Objective
Repeated hemarthrosis in hemophilia causes arthropathy with pain and dysfunction. The Hemophilia Joint Health Score (HJHS) was developed to be more sensitive for detecting arthropathy than ...the World Federation of Hemophilia (WFH) physical examination scale, especially for children and those using factor prophylaxis. The HJHS has been shown to be highly reliable. We compared its validity and sensitivity to the WFH scale.
Methods
We studied 226 boys with mild, moderate, and severe hemophilia at 5 centers. The HJHS was scored by trained physiotherapists. Study physicians at each site blindly determined individual and total joint scores using a series of visual analog scales.
Results
The mean age was 10.8 years. Sixty‐eight percent were severe (93% of whom were treated with prophylaxis), 15% were moderate (24% treated with prophylaxis), and 17% were mild (3% treated with prophylaxis). The HJHS correlated moderately with the physician total joint score (rs = 0.42, P < 0.0001) and with overall arthropathy impact (rs = 0.42, P < 0.0001). The HJHS was 97% more efficient than the WFH at differentiating severe from mild and moderate hemophilia. The HJHS was 74% more efficient than the WFH at differentiating subjects treated with prophylaxis from those treated on demand. We identified items on the HJHS that may be redundant or rarely endorsed and could be removed from future versions.
Conclusion
Both the HJHS and WFH showed evidence of strong construct validity. The HJHS is somewhat more sensitive for mild arthropathy; its use should be considered for studies of children receiving prophylaxis.
Quebec Platelet disorder (QPD) is a unique bleeding disorder that markedly increases urokinase plasminogen activator (uPA) in megakaryocytes and platelets but not in plasma or urine. The cause is ...tandem duplication of a 78 kb region of chromosome 10 containing PLAU (the uPA gene) and C10orf55, a gene of unknown function. QPD increases uPA in platelets and megakaryocytes >100 fold, far more than expected for a gene duplication. To investigate the tissue-specific effect that PLAU duplication has on gene expression and transcript structure in QPD, we tested if QPD leads to: 1) overexpression of normal or unique PLAU transcripts; 2) increased uPA in leukocytes; 3) altered levels of C10orf55 mRNA and/or protein in megakaryocytes and leukocytes; and 4) global changes in megakaryocyte gene expression. Primary cells and cultured megakaryocytes from donors were prepared for quantitative reverse polymerase chain reaction analyses, RNA-seq and protein expression analyses. Rapidly isolated blood leukocytes from QPD subjects showed only a 3.9 fold increase in PLAU transcript levels, in keeping with the normal to minimally increased uPA in affinity purified, QPD leukocytes. All subjects had more uPA in granulocytes than monocytes and minimal uPA in lymphocytes. QPD leukocytes expressed PLAU alleles in proportions consistent with an extra copy of PLAU on the disease chromosome, unlike QPD megakaryocytes. QPD PLAU transcripts were consistent with reference gene models, with a much higher proportion of reads originating from the disease chromosome in megakaryocytes than granulocytes. QPD and control megakaryocytes contained minimal reads for C10orf55, and C10orf55 protein was not increased in QPD megakaryocytes or platelets. Finally, our QPD megakaryocyte transcriptome analysis revealed a global down regulation of the interferon type 1 pathway. We suggest that the low endogenous levels of uPA in blood are actively regulated, and that the regulatory mechanisms are disrupted in QPD in a megakaryocyte-specific manner.
