| Popis: |
This thesis described our findings of several studies which are aimed to shed light on the mechanisms of bleeding and clotting. Firstly, we investigated the role of erythrocytes in thrombus formation. In contrast to the common notions that erythrocytes are bystanders in thrombus formation, we have found evidence that erythrocyte can actively influence thrombus formation by interacting with platelets. Erythrocytes can bind to platelets under flow conditions. The binding of red blood cells to platelets is mediated by a protein called intercellular adhesion molecule-4 (ICAM-4) on the red blood cell membrane and its receptor protein called αIIbβ3 on the platelet membrane. Our data indicates that blocking the ICAM-4 mediated erythrocyte-platelet interaction leads to reduced thrombus formation. Based on the above findings, we think that the drugs that target the red blood cell-platelet interaction may become one of the new therapeutic strategies to treat or prevent thrombotic conditions, such as in the situations of heart attack and stroke. Secondly, we investigated the mechanisms by which the transfused platelets stored at cold conditions are cleared rapidly after transfusion. When the platelet count in blood drops to a certain amount (severe thrombocytopenia), patients should receive prophylactic platelet transfusion to reduce the risk of bleeding. Platelet products from blood banks are currently stored at room temperature, which leads to a short shelf life (max 7 days) and the risks of bacterial contamination in the products. Cold storage (0-4°C) would be better in preserving the quality of platelet products. However, the cold-stored platelets are known to be cleared rapidly from the circulation after transfusion. Our study showed that low temperature can induce a structural change in GP1b on the platelet surface. This change induces signaling transductions inside platelets which in the end lead to platelet apoptosis. The apoptotic platelets are phagocysed by macrophages. By interfering with the GP1b structural change, we may be able to prevent platelet apoptosis and render platelet cold storage more feasible. Thirdly, we looked into the mechanism behind the thrombocytopenia in von Willebrand type 2 B patients. Patients with VWD-type 2B have enhanced VWF-platelet interaction but with bleeding tendency rather than hyper blood clotting. The bleeding tendency in these patients is related to the severity of thrombocytopenia. We found that the thrombocytopenia is at least partially caused by the increased uptake of VWF/platelet complex by Macrophages in both liver and spleen. Fourthly, we looked into the physiological role of β2GPI in thrombosis and hemostasis. β2GP1 is a plasma protein that is best known as the antigen against which anti-phospholipid antibodies are developed. The detection of antiphospholipid antibodies in blood is one of the diagnostic criteria for the anti-phospholipid syndrome (APS)—a disease that is characterized by vascular thrombosis and pregnancy loss. In addition to its role in APS, β2GPI has been shown to possess other biological functions. Our data suggest that β2GPI can play a protective function in patients with thrombotic thrombocytopenic purpura by binding to ultra large VWF. |
