treat bleeding episodes in hemophilia A and B patients with inhibitor antibodies against factor VIII (FVIII) and factor IX. rFVIIIa has been studied in home treatment of mild-to-moderate joint, muscle, and mucocutaneous bleeds to assess safety and efficacy. Treatment with other factor concentrates was allowed according to treating physician's judgment. Blood samples were drawn before study start and after 6 and 12 months. It has thus been possible to follow the inhibitor titres during this period. Analyses of 53 patients (49 hemophilia A, four hemophilia B) showed inhibitor levels up to 1,208 BU/ml before study start. Based on the first analysis, hemophilia A patients were divided into high responders (> 5 BU/ml; 28 patients), low responders (> 1 and < 5 BU/ml; 15 patients) and very low responders (< or = 1 BU/ml; six patients). In high responders receiving rFVIIa as only treatment, FVIII inhibitor titre decreased to one-third of the initial level. For high responders receiving other factor treatments such as FVIII or prothrombin complex concentrates, inhibitor titre remained unchanged. Titres for low responders and very low responders remained unchanged independent of treatment. Thus, when rFVIIa is used as the only coagulation factor to treat hemophilia A/B high-responder inhibitor patients, inhibitor level declines significantly.     

Joint range-of-motion limitations among young males with hemophilia: prevalence and risk factors

Chronic joint disease from repeated bleeding into joints is a serious complication of hemophilia. To measure the extent of and to identify risk factors for deviations from normal in joint range of motion (ROM), we used cross-sectional data collected from 4343 males with hemophilia aged 2 to 19 years who received care at 136 US hemophilia treatment centers (HTCs). Factors examined included age, race/ethnicity, family history, insurance status, age at diagnosis and first HTC visit, frequency of HTC visits, hemophilia type, bleeding frequency, prophylaxis use, inhibitor status, body mass index (BMI), and recent orthopedic procedures. Trained personnel using a standard protocol obtained ROM measurements on 10 joints (hips, knees, shoulders, elbows, and ankles). Analyses used multiple linear regression to model overall ROM limitation separately by disease severity. For persons in all severity groups, joint ROM limitation was positively associated with older age, nonwhite race, and increased BMI. For those with severe disease, ROM limitation was also positively associated with number of bleeds and was greater for those with inhibitors or recent orthopedic procedures. We conclude that ROM limitations begin at an early age, especially for those with severe and moderate disease, and that BMI is an important, potentially modifiable risk factor.     

Adults with Ebstein's anomaly--Cardiopulmonary exercise testing and BNP levels exercise capacity and BNP in adults with Ebstein's anomaly

INTRODUCTION: Ebstein's anomaly is defined as the significant apical displacement of the part of the tricuspid valve causing significant tricuspid regurgitation and reduction of the functional right ventricle. The aim of the study was to evaluate exercise capacity with cardiopulmonary stress testing and to determine plasma BNP levels in adults with Ebstein's anomaly, and to establish their relation with echocardiogaphic grading of the lesion severity. MATERIALS AND METHODS: Study group consisted of 21 patients (16 males, aged 40.3+/-11.5 years). The control group: 19 healthy individuals (13 males, aged mean 39.9+/-9.3 years). On echocardiography the grade of the lesion severity was calculated (EGE) and used to define the following four groups: I < 0.5, II: 0.5-0.9, III: 1.0-1.49, IV > 1.5. The forced vital capacity (FVC), first second forced expiratory volume (FEV1), peak oxygen uptake (peak VO2), and VE/VCO2 slope were assessed with cardiopulmonary stress test and plasma BNP levels measured with radioimmunometric assay. RESULTS: In the studied group VO2 was lower than in control (21.9+/-5.4 vs. 33.6+/-8.3 mL/kg/min [p = 0.00001]), VE/VCO2 slope was higher in Ebstein's group (40.1+/-8.1, p = 0.00001). BNP levels were higher in the Ebstein group then in controls (35.9+/-25.0 vs. 17.2+/-9.9 pg/mL [p = 0.0002]) and did not differ significantly between EGE groups. PeakVO2 of 24.5+/-3.9 in patients from II EGE group were higher than in patients from EGE groups: III (17.2+/-5.2 p = 0.007) and IV (22.9+/-4.7 p = 0.05). CONCLUSIONS: Exercise capacity of adults with Ebstein's anomaly is significantly reduced and plasma BNP levels are higher compared to healthy individuals. Exercise capacity in patients with Ebstein's anomaly becomes gradually lower alongside the EGE severity; however, BNP levels do not correlate significantly with this parameter.     

