Interference with the Host Haemostatic System by Schistosomes

Schistosomes, parasitic flatworms that cause the tropical disease schistosomiasis, are still a threat. They are responsible for 200 million infections worldwide and an estimated 280,000 deaths annually in sub-Saharan Africa alone. The adult parasites reside as pairs in the mesenteric or perivesicular veins of their human host, where they can survive for up to 30 years. The parasite is a potential activator of blood coagulation according to Virchow's triad, because it is expected to alter blood flow and endothelial function, leading to hypercoagulability. In contrast, hepatosplenic schistosomiasis patients are in a hypocoagulable and hyperfibrinolytic state, indicating that schistosomes interfere with the haemostatic system of their host. In this review, the interactions of schistosomes with primary haemostasis, secondary haemostasis, fibrinolysis, and the vascular tone will be discussed to provide insight into the reduction in coagulation observed in schistosomiasis patients.Interference with the haemostatic system by pathogens is a common mechanism and has been described for other parasitic worms, bacteria, and fungi as a mechanism to support survival and spread or enhance virulence. Insight into the mechanisms used by schistosomes to interfere with the haemostatic system will provide important insight into the maintenance of the parasitic life cycle within the host. This knowledge may reveal new potential anti-schistosome drug and vaccine targets. In addition, some of the survival mechanisms employed by schistosomes might be used by other pathogens, and therefore, these mechanisms that interfere with host haemostasis might be a broad target for drug development against blood-dwelling pathogens. Also, schistosome antithrombotic or thrombolytic molecules could form potential new drugs in the treatment of haemostatic disorders

Медико-психологическая характеристика и дифференциальная диагностика дезадаптивных состояний у военнослужащих

Діагностична і експертна оцінка дезадаптивних станів є актуальною проблемою сучасної психіатрії. У цієї роботі розглядаються дезадаптивні стани з погляду девіантної поведінки у акцентуйованих осіб. Результати дослідження підтверджувалися психологічними, нейрофізіологічними методами.Diagnostics and expert estimation of deadaptation states is a topical problem of modern psychiatry. This article represents an examination of deadaptation states from the point of view of deviant behavior of accentuated personalities. The research results were confirmed by psychological and neurophysiological methods

Haemostatic changes in urogenital schistosomiasis haematobium: A case-control study in Gabonese schoolchildren

In many tropical areas schistosomiasis is a major health problem causing hepatosplenic, intestinal or urogenital complaints. Hepatosplenic schistosomiasis mansoni is also characterized by blood coagulation abnormalities. Liver pathology plays a role in the development of haemostatic changes and the parasitic infection may directly affect coagulation. However, these contributing factors cannot be studied separately in hepatosplenic schistosomiasis infections. This pilot study provides insight in haemostatic changes in urinary schistosomiasis by studying coagulation parameters in schistosomiasis haematobium-infected Gabonese schoolchildren. Selection on urinary schistosomiasis patients without hepatosplenic complaints allows for the investigation of the direct effects of the parasite on haemostasis. Levels of von Willebrand Factor (VWF) antigen, active VWF and osteoprotegerin were elevated, indicating inflammation-mediated endothelial activation. In contrast to hepatosplenic schistosomiasis, thrombin-antithrombin complex and D-dimer levels were not affected. Despite its small sample size, this study clearly indicates that Schistosoma haematobium directly alters the activation status of the endothelium, without initiation of coagulation

Flow cytometric mepacrine fluorescence can be used for the exclusion of platelet dense granule deficiency

Background: δ-storage pool disease (δ-SPD) is a bleeding disorder characterized by a reduced number of platelet-d

The limitation of genetic testing in diagnosing patients suspected for congenital platelet defects

