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  • 1
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    Insufficient evidence to suggest less stringent therapy in hemophilia B?
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 23 ( 2009-11-26), p. 4907-4907
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 23 ( 2009-11-26), p. 4907-4907
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2009-08-241240
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    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 2
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    The effects of postponing prophylactic treatment on long-term outcome in patients with severe hemophilia
    American Society of Hematology ; 2002
    In:  Blood Vol. 99, No. 7 ( 2002-04-01), p. 2337-2341
    Details
    In: Blood, American Society of Hematology, Vol. 99, No. 7 ( 2002-04-01), p. 2337-2341
    Abstract: To prevent hemophilic arthropathy, prophylactic treatment of children with severe hemophilia should be started before joint damage has occurred. However, treatment is expensive, and the burden of regular venipunctures in young children is high. With the aim of providing information on starting prophylaxis on the basis of individual patient characteristics, the effect of postponing prophylaxis on long-term arthropathy was studied in a cohort of 76 patients with severe hemophilia born between 1965 and 1985. The median age at first joint bleed was 2.2 years (range, 0.2-5.8). Prophylaxis was started at a median age of 6 years (interquartile range [IQR], 4-9), and the median annual clotting factor use on prophylaxis was 1750 IU/kg/y (31 IU/kg/wk). Hemophilic arthropathy was measured by the Pettersson score (maximum, 78 points). At a median age of 19 years, the median Pettersson score was 7 points (IQR, 0-17). After 2 decades of follow-up, the Pettersson score was 8% higher (95% confidence interval, 1%-16%) for every year prophylaxis was postponed after the first joint bleed. This effect was independent of age at Pettersson score, age at first joint bleed, and prophylactic dose used. In conclusion, most patients have their first joint bleed after the age of 2 years. Patients who start prophylaxis soon after the first joint bleed show little arthropathy in adulthood. The longer the start of prophylaxis is postponed after the first joint bleed, the higher the risk of developing arthropathy.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V99.7.2337
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2002
    detail.hit.zdb_id: 1468538-3
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  • 3
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    Variability in Bleeding Pattern of Severe Hemophilia.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 3094-3094
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 3094-3094
    Abstract: Introduction The aim of this study was to describe variability in bleeding pattern in a single center cohort of severe hemophilia patients treated with prophylaxis. Methods At the Van Creveldkliniek, all patients with severe hemophilia born between 1944 and 2002 were followed from 1972 onwards. Data on bleeding characteristics and treatment were collected yearly and Pettersson scores were performed with five-year intervals. Prophylactic dose was adjusted always according to bleeding pattern. Since the number of accepted bleeds has decreased over the years, each treatment dependent indicator was described stratified for age. Age specific quartiles for the different indicators were used as arbitrary cut-off values. Results Data on prophylaxis were available for 247 patients, and a total of 2760 follow up years on prophylaxis were collected. Variability in treatment characteristics is shown in Table 1. Treatment characteristics and clinical manifestations per age group Year of birth 1985–2002 1968–1985 1944–1968 Values are means (interquartile range) n 66 87 94 Follow-up per patient (yr) 6.6 18.0 22.6 Age at first joint bleed (yr) 1.8 (0.7–3.7) - Annual clotting factor use (IU/kg/yr) 2790 (2282–3321) 1989 (1654–2350) 1458 (1119–1790) Joint bleeds per year 2.6 (1.0–3.7) 2.9 (1.3–5.1) 4.5 (2.2–9.9) Pettersson score (max 78 points) 0.0 (0.0–2.5) 15.1 (6.0–22.0) 44.8 (35.5–56.2) The variation in annual clotting factor use was used as a marker of bleeding pattern. Age at first joint bleed was inversely related to annual clotting factor use in the youngest age group. Using cut off levels of the 25th and 75th percentiles (P25 and P75) of age at first joint bleed and annual clotting factor use, 10% of patients were identified as patients with a milder bleeding pattern (i.e. age at first joint bleed above P75 and annual clotting factor use below P25) and 9.3% as patients with a more severe bleeding pattern. Using annual clotting factor use and joint bleed frequency in the middle group, 8.0% of patients were identified as patients with a milder phenotype and 10.3% as patients with a more severe bleeding pattern. In the oldest group, Pettersson scores were positively associated with annual clotting factor use. Using these parameters, 14% of the patients were identified as patients with a milder bleeding pattern. Due to the ceiling effect of the Pettersson score, these parameters could not be used to identify patients with a more severe bleeding pattern. Conclusion There is considerable variation in bleeding pattern of patients with severe hemophilia. Combinations of bleeding and treatment characteristics could be used as indicators of phenotype identifying 8 to 14% patients with a milder bleeding pattern and 9 to 10% of patients with a more severe bleeding pattern.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.3094.3094
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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  • 4
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    Biomarkers of Cartilage and Bone Damage as a Measure of Joint Damage in Haemophilia.