Impact of inhibitors on hemophilia a mortality in the United States

The previously published mortality studies are limited in hemophilia populations but suggest that there is no increased risk of mortality in factor VIII inhibitor patients. This retrospective study analyzed surveillance data collected on 7,386 males with severe hemophilia A over a 13‐year period to assess the association between a current inhibitor and death. During the study period, 432 participants died, among whom 48 were patients with an inhibitor. Clinical characteristics most strongly associated with death were increased number of reported bleeds, signs of liver disease, infection with either HIV or HCV, and the presence of inhibitor. Patients who underwent successful tolerization were not considered inhibitor patients in our analysis. In a multivariable analysis, the odds of death were 70% higher among patients with a current inhibitor compared to those without an inhibitor (P < 0.01). Deaths among patients with inhibitors were much more likely to be attributed to bleeding complications than those among patients without an inhibitor (42 vs. 12%, P < 0.0001). We conclude that males with severe hemophilia A and a current inhibitor are at increased risk of death.Am. J. Hematol. 90:400–405, 2015. © 2015 Wiley Periodicals, Inc.     

Coagulation disorders and inhibitors of coagulation in children from Mansoura,Egypt

Disorders of coagulation in children often prove challenging to the medical care team. The aims of this study were to assess the spectrum and prevalence of coagulation disorders among children attending Mansoura University Children Hospital (MUCH), Mansoura, Egypt. A total of 105 pediatric patients were referred to MUCH. They were divided into two groups: congenital coagulation disorders (75 cases, age 45.36 ± 48.59 months), and acquired coagulation disorders (30 cases, age 56.13 ± 61.61 months). All patients were subjected to thorough history taking including the nature of bleeding, family, past history, mode of inheritance, and detailed physical findings. Hemostatic tests included: platelet count, bleeding time (BT), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT). Specific tests in the congenital group include assay of coagulation factors according to each disorder, Von Willebrand factor assay, ristocetin aggregation test, APTT mixing study for detection of inhibitors in complicated hemophilia cases, F VIII C to VWAg ratio with cut off 0.7 for detection of carriers in some hemophilia A families. Congenital disorders constituted 71.4% of the studied cases vs. 28.6% for acquired disorders. Hemophilia A (42.85%), hemophilia B (14.28%) and liver diseases (14.28%) represented the majority of the studied cases. Mild and moderate cases of hemophilia A and B are more frequent than severe cases in both types. Male sex is more frequent than female in the congenital group (94.7 vs. 5.3%, P < 0.001). Direct correlation existed between factor level assay and severity of hemophilia (r = 0.73, P = 0.006). Three mothers and one sister were identified as carrier out of four families. Anti-clotting factors inhibitor was detected in 18.2% of patients with hemophilia A and in 9.1% with hemophilia B. In conclusion, our study found that hemophilias are the most prevalent congenital coagulation disorders among children. Attention must be given for detection of hemophilia carriers and inhibitors of clotting factors.     