Abstract Objective To explore the clinical impact of aspirin dosage adjustment in pregnant women at high risk of hypertensive disorders. Study design In this retrospective observational study ...including women with pre-existing hypertension, pre-gestational diabetes or previous placental-mediated complications, we compared the rates of pre-eclampsia, early-onset and severe pre-eclampsia between women who used 81 mg of aspirin (ASA) throughout pregnancy without platelet function analyser (PFA-100® ) monitoring (“group ASA no PFA”) and those in whom the aspirin dosage was adjusted according to PFA-100® results (“group ASA and PFA”). Results 270 women were included in the analyses, 111 in group ASA and PFA and 159 in group ASA no PFA. Aspirin was started before 13 weeks in 71.7% of women in group ASA no PFA and in 79.3% of those in group ASA and PFA. PFA-100® monitoring was associated with a lower rate of pre-eclampsia (15.3% vs . 30.8%; aOR 0.36, 95%CI 0.19–0.67) and severe pre-eclampsia (3.6% vs . 15.1%; aOR 0.22, 95% CI 0.07–0.66), after adjustment for various risk factors for pre-eclampsia. The rate of early-onset pre-eclampsia was not statistically different between the two groups (7.2% vs . 13.2%; aOR 0.42, 95%CI 0.17–1.04). The rate of pre-eclampsia was higher in women who needed an increase in aspirin dosage (11/43, 25.6%) than in those who did not (6/68, 8.8%, p = 0.03). Conclusion Our results suggest that a strategy involving platelet function testing and individualized dosing is effective in preventing pre-eclampsia in high risk women. PFA testing should not be considered as standard practice, however, until prospective controlled randomized trials have confirmed these observations.
Kinins (peptides related to bradykinin, BK) are formed from circulating substrates, the kininogens, by the action of two proteases, the kallikreins. The only clinical application of a BK receptor ...ligand, the B2 receptor antagonist icatibant, is the treatment of the rare hereditary angioedema (HAE) caused by the deficiency of C1-esterase inhibitor (C1-INH). Less common forms of HAE (genetic variants of factor XII, plasminogen, kininogen) are presumably mediated by increased BK formation. Acquired forms of BK-mediated angioedema, such as that associated with angiotensin-I converting enzyme (ACE) inhibition, are also known. Antibody-based analytical techniques are briefly reviewed, and support that kinins are extremely short-lived, prominently cleared by ACE. Despite evidence of continuous activation of the kallikrein–kinin system in HAE, patients are not symptomatic most of the time and their blood or plasma obtained during remission does not generate excessive immunoreactive BK (iBK), suggesting effective homeostatic mechanisms. HAE-C1-INH and HAE-FXII plasmas are both hyperresponsive to fibrinolysis activation. On another hand, we suggested a role for the alternate tissue kallikrein–kinin system in patients with a plasminogen mutation. The role of the BK B1 receptor is still uncertain in angioedema states. iBK profiles under in vitro stimulation provide fresh insight into the physiopathology of angioedema.
Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder with a unique, platelet-dependent, gain-of-function defect in fibrinolysis, without systemic fibrinolysis. The hallmark ...feature of QPD is a >100-fold overexpression of PLAU, specifically in megakaryocytes. This overexpression leads to a >100-fold increase in platelet stores of urokinase plasminogen activator (PLAU/uPA); subsequent plasmin-mediated degradation of diverse α-granule proteins; and platelet-dependent, accelerated fibrinolysis. The causative mutation is a 78-kb tandem duplication of PLAU. How this duplication causes megakaryocyte-specific PLAU overexpression is unknown. To investigate the mechanism that causes QPD, we used epigenomic profiling, comparative genomics, and chromatin conformation capture approaches to study PLAU regulation in cultured megakaryocytes from participants with QPD and unaffected controls. QPD duplication led to ectopic interactions between PLAU and a conserved megakaryocyte enhancer found within the same topologically associating domain (TAD). Our results support a unique disease mechanism whereby the reorganization of sub-TAD genome architecture results in a dramatic, cell-type-specific blood disorder phenotype.
Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder associated with reduced platelet counts and a unique gain-of-function defect in fibrinolysis due to increased expression and ...storage of urokinase plasminogen activator (uPA) by megakaryocytes. QPD increases risks for bleeding and its key clinical feature is delayed-onset bleeding, following surgery, dental procedures or trauma, which responds only to treatment with fibrinolytic inhibitors. The genetic cause of the disorder is a tandem duplication mutation of the uPA gene, PLAU, which upregulates uPA expression in megakaryocytes by an unknown mechanism. The increased platelet stores of uPA trigger plasmin-mediated degradation of QPD α-granule proteins. The gain-of-function defect in fibrinolysis is thought to be central to the pathogenesis of QPD bleeding as the activation of QPD platelets leads to release of uPA from α-granules and accelerated clot lysis. The purpose of this review is to summarize current knowledge on QPD pathogenesis and the recommended approaches to QPD diagnosis and treatment.