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 1214-1214
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 1214-1214
    Abstract: Purpose Biomarkers of bone and cartilage turnover have frequently been evaluated for joint diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA). Results have thus fare not been very conclusive. Some biomarkers such as urinary CTXII and serum COMP appear to correlate with severity of joint degeneration, whereas other are less distinctive. Hemophilic arthropathy (HA) is a very progressive joint degeneration as a result of frequent joint bleeds. From clinical practice it is concluded that the rate of degeneration exceeds that of OA and RA joints. This degeneration has characteristics of both inflammation mediated (as seen in RA) and degenerative (as seen in OA) joint disease. Furthermore, the joint damage is largely restricted to 3 major joints (ankle, knees, and elbows). Therefore, it might be that this rapidly progressive, localized joint degeneration can be used for the evaluation and validation of biomarkers of cartilage and bone turnover. In the present study we therefore investigated whether commercially available biomarkers of cartilage and bone in blood and/or urine are associated with severity of joint damage in patients with haemophilic arthropathy. Methods Blood and urine were collected from 36 patients suffering from haemophilia. Urine samples were assessed for the amount of CTX-I and CTX-II. Serum samples were assessed for the amount of CTX-I, CTX-II, COMP, C1,2C, C2C, and CS846. Radiographs of ankles, knees and elbows were scored according to Pettersson, a radiographic joint score specific for haemophilic arthropathy based on cartilage and bone changes. Results U-CTX-II (R=0.39; p=0.01), C1,2C (R=0.31; p=0.04) and CS846 (R=0.31; p=0.03) showed (marginal) correlations with the Pettersson score. Slightly better correlations were obtained when only narrowing of joint space width (JSW) as one of the items in the Pettersson score was used. The other biomarkers showed no correlation with the Pettersson score. Also the bone biomarkers did not correlate with specific bone changes. Interestingly, combined indexes of different markers, based on linear stepwise regression analysis, increased the correlation significantly up to R=0.65; p≤0.001) for the combination of U-CTX-II, COMP and CS846. Conclusions The present results show that even despite this rapidly progressive degeneration of 6 large joints, from the individual biomarkers determined only U-CTX-II, C1,2C and CS846 show correlation with the severity of arthropathy. Importantly, a relation improved when the markers were related to the process they are supposed to describe (cartilage degeneration markers with JSW narrowing). Most important, combination of markers, significantly improve the relation with the radiographically determined joint degeneration. In general however, it may be concluded that these markers alone seem not of sufficient value for evaluation of joint damage yet.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.1214.1214
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 5
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    IL-1β, in contrast to TNFα, is pivotal in blood-induced cartilage damage and is a potential target for therapy
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 19 ( 2015-11-05), p. 2239-2246
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 19 ( 2015-11-05), p. 2239-2246
    Abstract: Blood-induced joint damage is fully prevented by blocking IL-1β with a monoclonal antibody or receptor antagonist, not by TNFα blockade. IL-1β blockade prevents release of IL-6 but not TNFα from monocyte/macrophages, whereas TNFα blockade does not affect IL-1β or IL-6 release.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2015-03-635524
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 6
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    Successful treatment of severe bleeding in hemophilic target joints by selective angiographic embolization
    American Society of Hematology ; 2005
    In:  Blood Vol. 105, No. 7 ( 2005-04-01), p. 2654-2657
    Details
    In: Blood, American Society of Hematology, Vol. 105, No. 7 ( 2005-04-01), p. 2654-2657
