ATP binding cassette transporter A1 (ABCA1) is involved in regulation of intracellular lipid trafficking and export of cholesterol from cells to high density lipoproteins. ABCA1 defects cause Tangier ...disease, a disorder characterized by absence of high density lipoprotein and thrombocytopenia. In the present study we have demonstrated that ABCA1 is expressed in human platelets and that fibrinogen binding and CD62 surface expression in response to collagen and low concentrations of thrombin, but not to ADP, are defective in platelets from Tangier patients and ABCA1-deficient animals. The expression of platelet membrane receptors such as GPVI, α2β1 integrin, and GPIIb/IIIa, the collagen-induced changes in phosphatidylserine and cholesterol distribution, and the collagen-induced signal transduction examined by phosphorylation of LAT and p72syk and by intracellular Ca2+ mobilization were unaltered in Tangier platelets. The electron microscopy of Tangier platelets revealed reduced numbers of dense bodies and the presence of giant granules typically encountered in platelets from Chediak-Higashi syndrome. Further studies demonstrated impaired release of dense body content in platelets from Tangier patients and ABCA1-deficient animals. In addition, Tangier platelets were characterized by defective surface exposure of dense body and lysosomal markers (CD63, LAMP-1, LAMP-2, CD68) during collagen- and thrombin-induced stimulation and by abnormally high lysosomal pH. We conclude that intact ABCA1 function is necessary for proper maturation of dense bodies in platelets. The impaired release of the content of dense bodies may explain the defective activation of Tangier platelets by collagen and low concentrations of thrombin, but not by ADP.
The role of the platelet glycoprotein (GP) Ib-V-IX receptor in thrombin activation of platelets has remained controversial although good evidence suggests that blocking this receptor affects platelet ...responses to this agonist. The mechanism of expression of procoagulant activity in response to platelet agonists is also still obscure. Here, the binding site for thrombin on GPIb is shown to have a key role in the exposure of negatively charged phospholipids on the platelet surface and thrombin generation, in response to thrombin, which also requires protease-activated receptor-1, GPIIb-IIIa, and platelet-platelet contact. Von Willebrand factor binding to GPIb is not essential to initiate development of platelet procoagulant activity. Inhibition of fibrinogen binding to GPIIb-IIIa also failed to block platelet procoagulant activity. Both heparin and low molecular weight heparin block thrombin-induced platelet procoagulant activity, which may account for part of their clinical efficacy. This study demonstrates a new, critical role for platelet GPIb in hemostasis, showing that platelet activation and coagulation are tightly interwoven, which may have implications for alternative therapies for thrombotic diseases.
This article reviews the roles of blood platelets in haemostasis as well as in the pathogenesis of thromboembolic diseases. Besides the basic processes in primary haemostasis, platelet adhesion, ...platelet secretion, platelet aggregation, clot retraction, the new model of thrombin formation on the platelet surface is presented. The different signal transduction pathways in platelets are a main focus of this review.
Background. Heparin-induced thrombocytopenia type II (HIT II) is a rare but life-threatening side effect of heparin therapy. We describe the perioperative anticoagulative management of patients ...tested positive for HIT II and requiring implantation of a left ventricular assist device (LVAD).
Methods. We report on 3 patients with a different perioperative anticoagulative management (preoperative, intraoperative, and postoperative anticoagulation with danaparoid-sodium; preoperative anticoagulation with recombinant hirudin, anticoagulation with danaparoid-sodium intraoperatively and postoperatively; preoperative anticoagulation with recombinant hirudin, intraoperative anticoagulation with heparin, and postoperative anticoagulation with danaparoid-sodium) and discuss the difficulties of the treatment.
Results. Anticoagulation with alternative drugs such as recombinant hirudin and danaparoid-sodium led to serious and life-threatening bleeding complications as well as to thromboembolic events in the first 2 patients. Therefore the third patient underwent LVAD implantation using heparin for intraoperative anticoagulation to avoid administration of high doses of recombinant hirudin or danaparoid-sodium. Despite very low anti-factor Xa activities, when using danaparoid-sodium postoperatively, the patient suffered from a bleeding complication on the 4th day after LVAD implantation requiring reexploration.
Conclusions. In selected cases (negative heparin-induced platelet aggregation (HIPA) test at the time of LVAD implantation and continuation of postoperative anticoagulation with recombinant hirudin or danaparoid-sodium), heparin may be used for LVAD implantation in HIT II patients to reduce bleeding complications.
This article reviews the roles of blood platelets in different physiologic and pathologic processes in the human body. Besides the basic processes in primary haemostasis, platelet adhesion, platelet ...secretion, platelet aggregation, clot retraction, the new model of thrombin formation on the platelet surface is presented. The different signal transduction pathways in platelets are a main focus of this review.
Platelets are cells with key function in primary haemostasis. They localise coagulation to the haemostatic thrombus. After injury of the vessel wall blood contacts subendothelial matrix proteins as ...well as cells constitutively exposing tissue factor (TF). Platelets adhere to the subendothelial matrix, become activated, spread and secrete the contents of their granules. On the surface of the TF exposing cells minute amounts of thrombin are formed. These amounts of thrombin are inadequate to yield in a stable fibrin clot, but activate platelets and factors XI, VIII, V. In that way the consolidation pathway is triggered. Activated platelets aggregate and bind leukocytes. On the surface of the activated platelets coagulation (co)factor complexes are formed and protected in an optimal way. Thus large amounts of prothrombin are converted to thrombin, creating a so-called thrombin burst. This leads to the formation of a stable platelet-fibrin-clot. Platelets are not always prothrombotic. They have their own mechanisms to stop activation processes and thrombus growth. Besides, its key role in haemostasis platelets are involved in inflammation and innative immune defence.
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