Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684275 (haemophilia)
 10,958 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe haemophilia is a serious, haemorrhagic disorder of the plasmatic coagulation system. In this study we investigated, whether 'compensatory' activation of the platelet coagulation system occurs in this situation. Platelet function was investigated with aggregation, adhesion and flow cytometric assays. In addition, we performed clot and platelet plug formation tests and determined endogenous thrombin potentials in patients with severe haemophilia A or B; results were compared to those of healthy controls. Platelet aggregation in response to stimulation with ADP, ristocetin and epinephrine was similar in patients and controls; aggregation in response to collagen was reduced significantly in haemophiliacs. Flow cytometric analysis of P-selectin (CD 62P) and CD 63, of the conformationally changed GP IIb/IIIa with PAC 1 and of thrombospondin bound to CD 36 (GP IV) was performed at baseline and post stimulation. Baseline expression of all markers was similar in haemophiliacs and controls. After stimulation of the platelet thrombin receptors with the thrombin receptor activating peptide (TRAP) 6, the surface expression of all markers increased significantly; again, the expression was similar in haemophiliacs and controls. With thrombelastography and PFA 100 analysis, clot formation under low shear and platelet plug formation under high shear is measured. Both test results revealed a significantly reduced clot and platelet plug formation capacity in severe haemophiliacs. Our results did not reveal signs of enhanced platelet preactivation in haemophiliacs, indicating that baseline platelet reactivity in severe haemophilia remains in a neutral state, despite the severely haemorrhagic condition. As expected, both thrombin and clot formation capacities were impaired significantly in severe haemophilia. The reduced response to collagen-based platelet stimulation tests is indicative of a concomitant platelet function defect. This defect probably contributes to the intensity of bleeding events in patients with severe haemophilia.
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PMID:Absence of compensatory platelet activation in patients with severe haemophilia, but evidence for a platelet collagen-activation defect. 1248 78

High plasma levels of soluble P-selectin are associated with thrombotic disorders and may predict future cardiovascular events. Mice with high levels of soluble P-selectin have more microparticles in their plasma than do normal mice. Here we show that chimeras of P-selectin and immunoglobulin (P-sel-Ig) induced formation of procoagulant microparticles in human blood through P-selectin glycoprotein ligand-1 (PSGL-1; encoded by the Psgl1 gene, officially known as Selpl). In addition, Psgl1-/- mice produced fewer microparticles after P-sel-Ig infusion and did not spontaneously increase their microparticle count in old age as do wild-type mice. Injected microparticles specifically bound to thrombi and thus could be involved in thrombin generation at sites of injury. Infusion of P-sel-Ig into hemophilia A mice produced a 20-fold increase over control immunoglobulin in microparticles containing tissue factor. This significantly improved the kinetics of fibrin formation in the hemophilia A mice and normalized their tail-bleeding time. P-sel-Ig treatment could become a new approach to sustained control of bleeding in hemophilia.
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PMID:Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. 1289 56

Replacement therapy with factor VIII (FVIII) and factor IX (FIX) is routinely used in haemophilia patients with haemophilia A and B, respectively, while recombinant activated FVII (rFVIIa) has proven to induce haemostasis in haemophilia patients with inhibitors. To evaluate the effect of therapeutic intervention in patients with residual factor activities, the effects of increasing concentrations of rFVIIa or NN1731 on thrombin generation and platelet activation were measured in a cell-based model system mimicking severe, moderate and mild haemophilia A or B. Purified monocytes stimulated to express tissue factor and non-activated platelets from peripheral blood of healthy donors were incubated with a mixture of purified human coagulation factors in the absence or presence of increasing concentrations of FVIII or FIX. Sub-samples were analysed for thrombin activity and platelet activation measured as exposure of P-selectin by flow cytometry. Dose-dependent increases in thrombin generation and platelet activation were observed following increasing concentrations of rFVIIa or NN1731 in both haemophilia A- and B-like conditions. At 25 nm rFVIIa, which nears the peak levels in patient plasma after 90 microg kg(-1) intravenous dosing, the effects on maximum thrombin generation rate (maxTG) at 1-10% FVIII were comparable to those at 100% and 200% FVIII in the absence of rFVIIa. Normalization of maxTG required 500 nm rFVIIa and 25 nm NN1731 or 25-100 nm rFVIIa and 5 nm NN1731 in severe or moderate/mild haemophilia A and haemophilia B, respectively. This suggests that NN1731 holds its promise as a future bypassing agent for haemophilia patients with and without inhibitors.
Haemophilia 2009 Nov
PMID:Thrombin generation and platelet activation induced by rFVIIa (NovoSeven) and NN1731 in a reconstituted cell-based model mimicking haemophilia conditions. 1965 96