    Abstract: Bleeding into the joints is common in patients with hemophilia. After total knee or elbow replacement, profuse intraarticular bleeding unresponsive to high-dose clotting factor replacement sometimes occurs. In some patients who have severely damaged elbow or knee joints the same profuse bleeding pattern can be seen. To control bleeding in these patients, selective catheterization with a microcatheter and therapeutic embolization with microcoils was performed whenever a severe blush or microaneurysm was observed on angiography. Over 12 years, in 23 cases of massive joint bleeding in 18 patients with hemophilia selective catheterization was performed. In 15 cases the bleeding was postoperative and in 8 spontaneous. Results of angiographic imaging revealed vascular blush, false aneurysm, true aneurysm, and arteriovenous shunt in combination with an aneurysm as cause of bleeding. In 2 patients, the cause of bleeding was not found. In 21 cases an embolization procedure was performed, in which the bleeding was completely controlled by a single procedure in 14 cases. Recurrence of the bleeding occurred in 7 cases and required a second embolization procedure; in one patient even a third embolization was required to stop the bleeding completely. No difference in the outcome, that is, clinical end of bleeding and joint range of motion, was observed, when comparing postoperative and spontaneous bleeding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2004-06-2063
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 7
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    Very Rapid Clearance after a Joint Bleed Knee Can Not Prevent Adverse Effects on Cartilage and Synovial Tissue: A Canine in Vivo Study.
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 2273-2273
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 2273-2273
    Abstract: Purpose Joint bleeds lead to joint destruction. In vitro exposure of human and canine cartilage to blood results in long lasting severe adverse changes in cartilage. An in vivo joint haemorrhage in the canine knee joint demonstrates similar adverse effects although less outspoken and long-lasting. We investigated the clearance rate of blood from canine knee joints as a possible explanation for this discrepancy. Methods Blood was injected into the knee joint of Beagle dogs, either 48h, 24h or 15m before termination. The amount of red and white blood cells present in the joint cavity was determined. Chondrocyte activity and cartilage matrix integrity as well as cartilage destructive activity of synovial tissue were determined biochemically. Additionally, synovial tissue was analyzed by use of histochemistry. Results Fifteen minutes after the injection of autologous blood, the red blood cell count was 5,7*1012/L, comparable to the amount present in whole blood, and gradually decreased (1,6*1012/L at 24 hours) to 0,2*1012/L within 48 hours (less than 5%). The amount of white blood cells increased in the first 24 hours, and was still increased after 48 hours, although less than after 24 hours. The proteoglycan synthesis rate and -release were adversely affected already within 24 hours (−22% and +24% respectively), and these effects were more severe 48 hours post-injection (−34% and +53% resp.). Synovial tissue culture supernatants demonstrate cartilage destructive properties as expressed by an increased release, a decreased synthesis rate, and decreased content of cartilage proteoglycans; increasing with time after the experimental haemorrhage (+207%/+247%; −58%/−62%; −8%/−28% respectively, for 24/48 hours). Evaluation of the synovial tissue revealed at 15 minutes post-injection countless numbers of intact RBC that were almost completely disappared after 48 hours, withonly limited recruitment of macrophages and iron deposition. Conclusions Blood is cleared very rapidly from the canine knee joint, but in that short time span already has adverse effects on both cartilage and synovial tissue. This rapid clearance can play a role in the discrepancy between long-term in vitro and in vivo effects of blood-induced joint damage since more than 10% v/v blood for 48 hours is needed induced to long-term adverse effects in vitro. Irrespectively, blood has devastating effects on articular cartilage very rapidly, and in this respect it is important to prevent (traumatic) joint haemorrhages and if they occur, to treat them properly.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.2273.2273
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 8
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    Factor VIII Half-Life and Clinical Characteristics of Severe Hemophilia A.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 3091-3091
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 3091-3091
