M.E. van Meegeren

Consequences of intra-articular bleeding in haemophilia: science to clinical practice and beyond

Summary.  Blood in the joint causes a number of physiological and pathological events that eventually lead to haemophilic arthropathy. Animal models show that blood in the joint induces inflammation that continues long after blood has been cleared [ 1 ]. TNF‐alpha, IL‐1beta and IL‐6 are inflammatory mediators that increase following haemarthrosis in haemophilic mice [ 2 ]. Conventional anti‐inflammatory drugs have failed to demonstrate a lasting effect in preventing haemophilic arthropathy. A new TNF‐alpha antagonist has shown promising results in haemophilic mice [ 3 ]. Similarly, the use of cyclo‐oxygenase‐2 inhibitors may reduce angiogenesis associated with the healing process following bleeding and the associated tissue damage [ 4 ]. Animal models are useful for studying the pathophysiology of haemarthropathy, however, when applying results from animals to humans, the differences in matrix turnover rate, thickness of cartilage and joint biomechanics must be kept in mind [ 5 ]. In people with haemophilia, there is a variable response to haemarthrosis as demonstrated by magnetic resonance imaging (MRI). Up to 30% of subjects have normal MRI despite having three or more haemarthroses into the same joint [ 6 ]. Once bone damage is present, little can be done to restore anatomic integrity. Several molecules, including members of the bone morphogenic protein subfamily, have been injected into bone defects in non‐haemophilic subjects with some evidence of benefit [ 7 ]. To achieve the primary goal of reducing blood in the joint and the negative sequelae, it is questionable to use ice to treat haemarthrosis. Indeed low temperature is associated with impairment of coagulation enzyme activity and platelet function [ 8 ].

Update on pathogenesis of the bleeding joint : an interplay between inflammatory and degenerative pathways

One of the most relevant goals of the musculoskeletal care in hemophilia is to prevent intraarticular bleeding. In the past, usual clinical practice allowed for a tacit, moderate degree of tolerance for sporadic intraarticular hemorrhages, based on the clinical observation that joints were able to tolerate an infrequent bleed with little or no harm. However, increasing knowledge on the pathophysiology of hemarthrosis in vitro and in vivo, as well as in clinical experiments, indicates that we need to move towards a more stringent policy with regards to the prevention of occasional and subclinical intraarticular hemorrhages [1–3].

Clinical phenotype in genetically confirmed von Willebrand disease type 2N patients reflects a haemophilia A phenotype

Introduction: Von Willebrand disease (VWD) type 2N is characterized by a defective binding of factor VIII (FVIII) to von Willebrand factor (VWF) resulting in diminished plasma FVIII levels and a clinical phenotype mimicking mild haemophilia A. Several mutations in the FVIII binding site of VWF have been reported. Aim: This study aims to examine the effect of genotype on clinical phenotype in a cohort of VWD 2N patients. Methods: Patients with at least one genetically confirmed 2N mutation were selected retrospectively from a cohort of patients with suspected VWD. Clinical and laboratory phenotypes including bleeding scores (BS) were obtained and analysed. Results: Forty‐two VWD 2N patients with a mean age of 44 years were included. Eleven patients were homozygous or compound heterozygous (genetically confirmed group) and 31 patients were heterozygously affected (carriers group). Statistically significant differences between genetically confirmed VWD 2N patients and carriers were found in FVIII activity, VWF antigen levels, VWF‐FVIII binding capacity, FVIII/VWF antigen ratio (all P<0.001), VWF‐ristocetin activity (p=0.001) and VWF collagen binding (P = 0.002). Median BS was 6 in genetically confirmed VWD 2N patients compared with 3 in carriers (P = 0.047). Haemarthrosis, muscle haematomas and postpartum haemorrhage were only reported in genetically confirmed 2N patients. Conclusion: Phenotypic analysis showed that all laboratory parameters are lower in genetically confirmed VWD 2N patients compared with heterozygous 2N carriers. The clinical phenotype in genetically confirmed VWD 2N patients is comparable to mild haemophilia A patients and more severe than heterozygous 2N carriers.