Haemophilia A replacement therapy is dosed according to patient's weight and plasma FVIII activity (FVIII:C). The FVIII interacts with platelet membrane but limited data on the impact of platelet procoagulant activity (PCA) are available in haemophilia A. Our aim was to characterize individual PCA in vitro in 20 adult haemophilia A patients at various FVIII:C levels. We detected thrombin generation in platelet-poor (PPP) and platelet-rich plasma (PRP) using: (i) calibrated automated thrombography (CAT) triggered with tissue factor, (ii) adhesion-induced PCA upon collagen and (iii) annexin V binding, expression of P-selectin and active glycoprotein (GP) IIbIIIa on platelets after stimulation of GPVI with collagen-related peptide. The FVIII:C levels varied between <1% and 37%. Thrombin generation was individual and strongly enforced by platelets and associated within the three methods. Range of thrombin generation was maximal (up to 30-fold) at FVIII:C levels 1-5%, underlining the impact of platelets in the presence of traces of replacement therapy. At FVIII:C > 5% platelet contribution in the variance faded. Platelet PCA and P-selectin exposure lead to a fivefold variation. Intriguingly, at FVIII:C < 1% thrombin generation in PPP associated negatively with platelet GPVI activation, suggestive of a regulatory interplay between plasma and platelets. In haemophilia A, the variability in thrombin generation is partially related to plasma FVIII:C, but mainly dependent on platelet procoagulant capacity. Annexin V binding and PCA in response to activation by collagen receptors contribute to this variability. In all, platelet PCA at least following collagen interaction significantly impacts thrombin generation in haemophilia A.
Haemophilia 2011 Sep
PMID:Platelets significantly modify procoagulant activities in haemophilia A. 2168 25

The effects of coagulation factor concentrate infusion on restoring secondary haemostasis in patients with haemophilia are obvious. It is not known whether coagulation factor concentrate infusion affects primary haemostasis or induces an acute inflammatory response. In this study, the influence of a factor VIII (FVIII) concentrate bolus infusion on platelet activation and responsiveness, endothelial activation, and inflammation in adult patients with severe haemophilia A was assessed. VWF showed a mild, but significant decrease 15 min after FVIII infusion (85.02 IU dL(-1)) vs. before infusion (92.04 IU dL(-1) ; P = 0.017), while ADAMTS-13 levels also show a mild but significant decrease from 66.1 ng mL(-1) before infusion, to 53.9 ng mL(-1) (P = 0.012) 15 min after and 50.8 ng mL(-1) (P = 0.050) 60 min after infusion. Platelet P-selectin expression decreased 15 min (33.3 AU) and 60 min (38.7 AU) after infusion compared to before infusion (41.3 AU; P = 0.018 and 0.036). In conclusion, a single infusion of a high dose FVIII concentrate in haemophilia A patients may influence primary haemostasis by decreasing VWF, ADAMTS-13 and the number of circulating activated platelets. These effects possibly occur as a consequence of binding of the infused FVIII to VWF, influencing its processing. When treating severe haemophilia A patients with coagulation concentrate infusion, one should realize this does not merely correct FVIII levels but also may influence primary haemostasis.
Haemophilia 2014 Jan
PMID:Factor VIII concentrate infusion in patients with haemophilia results in decreased von Willebrand factor and ADAMTS-13 activity. 2402 72

Recently we reported data suggesting that platelets could compensate for the bleeding phenotype in severe haemophilia A (HA). The aim of this study was to confirm these results in a larger population with a detailed characterisation of clinical phenotype. Patients with diagnostic severe HA (FVIII:C <1%) were scored for clinical phenotype by integrating data on age at first joint bleed, joint damage, bleeding frequency and FVIII consumption. Phenotype was defined as onset of joint bleeding-score + arthropathy-score + joint bleeding-score + (2* treatment intensity-score). After a washout period of three days, blood was collected for measurement of basal level of platelet activation, platelet reactivity, endothelial cell activation and presence of procoagulant phospholipids in plasma. Thirty-three patients with severe HA were included, 13 patients with a mild, 12 patients with an average and eight patients with a severe clinical phenotype. No relevant differences in basal level of platelet activation, platelet reactivity, endothelial cell activation and procoagulant phospholipids between all three groups were observed. The mean annual FVIII consumption per kg did not correlate with the platelet P-selectin expression and glycoprotein (GP)IIbIIIa activation on platelets. In conclusion, variability in clinical phenotype in patients with diagnostic severe HA is not related to platelet activation or reactivity, measured as platelet degranulation and platelet GPIIbIIIa opening.
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PMID:Platelet degranulation and glycoprotein IIbIIIa opening are not related to bleeding phenotype in severe haemophilia A patients. 2447 67