    Abstract: Introduction Patients with severe hemophilia A have considerably different factor VIII half-lives. Whether this is associated with clinical characteristics has not been reported. The aim of this study was to describe the effect of half-life on the clinical characteristics of patients with severe hemophilia. Patients and Methods Patients were selected from a single-centre cohort of 214 patients with severe hemophilia, born between 1944 and 1995. To improve efficiency we measured factor VIII half-life in the patients with the most severe and the mildest clinical phenotypes of severe hemophilia. Patients were selected according to age at first joint bleed, annual joint bleed frequency, clotting factor consumption and radiological Pettersson scores. A first blood sample was taken after a period of 72 hours in which the patient did not use factor VIII. After infusion with 50 IU factor VIII/kg, blood was collected at 15, 30 minutes and 1, 3, 5, 24, 30, 48 and 60 hours. From 1972 onwards, data on joint bleed frequency, clotting factor use and age at first joint bleed were collected from the patients’ files. Pettersson scores were performed at five-year intervals. For calculations of annual clotting factor use (IU/kg/yr) and number of joint bleeds per year, the last 5 years of follow-up were used. Linear regression analysis was used to assess the relation between clinical characteristics and factor VIII half-life. Results Factor VIII half-life was measured in 42 patients and ranged from 7.4–20.4 hours, with a median of 11.8 hours. One hour increase in factor VIII half life was associated with a decrease of 96 (SD 45) IU clotting factor use per kg per year (p & lt;0.05). Joint bleed frequency was similar in patients with a shorter and a longer factor VIII half-life. Median number of joint bleeds was 2.9 per year (interquartile range (IQR) 1.1–4.4) in patients with a factor VIII half-life shorter than 12 hours and 2.6 per year (IQR 1.0–4.8) in patients with a factor VIII half-life longer than 12 hours (p=0.84). Patients with a factor VIII half-life shorter than 12 hours had a median Pettersson score of 52 points (IQR 12–61) and patients with a factor VIII half-life longer than 12 hours had a median Pettersson score of 29 points (IQR 16–52; p=0.90). Conclusion: Patients with a shorter factor VIII half-life need more clotting factor to prevent joint bleeds and subsequent arthropathy than patients with a longer factor VIII half-life.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.3091.3091
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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  • 9
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    Hepatitis G Virus RNA and Hepatitis G Virus-E2 Antibodies in Dutch Hemophilia Patients in Relation to Transfusion History
    American Society of Hematology ; 1998
    In:  Blood Vol. 92, No. 6 ( 1998-09-15), p. 2164-2168
    Details
    In: Blood, American Society of Hematology, Vol. 92, No. 6 ( 1998-09-15), p. 2164-2168
    Abstract: The prevalence of hepatitis G virus (HGV)-RNA and HGV-E2 antibodies was studied in a cohort of Dutch hemophilia patients in relation to clotting products used, age, and coinfection with hepatitis C. Between 1991 and 1995, blood samples were taken from 294 patients with hemophilia A, B, or von Willebrand disease. From each patient one fresh frozen sample was tested for HGV cDNA polymerase chain reaction (PCR) and HCV cDNA PCR. Alanine aminotransferase (ALT) tests were performed on plasma samples of all patients. The presence of HGV-E2 antibodies was tested on plasma samples from a subset of 169 patients representing all age groups. Based on the origin and viral safety of the products used, three subgroups of patients were distinguished. Group A: patients who used viral noninactivated factors derived from small and large donor pools; group B: patients who used factors prepared with inadequate viral inactivation techniques derived from small and large donor pools; and group C: patients treated only with optimally viral inactivated large pool clotting factor or recombinant clotting factor concentrate. The prevalence of HGV-RNA was 18%. In group A patients the prevalence was 71%, in group B 50%, and in group C 6%. When related to age, the highest prevalence of HGV-RNA (35%) was seen in patients born between 1980 and 1989. The prevalence of HGV-E2 antibodies increased with age. Of HGV-RNA–negative patients born before 1950, 96% tested positive. HGV viremia did not affect ALT levels, neither in HCV-RNA positive nor in HCV-RNA negative patients. HGV infection is frequently seen in patients with hemophilia. In older age groups a lower rate of HGV-RNA positivity is seen coinciding with a higher rate of antienvelope antibodies. © 1998 by The American Society of Hematology.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V92.6.2164