Joint distraction: a treatment to consider for haemophilic arthropathy.

program. Haplotypes were estimated using the MLocus software. Thirty-nine of the patients studied developed inhibitors, and nine of them were classified as high-titre inhibitors. Table 1 shows the distribution of the tested polymorphisms in haemophilic patients with and without inhibitors, giving the probability values for the differences. The frequencies found were those generally observed in European populations, as shown in the National Center for Biotechnology Information databank (http://www.ncbi.nlm.nih.gov/SNP/index.html). Only two of the 45 tested distributions significantly deviated from HardyWeinberg equilibrium (IL4R 1902A > G and IL10 592 C > A samples in patients with inhibitors and without inhibitors respectively), a value that was expected due to random sampling only. The differences in frequencies between patients with and without inhibitors were small and did not reach statistical significance for HLA-G, PTPN22, IL4, IL4R, TNFa, TNFR1 and CTLA4. However, the two polymorphisms analysed in the IL10 promoter region ( 819 C > T and 592 C > A) showed different genotypic (P = 0.024 and P = 0.016 respectively) and allelic frequencies ( 819 T = 0.40 vs. 0.26; P = 0.028 and 592 A = 0.40 vs. 0.25; P = 0.019) between patients with and without inhibitors, suggesting an association. These polymorphisms are in complete linkage disequilibrium and the TA haplotype frequencies also differ in a significant way in the two groups. Carriers of these alleles seem to be more prone to develop inhibitors than those carrying their alternative forms [ORs for carriers of the risk alleles: IL10 819:3.21(CI: 1.45–7.1); IL10 592:3.00 (CI: 1.36–6.49); TA haplotype: 2.61 (CI: 1.22–5.59)]. Significant differences in the same direction (T and A risk alleles) were obtained in a recent study [7] in a very different (Chinese) ethnic population, reinforcing our findings. But Pavlova et al. [8] found exactly the same frequencies for the 819 C > T and 592 C > A polymorphisms in patients with and without inhibitors. Curiously, the same authors reported significant differences, but in another IL10 SNP ( 1082 A > G) between the two groups of patients. As far as we know, the data onHLA-G ins/del 14 bp and 3142 C > G; IL 4R 1902 A > G; TNFa 1031 T > C and 863 A > C; and TNFR1 303 A > G are the first reported in the literature. The absence of significant differences between patients with and without inhibitors was also found previously for PTPN221858 C > T, IL4 590C > T,TNFa 827 C > T and 238 G > A, and CTLA4 49 A > G by other authors. However, for two others, the results are in conflict: (i) TNFa 308 G > A, and (ii) CTLA4 318 C > T, which did not present association in our study were reported as showing association by other researchers. The reasons for the heterogeneous results found in many association studies are numerous and varied. Sample sizes, ascertainment differences, population and trait genetic heterogeneities may be mentioned. In addition, in quantitative characteristics, most factors account for only a small proportion of the total genetic risk. In conclusion, there is evidence that two SNPs in the interleukin 10 system (IL10 819 C > T and 592 C > A) influence the susceptibility to develop factor VIII inhibitors. Nucleotides T and A are risk factors for this condition. As the same association was previously independently found in an ethnically diverse population, the significance of our finding is strengthened.

Bone cysts in patients with afibrinogenaemia: a literature review and two new cases

Afibrinogenaemia is an autosomal recessive disease with an estimated prevalence of approximately one in a million. The most common symptoms of afibrinogenaemia are umbilical cord bleeding, bleeding into skin, mouth, muscles, gastrointestinal and genitourinary tracts and the central nervous system. Other recognized complications include; haemarthroses, spontaneous splenic rupture, epistaxis, menorrhagia, recurrent abortion and venous and arterial thromboembolism. Bone cysts have also been described as a rare complication of afibrinogenaemia. The aim of this study was to conduct a systematic literature review, summarize the reported cases and to report two new cases. Three electronic databases were searched for relevant publications: PubMed, Medline and EMBASE. The following search criteria were used: ‘(bone cysts OR intraosseous haematoma OR intraosseous haemorrhage) AND (afibrinogenaemia OR fibrinogen deficiency)’. The reference lists of the selected papers were searched for more relevant literature. In total, eight patients had bone cysts as complication of afibrinogenaemia and six of them suffered from pain in their extremities. Bone cysts were primarily located in the vicinity of the cortex or trabeculae in the diaphysis of the long bones, especially in the femora, tibiae and humeri. Some were regressive, probably due to reactive bone remodelling. A number of cysts were filled with serosanguinous fluid. It might be useful to check for bone cysts when patients with congenital afibrinogenaemia complain of ‘rheumatic’ pains in their extremities. Whole body magnetic resonance imaging is the diagnostic imaging technique of choice. Recurrent episodes of pain, but not radiological deterioration, appear to benefit from prophylactic therapy with fibrinogen concentrate.