The influence of aetiology on inflammatory and neurohumoral activation in patients with severe heart failure: a prospective study comparing Chagas' heart disease and idiopathic dilated cardiomyopathy

Patients with Chagas' cardiomyopathy have the worst prognosis when compared to other aetiologies. It has been suggested that a more intense inflammatory activation could be responsible for this excessive mortality. We studied 35 patients with idiopathic dilated cardiomyopathy (IDC group) and 28 patients with Chagas' heart disease (Chagas' group) and 12 control subjects. We compared plasma tumor necrosis factor alpha (TNF-alpha), soluble TNF-alpha receptor type 1 (sTNF-R1), soluble Fas (sFas), interleukin 6 (IL-6), and brain natriuretic peptide type B (BNP) concentrations between the groups. TNF-alpha and IL-6 concentrations were higher in the IDC and Chagas groups as compared to controls (p<0.001 and p=0.001, respectively). sTNF-R1 concentration was higher in IDC after stratification for functional class (p=0.039), and there was a trend toward higher plasma TNF-alpha concentration in the Chagas' group (p=0.092). IL-6 concentration was higher in Chagas than in IDC (p=0.005). Higher IL-6 levels were associated with worse outcome (p=0.03 for Chagas; p=0.003 for IDC). sFas concentration was similar among groups. BNP concentrations were higher in IDC (350 pg/ml) and in Chagas (444.6 pg/ml) as compared to the controls (20.3 pg/ml; p<0.01). Higher BNP levels were associated with death and heart transplantation in both aetiologies. Inflammatory activation in Chagas heart disease differs from IDC and is associated with heart failure severity.     

Trends in bleeding patterns during prophylaxis for severe haemophilia: observations from a series of prospective clinical trials

Summary. Replacement therapy or prophylaxis, has become the standard of care for the treatment of severe haemophilia A. To describe bleeding patterns in children, adolescents and adults on prophylaxis and their observed relationships to times of infusion (during the week and during the day) as well as season of the year. Data from Advate pre‐licensure prospective clinical trials from 145 patients with factor VIII (FVIII) <1%, were used. All patients underwent a 48‐h pharmacokinetic study. The 10–65 year group had ≥75 exposure days on fixed prophylaxis (25–40 IU kg^?1 3–4x per week). Prophylaxis was not fixed but similar for 1–6 year olds. Bleeding patterns were analysed. Overall, 700 bleeds were observed in 110/145 patients. All were treated with prophylaxis, mean dose 108 IU kg^?1 week^?1 in on average 2.9 infusions (1–6 years), 86 IU kg ^?1week^?1 in 2.7 infusions (10–17 years),and 75 IU kg ^?1week^?1 in 2.6 infusions (18–65 years), respectively. On prophylaxis, median total bleeds per year were low at 3.1 for patients aged 1–6 years, 3.3 for those aged 10–17 years and 2.1 for patients aged 18–65 years. Patients aged 1–6 years had predominantly soft tissue bleeds (79%). Incidence of joint bleeding was not associated with season, but was significantly lower in patients who infused FVIII in the mornings: median 0 per year (IQR 0.0–0.4) compared to those who infused later [median 1.8 per year (IQR 0.0–5.2)]. Older patients predominantly experienced joint bleeds (50% and 62%, respectively). More joint bleeds occurred during the summer [43 and 46% respectively, (P < 0.01)]. Bleeding patterns in patients on prophylaxis varied according to age. In addition, the 10–65 year olds showed increased bleeding during the summer. After confirmation in prospective studies, this information may be used to improve tailoring of prophylactic treatment.     

Long-term survivors after variceal haemorrhage. Follow-up of a controlled study of endoscopic sclerotherapy versus conservative management

In a prospective controlled trial of conservative therapy (vasopressin/balloon tamponade (control group] versus endoscopic sclerotherapy (ST) for the acute bleeding and at rebleeding, 107 cirrhotic patients with major variceal haemorrhage were studied from 1979 to 1983. The prospective follow-up study is now presented of the 51 patients surviving for more than 1 year. The present ST group (30 patients) was followed for a median of 5 years (range, 1-7.5 years), and the controls for 4 years (3-5.5 years). Variceal eradication was obtained in 22 ST patients in the 1st year after a median of 6 months and 5 ST sessions, and in 7 ST patients after 21 months and 9 ST sessions. The delay was due to alcoholic abuse. Eleven ST patients and 11 controls (NS) rebled on 30 and 45 occasions during a total follow-up time of 1364 and 696 months and 0.0220 and 0.0647 bleeds per patient-month, respectively (p = 0.098). Eight ST patients experienced 12 variceal bleeds, 11 controls had 39 haemorrhages with variceal aetiology, 0.0088 and 0.0560 bleeds per patient-month (p = 0.016), respectively. Five ST patients had recurrent varices on nine occasions with five episodes of bleeding a median of 13 months after completion of the initial serial ST. Reelimination was achieved with a median of three ST sessions during 3 months, but three patients had a second variceal recurrence 14-24 months later, successfully treated with one ST session in two of them. There was no difference in survival.(ABSTRACT TRUNCATED AT 250 WORDS)     