Bradykinin (BK)-mediated angioedema (AE) states are rare acquired or hereditary conditions involving localized edema of the subcutaneous and submucosal tissues. Citrated plasma from healthy ...volunteers or patients with hereditary angioedema (HAE) with normal level of C1-inhibitor (C1-INH) was used to investigate pathways of BK formation and breakdown relevant to AE physiopathology. The half-life of BK (100 nM) added to normal plasma was 34 s, a value that was increased ~12-fold when the angiotensin converting enzyme (ACE) inhibitor enalaprilat (130 nM) was added (enzyme immunoassay measurements). The BK half-life was similarly increased ~5-fold following 2 daily oral doses of enalapril maleate in healthy volunteers, finding of possible relevance for the most common form of drug-associated AE. We also addressed the kinetics of immunoreactive BK (iBK) formation and decline, spontaneous or under three standardized stimuli: tissue kallikrein (KLK-1), the particulate material Kontact-APTT™ and tissue plasminogen activator (tPA). Relative to controls, iBK production was rapid (10–20 min) and very intense in response to tPA in plasma of female heterozygotes for variants in gene
F12
coding for factor XII (FXII) (p.Thr328Lys, 9 patients; p.Thr328Arg, one). An increased response to Kontact-APTT™ and an early tPA-induced cleavage of anomalous FXII (immunoblots) were also observed. Biotechnological inhibitors showed that the early response to tPA was dependent on plasmin, FXIIa and plasma kallikrein. Results from post-menopausal and pre-menopausal women with HAE-FXII were indistinguishable. The iBK production profiles in seven patients with the plasminogen p.Lys330Glu variant (HAE-PLG) did not significantly differ from those of controls, except for an unexpected, rapid and lanadelumab-resistant potentiation of KLK-1 effect. This enzyme did not cleave plasminogen or factor XII, suggesting a possible idiosyncratic interaction of the plasminogen pathogenic variant with KLK-1 activity. KLK-1 abounds in salivary glands and human saliva, hypothetically correlating with the clinical presentation of HAE-PLG that includes the swelling of the tongue, lips and contiguous throat tissues. Samples from HAE patients with normal C1-INH levels and
F12
gene did not produce excessive iBK in response to stimuli. The
ex vivo
approach provides physiopathological insight into AE states and supports the heterogeneous physiopathology of HAE with normal C1-INH.
Objective
The primary objective of this study was to assess whether there are different patterns (classes) of joint health in young boys with severe haemophilia A (SHA) prescribed primary tailored ...prophylaxis. We also assessed whether age at first index joint bleed, blood group, FVIII gene abnormality variant, factor VIII trough level, first‐year bleeding rate and adherence to the prescribed prophylaxis regimen significantly predicted joint damage trajectory, and thus class membership.
Methods
Using data collected prospectively as part of the Canadian Hemophilia Primary Prophylaxis Study (CHPS), we implemented a latent class growth mixture model technique to determine how many joint damage classes existed within the cohort. We used a multinomial logistic regression to predict the odds of class membership based on the above predictors. We fitted a survival model to assess whether there were differences in the rate of dose escalation across the groups.
Results
We identified three distinct classes of trajectory: persistently low, moderately increasing and rapidly increasing joint scores. By multinomial regression, we found that only age at first index joint bleed predicted rapidly increasing joint scores. The rapidly increasing joint score class group moved through dose escalation significantly faster than the other two groups.
Conclusions
Using tailored prophylaxis, boys with SHA follow one of three joint health trajectories. By using knowledge of disease trajectories, clinicians may be able to adjust treatment according to a subject's predicted long‐term joint health and institute cost‐effective programmes of prophylaxis targeted at the individual subject level.
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