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 1998
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  • 10
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    Interleukin-1β Is Essential for Blood-Induced Cartilage Damage In Vitro
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 240-240
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 240-240
    Abstract: Objective: Joint damage due to recurrent joint bleeds remains the most common complication in hemophilia. The combination of cartilage degeneration and synovial inflammation ultimately lead to hemophilic arthropathy. Cartilage destruction is considered to result from both cartilage matrix-degrading proteases as well as cartilage-destructive pro-inflammatory cytokines such as interleukin (IL)-1b. To unravel the role of IL1b in the pathogenesis of blood-induced cartilage damage, we investigated whether direct blocking of IL1b specifically prevents blood-induced cartilage damage in vitro. Moreover, we investigated whether blocking IL1b after the onset of a bleed can still avert cartilage damage. Methods: Full thickness healthy human articular cartilage explants, obtained post-mortem, were cultured for four days in presence or absence of 50% v/v whole blood. A recombinant human IL1b monoclonal antibody (IL1bmAb) was added at the moment of blood exposure in a concentration of 0, 1, 3, 10, 30, or 100ng/mL (n=8). Furthermore, 100ng/mL IL1bmAb was administered directly or after a delay of several hours up to two days (n=7). Cartilage matrix proteoglycan turnover was determined 12 days later to analyse long-term effects. To investigate the direct effects of IL1bmAb on cartilage, explants were cultured for four days in the presence of 10ng/mL IL1bmAb in the absence of blood (n=7). Results: Exposure to blood decreased the proteoglycan synthesis rate and -content, and increased the proteoglycan release (all p 〈 0.05). Adding IL1bmAb resulted in a dose-dependent increase of the proteoglycan synthesis rate leading to normalisation at higher concentrations (see figure A). Proteoglycan release and content also normalised after addition of IL1bmAb. Its protective effect was most pronounced when IL1bmAb was administered within 4 hours after the bleed, but significant recovery was still achieved by administration within 8-24 hours (see figure B for proteoglycan synthesis). In the absence of blood, IL1bmAb did not have direct effects on cartilage proteoglycan turnover (for all three parameters p 〉 0.50). Conclusions: This study demonstrates that IL1b is a crucial factor in the development of blood-induced cartilage damage in vitro. Blocking this pro-inflammatory cytokine with a monoclonal antibody protects cartilage from the damaging effects of blood exposure in a dose-dependent way. Early administration after blood-exposure is most beneficial. Further research is warranted to investigate the in vivo capacity of IL1bmAb in prevention and its position as a treatment to limit joint damage upon joint bleeding. Figure - Effect of IL1bmAb on cartilage proteoglycan synthesis rate is dose-dependent (A) and time-dependent (B). Median values ± IQR of at least 7 individual cartilage and blood donors are shown. Hash tags indicate a statistically significant difference from control values, whereas asterisks indicate a statistically significant difference from blood-exposed cartilage without IL1bmAb addition (p 〈 0.05). Figure -. Effect of IL1bmAb on cartilage proteoglycan synthesis rate is dose-dependent (A) and time-dependent (B). Median values ± IQR of at least 7 individual cartilage and blood donors are shown. Hash tags indicate a statistically significant difference from control values, whereas asterisks indicate a statistically significant difference from blood-exposed cartilage without IL1bmAb addition (p 〈 0.05). Figure - Effect of IL1 b mAb on cartilage proteoglycan synthesis rate is dose-dependent (A) and time-dependent (B). Median values ± IQR of at least 7 individual cartilage and blood donors are shown. Hash tags indicate a statistically significant difference from control values, whereas asterisks indicate a statistically significant difference from blood-exposed cartilage without IL1 b mAb addition (p 〈 0.05). Disclosures Schutgens: CSL Behring: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.240.240
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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