Response of patients with mild and moderate hemophilia A and von Willebrand's disease to treatment with desmopressin

Desmopressin was administered intravenously to 68 patients with hemophilia and von Willebrand's disease of mild or moderate severity to assess the safety, reproducibility, and range of response to this new therapeutic alternative. A rise in factor VIII-von Willebrand factor levels was seen in 64 patients, and the magnitude was sufficient to provide normal hemostasis in 55 to 68 spontaneous or traumatic bleeding episodes, dental procedures, or operations. Thus, our experience shows that most patients with mild or moderate hemophilia and von Willebrand's disease can be treated effectively without plasma derivatives. Patients who had two or more infusions of desmopressin at different times had similar responses each time, and members of the same family also had similar responses after desmopressin infusions. Because this drug can be administered without significant side effects, it should have an important role in the management of patients with mild or moderate hemophilia and von Willebrand's disease.     

Turning severe into moderate haemophilia by prophylaxis: are we reaching our goal?

Background

Since the introduction of prophylaxis, physicians have tried to convert the clinical phenotype of severe haemophilia (SH) into that of moderate haemophilia (MH), but the outcome of patients with SH has never been compared to that of patients with MH.

Material and methods

The outcome of 80 patients with SH on long-term, intermediate dose prophylaxis was compared to that of 40 patients with MH in a single-centre study. Data on treatment history, activities (assessed by the IPAQ and HAL), quality of life (assessed by the SF-36 and EQ5D), and 5-year bleeding and clotting factor consumption were collected for patients born between 1970–1995.

Results

The median age of the patients was 24 years (IQR 18–30). All patients with SH received long-term prophylaxis, which was started at a median age of 4.8 years (IQR 3.2–6.2). Among the patients with MH, ten (25%) received prophylaxis, starting at a median age of 10.8 years (IQR 3.8–13.8). The annual number of bleeds, including joint bleeds, was significantly higher in patients with SH (median 2.0 joint bleeds/year, IQR =0.8–3.7) than in patients with MH (median 0.8 joint bleeds/year, IQR =0–1.2). Due to greater use of prophylaxis, the annual clotting factor consumption of SH patients (median 2,120 IU/kg; IQR 1,514–2,768), was higher than that of MH patients (median 133 IU/kg; IQR 49–468). Patients with SH showed slightly but significantly more loss of clinical function (assessed by the Haemophilia Joint Health Score): a median of 8 points (IQR 3–15) vs a median of 2 points, IQR 0–6). Quality of life, as measured by the SF-36, EQ5D and physical activity, was similar between patients with disease of different severity, as well as compared to that of the general population.

Discussion

When comparing unselected cohorts, the bleeding pattern of patients with SH does not appear to be fully converted to that of the milder bleeding pattern of MH by long-term, intermediate-dose prophylaxis, although activities and quality of life were similar.     

Assessment of individual dose utilization vs. physician prescribing recommendations for recombinant activated factor VII (rFVIIa) in paediatric and adult patients with congenital haemophilia and alloantibody inhibitors (CHwI): the Dosing Observational Study in Hemophilia (DOSE)