Thrombosis and Hemostasi

Arterial thrombosis in the antiphospholipid syndrome

The antiphospholipid syndrome (APS) is a non-inflammatory autoimmune disease that mainly affects young women. The syndrome is characterized by recurrent thrombosis or pregnancy morbidity in association with the persistent serological presence of antiphospholipid antibodies. Antiphospholipid antibodies are heterogeneous and recognize a wide variety of protein ligands, all of which have phospholipid binding properties. The plasma protein beta2-glycoprotein I (beta2-GPI) is considered the most relevant antigen in the syndrome. Although the consensus is that antiphospholipid antibodies increase the risk of a thrombotic event, the extent of this increase in risk is unclear. We therefore assessed the antiphospholipid antibody-related risk of myocardial infarction or ischemic stroke in women below age 50. Although several antiphospholipid antibody subpopulations are reported to be associated with an increased risk of thrombosis, only the lupus anticoagulant subpopulation was associated with an increased risk of myocardial infarction (5-fold increased risk) or ischemic stroke (43-fold increased risk). The presence of additional risk factors such as smoking or oral contraceptive use increased the risk of both myocardial infarction or ischemic stroke further. While lupus anticoagulant appeared to be a strong risk factor for myocardial infarction in young women, we could not confirm these results in men below age 70. Our understanding of the molecular mechanisms through which antiphospholipid antibodies exert their prothrombotic influence has increased over the years. Antiphospholipid antibodies are known to induce endothelial cell activation, cause increased platelet activation and influence the coagulation system. Several cellular receptors are postulated to mediate the prothrombotic effects of antiphospholipid antibodies. One of these receptors is Apolipoprotein E receptor 2’ (ApoER2’), a member of the low density lipoprotein-receptor family. Previous work has shown antiphospholipid antibody-beta2-GPI complexes bind to both ApoER2’ and the platelet adhesive receptor glycoprotein Ibalpha (gpIbalpha) with high affinity, which mediates increased thrombus formation in in-vitro flow models. We further investigated the role of both gpIbalpha and ApoER2’ in antiphospholipid antibody induced platelet activation. Upon stimulation of platelets with antiphospholipid antibodies or a recombinant dimer of beta2GPI that mimics the function of antiphospholipid antibodies, intracellular signalling that originated from both gpIbalpha and ApoER2’ was observed. Inhibition of the interaction of dimers of beta2-GPI with either receptor completely abrogated platelet activation in an in-vitro flow model, despite continued signalling through the uninhibited receptor. These results suggest both receptors are crucial in the mechanism behind platelet activation in the antiphospholipid syndrome. The role of ApoER2 in the thrombotic manifestations of the antiphospholipid syndrome was further investigated in a murine thrombosis model. Intraperitoneal administration of dimers of beta2-GPI or patient-derived antiphospholipid antibodies to wild-type mice resulted in increased thrombus formation upon induction of vascular injury, increased vascular tissue factor activity and increased monocytic tissue factor activity compared with mice injected with buffer. Administration of dimers of beta2-GPI or purified antiphospholipid antibodies to ApoER2-deficient mice caused normal thrombus formation after vascular injury, normal vascular tissue factor activity and normal monocyte activation, which confirms the importance of ApoER2 in the chain of events leading to thrombosis in the antiphospholipid syndrome

Leukocyte-associated Ig-like receptor-1 is a novel inhibitory receptor for surfactant protein D

The collagenous C-type lectin, SP-D, is a multitrimeric glycoprotein present at mucosal surfaces and is involved in host defense against infections in mammals. SP-D has immunomodulatory properties, but the underlying mechanisms are incompletely understood. SP-D contains collagen domains. LAIR-1 is an inhibitory immune receptor at the cell surface of various immune-competent cells that binds collagen. We hypothesized that the immunomodulatory functions of SP-D can be mediated via interactions between its collagen domain and LAIR-1. Binding assays show that SP-D interacts via its collagenous domain with LAIR-1 and the related LAIR-2. This does not affect the mannan-binding capacities of SP-D, which induces cross-linking of LAIR-1 in a cellular reporter assay. Functional assays show that SP-D inhibits the production of FcαR-mediated reactive oxygen via LAIR-1. Our studies indicate that SP-D is a functional ligand of the immune inhibitory receptor LAIR-1. Thus, we have identified a novel pathway for the immunomodulatory functions of SP-D mediated via binding of its collagenous domains to LAIR-1. This may provide a mechanism for the unexplained immunomodulatory function of the collagenous domains of SP-D

Platelets express three different splice variants of ApoER2 that are all involved in signaling