The major therapy for haemophilia is plasma derived or recombinant clotting factors which are evolving steadily to increase potency, stability and half-life. Research in the area of haemophilia therapeutics, however, is not restricted only to modifications in the recombinant products, but alternate therapeutic strategies are being developed which are in different phases of experimental and clinical trials. This chapter reviews the diverse molecular innovations which are being developed for alternate therapeutic approaches in haemophilia. The data is mainly extracted from the literature and the Conference abstracts. Some of the novel therapeutic approaches include inhibition of anticoagulant pathway factors (activated protein C, antithrombin, tissue factor pathway inhibitor) by monoclonal antibodies, peptide inhibitors, DNA or RNA aptamers, use of variant coagulation factors (factor Xa, factor Va) which are more resistant to inactivation or enzymatically more active and antibody-mediated therapy including a humanized anti-factor IXa/X bispecific antibody mimicking factor VIII. Other approaches include nonsense mutation suppression, induction of prothrombotic microparticles by P-selectin-immunoglobulin chimeras, suppression of fibrinolytic potential either by antifibrinolytics or by the use of mutant molecules of fibrinolytic inhibitors. Few products are proposed as 'stand alone' treatment for haemophilia, while a few can be used as adjuvant therapies to recombinant factors with an aim to reduce the amount of factor intake. All efforts are underway to produce an alternate, novel drug for haemophilia which will have an increased half-life, subcutaneously injectable, non-immunogenic and effective both in the presence and absence of inhibitors.
Haemophilia 2015 Mar
PMID:Novel therapeutic approaches for haemophilia. 2552 66

Hemophilic arthropathy is the most common chronic complication in patients with hemophilia. The pathogenesis of hemophilic arthropathy involves the inflammatory processes associated with rheumatoid arthritis (RA). Determining the severity and/or progression of joint damage is crucial when evaluating the effect of treatment modalities. Identifying reliable biomarkers in the peripheral blood of patients with hemophilic arthropathy may be beneficial in clinical practice. Circulating soluble vascular cell adhesion molecule-1 (sVCAM-1), E-selectin, and P-selectin levels are elevated in patients with RA. Our study investigated whether these soluble adhesion molecules can be used as biological indicators in the course of joint damage in patients with hemophilia A.Patients with hemophilia A (mild, moderate, and severe) were enrolled. The plasma levels of sVCAM-1, E-selectin, and P-selectin in patients with hemophilia A and control were measured using specific enzyme-linked immunosorbent assay kits. Joint damages were evaluated using Pettersson scores.No statistically significant differences were observed in E-selectin and P-selectin levels between patients and controls. The sVCAM-1 level was significantly higher in patients with hemophilia A than in controls. The differences remained significant in patients with severe hemophilia A but not in patients with mild or moderate hemophilia A. The degree of hemophilic arthropathy was evaluated using Pettersson scores, and a score higher than 5 indicated marked arthropathy. Patients with more than 1 joint with marked arthropathy showed significantly higher sVCAM-1 levels.sVCAM-1 levels in patients with hemophilia A are associated with the severity of hemophilic arthropathy.
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PMID:Soluble vascular cell adhesion molecular-1 is a potential biological indicator of hemophilic arthropathy. 2786 72

Hemophilia A and B are inherited bleeding disorders due to deficiencies of the clotting factors VIII and IX, respectively. The severity of the disease correlates with remaining factor levels, although individual differences in bleeding tendency are seen despite similar factor levels. While thrombin generation is severely impaired in persons with hemophilia, primary hemostasis, i.e. platelet function, has been generally considered to be normal. However, some studies reported prolonged bleeding times in hemophilia, suggesting that also primary hemostasis is affected. In several other studies different aspects of platelet function in hemophilia have been investigated in more detail and various alterations were discovered, such as increased platelet P-selectin expression, a lower number of procoagulant, so-called 'coated' platelets, lower aggregation upon co-incubation with tissue factor, or reduced platelet contractile forces during clot formation in comparison to healthy individuals. An influence of platelet function on clinical phenotype was suggested, which might contribute in part to variations in bleeding tendency in hemophilic patients with similar factor levels. However, the available evidence is currently limited and no clear correlations between platelet function parameters and clinical phenotypes have been demonstrated. The impact of alterations of platelet function in hemophilia remains to be better defined. Another interesting role of platelets in hemophilia has been reported recently by establishing a novel gene-therapeutic strategy using platelets as a delivery system for FVIII, showing promising results in animal models. This review gives an overview on the currently published literature on platelet function and the potential roles of platelets in hemophilia.
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PMID:Platelets and hemophilia: A review of the literature. 2855 Jul 58