Recent data from the Dosing Observational Study in Hemophilia diary study has described home treatment with recombinant activated factor VII (rFVIIa) in congenital haemophilia with inhibitors (CHwI). The current analysis compares prescribed and patient/caregiver‐reported rFVIIa administration in paediatric and adult CHwI patients in this study. Patients with ≥4 bleeding episodes within a 3‐month period prescribed rFVIIa as first‐line therapy for bleeding episodes were eligible. Patients/caregivers completed a diary for ≥90 days or until the patient experienced four bleeds. Initial, total and mean rFVIIa doses reported for each bleeding episode were calculated and compared with the physician‐prescribed doses. Of 52 enrolled patients (25 children; 27 adults), 39 (75%) completed the study. Children and adults had similar mean durations of bleeding episodes. Both patient groups were administered higher initial rFVIIa doses for joint bleeds than prescribed: median (range) 215.2 (74.1–400.0) mcg kg^?1 vs. 200.0 (61.0–270.0) mcg kg^?1 for children, and 231.3 (59.3–379.7) mcg kg^?1 vs. 123.0 (81.0–289.0) mcg kg^?1 for adults. The median infused dose for joint bleeds was higher in adults than children (175.2 vs. 148.0 mcg kg^?1), but children received significantly more doses per joint bleed than adults (median 6.5 vs. 3.0). The median total dose per joint bleed was higher in children than adults (1248.7 vs. 441.6). For children and adults, both initial and additional doses administered for bleeds were higher than prescribed. Children received higher total doses per bleed due to an increased number of infusions per bleed.     

The characteristics and the prognosis for patients presenting with actively bleeding esophageal varices at endoscopy

BACKGROUND: It remains unresolved whether the prognosis is worse for patients who present with actively bleeding varices at endoscopy compared with those in whom variceal bleeding has stopped. METHODS: Patients with acute esophageal variceal bleeding were enrolled in this study and were divided into two groups: an active bleeding group and an inactive bleeding group. All patients had band ligation shortly after endoscopic examination and underwent elective ligation procedures until the varices were obliterated. Patients were followed for 1 year or until death. Short- and long-term prognoses were compared. RESULTS: The active bleeding group included 54 patients and the inactive bleeding included 251 patients. Initial hemostasis was achieved in 93% in the active group and 99% in the inactive group ( p = not significant). The rate of recurrent variceal bleeding within 30 days was 24% in the active bleeding group vs. 12% in the inactive bleeding group ( p = 0.01); the mortality rates were 18% and 8%, respectively ( p = 0.03 in a single statistical test; however, Bonferroni correction for the multiple testing of data removed this significance). The rate of recurrent variceal bleeding within 1 year was 37% in the active bleeding group and 27% in the inactive bleeding group ( p = 0.06); the mortality rates were 22% and 21%, respectively ( p = not significant). CONCLUSIONS: Whether variceal bleeding is active or inactive at endoscopy, variceal ligation is equally effective for control of bleeding. The rates of recurrent bleeding and mortality at 1 month were significantly higher among patients with active bleeding. However, the mortality rate was similar for both groups at 1 year.     

Coagulation disorders and inhibitors of coagulation in children from Mansoura, Egypt

Disorders of coagulation in children often prove challenging to the medical care team. The aims of this study were to assess the spectrum and prevalence of coagulation disorders among children attending Mansoura University Children Hospital (MUCH), Mansoura, Egypt. A total of 105 pediatric patients were referred to MUCH. They were divided into two groups: congenital coagulation disorders (75 cases, age 45.36 +/- 48.59 months), and acquired coagulation disorders (30 cases, age 56.13 +/- 61.61 months). All patients were subjected to thorough history taking including the nature of bleeding, family, past history, mode of inheritance, and detailed physical findings. Hemostatic tests included: platelet count, bleeding time (BT), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT). Specific tests in the congenital group include assay of coagulation factors according to each disorder, Von Willebrand factor assay, ristocetin aggregation test, APTT mixing study for detection of inhibitors in complicated hemophilia cases, F VIII C to VWAg ratio with cut off 0.7 for detection of carriers in some hemophilia A families. Congenital disorders constituted 71.4% of the studied cases vs. 28.6% for acquired disorders. Hemophilia A (42.85%), hemophilia B (14.28%) and liver diseases (14.28%) represented the majority of the studied cases. Mild and moderate cases of hemophilia A and B are more frequent than severe cases in both types. Male sex is more frequent than female in the congenital group (94.7 vs. 5.3%, P < 0.001). Direct correlation existed between factor level assay and severity of hemophilia (r = 0.73, P = 0.006). Three mothers and one sister were identified as carrier out of four families. Anti-clotting factors inhibitor was detected in 18.2% of patients with hemophilia A and in 9.1% with hemophilia B. In conclusion, our study found that hemophilias are the most prevalent congenital coagulation disorders among children. Attention must be given for detection of hemophilia carriers and inhibitors of clotting factors.     