Background: ß2-Glycoprotein I is themost relevant antigen in antiphospholipid syndrome. We have shown that binding of dimerized ß2-GPI to platelets viaApoER2¢ sensitizes platelets for second activating stimuli. Objective: Determine the region of ApoER2 involved in the binding of dimeric b2-GPI. Methods: Cultured human megakaryocytes (MK) and three different human megakaryocytic cell lines were used for mRNA isolation to clone and express recombinant soluble platelet ApoER2. Domain deletion mutants of ApoER2 were constructed to identify the binding site for dimeric ß2-GPI. The presence of ApoER2 splice variants in platelets was demonstrated by immuno-blotting. Results: Three different mRNA splice variants were isolated from all four types of megakaryocytic cells used. Sequence analysis identified the splice variants: (i) shApoER2D5 lacking low-density lipoprotein (LDL) binding domains 4, 5 and 6; (ii) shApoER2D4-5 lacking LDL binding domains 3, 4, 5, 6 and (iii) shApoER2D3-4-5 lacking LDL binding domains 3, 4, 5, 6 and 7. The presence of three splice variants of ApoER2 on platelets was confirmed by immuno-blotting, with ApoER2D4-5 being the most abundantly expressed splice variant. Upon stimulation with dimeric ß2-GPI, all three splice variantswere translocated to the cytosol; however, ApoER2D4-5 translocation was most prominent. Dimeric b2-GPI binds platelet ApoER2 variants via LDLbinding domain 1. Conclusions: Three different ApoER2 mRNA splice variants were isolated from MK and platelets express all three splice variants. All splice variants were shown to be functional by translocation upon stimulationwith dimeric ß2-GPI. All three splice variants express LDL-binding domain 1

Leukocyte-associated Ig-like receptor-1 is a novel inhibitory receptor for surfactant protein D

The collagenous C-type lectin, SP-D, is a multitrimeric glycoprotein present at mucosal surfaces and is involved in host defense against infections in mammals. SP-D has immunomodulatory properties, but the underlying mechanisms are incompletely understood. SP-D contains collagen domains. LAIR-1 is an inhibitory immune receptor at the cell surface of various immune-competent cells that binds collagen. We hypothesized that the immunomodulatory functions of SP-D can be mediated via interactions between its collagen domain and LAIR-1. Binding assays show that SP-D interacts via its collagenous domain with LAIR-1 and the related LAIR-2. This does not affect the mannan-binding capacities of SP-D, which induces cross-linking of LAIR-1 in a cellular reporter assay. Functional assays show that SP-D inhibits the production of FcαR-mediated reactive oxygen via LAIR-1. Our studies indicate that SP-D is a functional ligand of the immune inhibitory receptor LAIR-1. Thus, we have identified a novel pathway for the immunomodulatory functions of SP-D mediated via binding of its collagenous domains to LAIR-1. This may provide a mechanism for the unexplained immunomodulatory function of the collagenous domains of SP-D

Platelet dysfunction contributes to bleeding complications in patients with probable leptospirosis

Contains fulltext : 177417.pdf (publisher's version ) (Open Access)BACKGROUND: Severe leptospirosis is frequently complicated by a hemorrhagic diathesis, of which the pathogenesis is still largely unknown. Thrombocytopenia is common, but often not to the degree that spontaneous bleeding is expected. We hypothesized that the hemorrhagic complications are not only related to thrombocytopenia, but also to platelet dysfunction, and that increased binding of von Willebrand factor (VWF) to platelets is involved in both platelet dysfunction and increased platelet clearance. METHODOLOGY/PRINCIPAL FINDINGS: A prospective study was carried out in Semarang, Indonesia, enrolling 33 hospitalized patients with probable leptospirosis, of whom 15 developed clinical bleeding, and 25 healthy controls. Platelet activation and reactivity were determined using flow cytometry by measuring the expression of P-selectin and activation of the alphaIIbbeta3 integrin by the binding of fibrinogen in unstimulated samples and after ex vivo stimulation by the platelet agonists adenosine-diphosphate (ADP) and thrombin-receptor activating peptide (TRAP). Platelet-VWF binding, before and after VWF stimulation by ristocetin, as well as plasma levels of VWF, active VWF, the VWF-inactivating enzyme ADAMTS13, thrombin-antithrombin complexes (TAT) and P-selectin were also measured. Bleeding complications were graded using the WHO bleeding scale. Our study revealed that platelet activation, with a secondary platelet dysfunction, is a feature of patients with probable leptospirosis, especially in those with bleeding manifestations. There was a significant inverse correlation of bleeding score with TRAP-stimulated P-selectin and platelet-fibrinogen binding (R = -0.72, P = 0.003 and R = -0.66, P = 0.01, respectively) but not with platelet count. Patients with bleeding also had a significantly higher platelet-VWF binding. Platelet counts were inversely correlated with platelet-VWF binding (R = -0.74; P = 0.0009. There were no correlations between platelet-VWF binding and the degree of platelet dysfunction, suggesting that increased platelet-VWF binding does not directly interfere with the platelet alphaIIbbeta3 signaling pathway in patients with probable leptospirosis. CONCLUSION/SIGNIFICANCE: Platelet dysfunction is common in probable leptospirosis patients with manifest bleeding. Increased VWF-platelet binding may contribute to the activation and clearance of platelets