Increased plasma fibrinolytic activity in bleeding gastrointestinal angiodysplasia

OBJECTIVE: Gastrointestinal angiodysplasia is a major cause of recurrent bleeding. Haemostatic abnormalities have been implicated in the haemorrhage from these common vascular lesions but their precise contribution remains to be established. Our aim was to investigate whether bleeding angiodysplasia is associated with any specific coagulation disorder. METHODS: Clinical features and blood samples were prospectively obtained from 21 patients with bleeding gastrointestinal angiodysplasia 3 months after the last episode of haemorrhage. Plasma levels of von Willebrand factor, D-dimer, plasminogen activator inhibitor type 1 (PAI-1), tissue-plasminogen activator activity, tissue factor pathway inhibitor and activated factor VII (FVIIa-rTF) were measured. A group of 14 patients with bleeding duodenal ulcer were similarly studied as controls. RESULTS: Mean plasma von Willebrand factor levels were higher in angiodysplasia patients (208+/-12%) than in controls (143+/-11%) (P<0.05). D-dimer levels (661+/-80 ng/ml) and tissue-plasminogen activator activity levels (2.04+/-0.14 IU/ml) were also higher than in controls: 395+/-99 ng/ml and 1.6+/-0.1 IU/ml, respectively (P<0.05), whereas levels of PAI-1, FVIIa-rTF and tissue factor pathway inhibitor were similar in both groups. However, PAI-1 levels (31.5+/-11 ng/ml) were lower in high-bleeding-rate angiodysplasia (more than two bleeding episodes/year) than in low-bleeding-rate angiodysplasia (< or = 2 bleeding episodes/year) (PAI-1 47+/-14 ng/ml) (P<0.05). In a multivariate regression analysis, the plasma level of PAI-1 was a predictor of haemorrhage from angiodysplasia (P<0.05). CONCLUSIONS: Increased plasma fibrinolytic activity may contribute to bleeding from angiodysplasia. Low plasma PAI-1 levels constitute a risk factor for bleeding tendency in patients with angiodysplasia.     

The role of HIF-1, angiopoietin-2, Dll4 and Notch1 in bleeding gastrointestinal vascular malformations and thalidomide-associated actions: a pilot in vivo study

OBJECTIVE: To investigate plasma levels of hypoxia inducible factor‐1 (HIF‐1), angiopoietin‐2 (Ang‐2), Delta‐like ligand 4 (Dll4) and Notch1 in patients with recurrent gastrointestinal bleeding due to gastrointestinal vascular malformation (GIVM) with or without thalidomide treatment. METHODS: Ten eligible patients with recurrent gastrointestinal bleeding due to GIVM, who received thalidomide 100 mg/d for 4 months, were followed up for 1 year. The effective response was the proportions of patients with yearly bleeding episodes reduced by ≥50% at 1 year after treatment. Plasma levels of HIF‐1, Ang‐2, Dll4 and Notch1 were measured using enzyme‐linked immunosorbent assay in the GIVM thalidomide treatment group before and after treatment (10 patients), the GIVM non‐thalidomide treatment group (25 patients) and the control group (18 participants). RESULTS: In the GIVM thalidomide treatment group, eight patients (8/10) achieved effective response and five (5/10) displayed complete cessation of bleeding. Mean plasma levels of HIF‐1, Ang‐2, Dll4 and Notch1 were all higher in the GIVM thalidomide and non‐thalidomide treatment groups than in the control group (all P < 0.001). However, Ang‐2 decreased more significantly in the effective subgroups (P = 0.003) and no‐bleeding patients (P = 0.008). CONCLUSIONS: HIF‐1, Ang‐2, Dll4 and Notch1 might participate in the formation of GIVM. Thalidomide is an effective and safe treatment agent for GIVM and its associated bleeding. The reduction degree of Ang‐2 after a 4‐month treatment of thalidomide may offer values for evaluating its prognosis and efficacy.     

A modeling approach to evaluate long-term outcome of prophylactic and on demand treatment strategies for severe hemophilia A

Background

Severe hemophilia requires life-long treatment with expensive clotting factor concentrates; studies comparing effects of different therapeutic strategies over decades are very difficult to perform. A simulation model was developed to evaluate the long-term outcome of on demand, prophylactic and mixed treatment strategies for patients with severe hemophilia A.

Design and Methods

A computer model was developed based on individual patients’ data from a Dutch cohort study in which intermediate dose prophylaxis was used and a French cohort study in which on demand treatment was used, and multivariate regression analyses. This model simulated individual patients’ life expectancy, onset of bleeding, life-time joint bleeds, radiological outcome and concentrate use according to the different treatment strategies.

Results

According to the model, life-time on demand treatment would result in an average of 1,494 joint bleeds during the hemophiliac’s life, and consumption of 4.9 million IU of factor VIII concentrate. In contrast, life-time intermediate dose prophylaxis resulted in a mean of 357 joint bleeds and factor consumption of 8.3 million IU. A multiple switch strategy (between prophylactic and on demand treatment based on bleeding pattern) resulted in a mean number of 395 joint bleeds and factor consumption of 6.6 million IU. The estimated proportion of patients with Pettersson scores over 28 points was 32% for both the prophylactic and the multiple switching strategies, compared to 76% for continuous on demand treatment.

Conclusions

The present model allows evaluation of the impact of various treatment strategies on patients’ joint bleeds and clotting factor consumption. It may be expanded with additional data to allow more precise estimates and include economic evaluations of treatment strategies.     

Acquired inhibitors of coagulation factors: part I-acquired hemophilia A

Acquired hemophilia A (AHA) is a rare, but often severe, bleeding disorder caused by autoantibodies against clotting factor VIII (FVIII). AHA occurs more frequently in the elderly and in association with several conditions, such as malignancies, autoimmune diseases, postpartum, or drug exposure; however, about half of the cases remain idiopathic. At variance with congenital hemophilia, where hemarthroses are the most common bleeding symptoms, hemorrhages in AHA involving soft tissues (muscle, skin) are more frequently reported. AHA is diagnosed in patients: with negative personal or family bleeding history; in which prolonged activated partial thromboplastin time is not corrected after mixing and incubating equal volumes of patient and normal plasma for ~2 hours at 37°C; FVIII levels are reduced; and a specific FVIII-inhibiting activity is detected. Prompt recognition and treatment of AHA are mandatory, as inadequate management and complications of the disease are associated with high mortality rates. Therapeutic approaches should aim to control acute bleeds, eradicate FVIII-autoantibody production, treat associated diseases, and when possible, eliminate them. Present knowledge about this often overlooked and challenging condition has significantly increased following establishment of recent national and international studies, as will also be reviewed in this article.     

Factor VIII half-life and intensity of treatment in hemophilic patients

It is well known that severe hemophilic patients have a considerable different factor VIII half-lives. Details of the effect of the inter-individual variation of Factor VIII half-live on treatment or clinical outcome has not been reported. Accordingly, during many years several strategies in prophylactic treatment for severe haemophilia have been used (intermediate-dose of plasma FVIII versus high-dose regime). In the retrospective study by van Dijk et al. (see page 494), the authors show an association between factor VIII half-live and the clinical characteristics of patients with severe hemophilia. Patients with shorter factor VIII half-life need more intensive treatment to prevent joint bleeds and arthropaty than patients with longer factor VIII half-life. Further prospective studies should necessary to confirm whether assessment of factor VIII half-life before the start of prophylaxis could modify the intensity of treatment and prevention of arthropaty among patients with severe hemophilia.