Platelets,prostaglandins and inflammation

In exudates of implanted sponges in rats, made thrombocytopenic by the administration of anti-platelet serum, there are significant reductions in the platelet and leucocyte counts and of the content of prostaglandin-like activity. It is concluded that platelets migrate into the developing sponge exudates, are the source of the prostaglandins and interact with complement to cause leucocyte migration. In normal animals the administration of indomethacin and sodium salicylate cause similar effects to thrombocytopenia whereas the injection of human plasma fraction affects only the leucocyte migration. One of the sites of the anti-inflammatory action of conventional non-steroidal drugs may be concerned with the migration of platelets into inflammatory lesions.     

Platelet polymorphisms in thrombotic disorders.

Plaque rupture and/or endothelial damage lead to exposure of von Willebrand factor (VWF) and collagen which facilitate the adhesion of circulating platelets via glycoprotein (GP) GPIb-IX-V and integrin alpha2 beta1, respectively, to the damaged vessel wall. This process activates the platelets and leads to a conformational change of a second integrin alphaIIb beta3 that facilitates fibrinogen binding and platelet aggregation. Thrombin generated at the blood-plaque interface converts fibrinogen to fibrin, which stabilizes thrombus growth. Therefore, any genetic differences that might alter surface expression or activity of these receptors could influence the risk for adverse outcome as a result of the hemostatic process. In the last five years, there has been a rapid accumulation of literature concerning the relationship between genetic variations in platelet glycoproteins and risk for coronary heart disease. In this study, we have presented a comprehensive review of the impact of platelet receptor polymorphisms and thrombotic risk.     

Acute thrombotic complications of myeloproliferative disorders in young adults

Two young adults with myeloproliferative disease had recurrent thrombotic episodes, which were life threatening or associated with a risk of serious disability. Both patients were treated for arterial occlusive disease, and treatment in one instance reversed spastic paraplegia. During a subsequent two-year period of observation, they have remained symptom free. During that time they have been treated with aspirin, and platelet counts have been maintained at one million/mm3 or less.     

The potential role of prostaglandins in skeletal and muscular disorders.

Musculoskeletal diseases such as rheumatoid arthritis and polymyositis are characterized by chronic inflammation. There is evidence to suggest that prostaglandins participate in the production of the inflammatory response. In several tissues, the production of inflammation has been associated with the release of prostaglandins. The inhibitory effect of some anti-inflammatory agents on prostaglandin synthesis further suggests a prostaglandin role in inflammation. Reduction by prostaglandins of release from cells of mediators of inflammation has been described. Prostaglandin treatment also suppresses acute and chronic inflammation in several experimental models. Thus, prostaglandins may serve to regulate the inflammatory response.     

Aspirin,salicylate and prostaglandins

The effects of aspirin, salicylic acid and gentisic acid on the paw swellings in the arachidonic acid-potentiated and in the conventional carrageenan-induced oedema tests as well as on the content of prostaglandin-like activity and leucocyte migration in the exudate of inert implanted sponges in the rat have been studied. It is concluded that aspirin exerts two separate inhibitory effects on prostaglandin formation in vivo, a rapid action of the intact molecule on easily accessible tissues and a later action due to its metabolic conversion to salicylic acid. Salicylic acid inhibits prostaglandin biosynthesis in vivo as the salicylate ion itself and there is no formation of a subsequent active metabolite.     

Platelets,acute inflammation and inflammatory mediators

The anti-inflammatory activity of aspirin-like drugs could derive, at least in part, by inhibiting synthesis and release of prostaglandins or rabbit aorta-contracting substance from platelets. Indeed, aggregation of platelets and the consequent release of inflammatory mediators has been frequently evoked as a factor in the development of the inflammatory reaction. The participation of platelets in acute inflammation was tested in three types of trauma in rats rendered thrombocytopenic with anti-platelet serum. Oedema in response to carrageenin, anti-platelet serum or passive cutaneous anaphylaxis was no different from the controls in thrombocytopenic rats.     

Platelets,arthus-type reactions and inflammatory mediators

The release of inflammatory mediators and the appearance of necrohaemorrhagic lesions induced by subcutaneous implantation of sponges containing antiplatelet serum globulins were studied in control and thrombocytopenic rats. In thrombocytopenic animals, antiplatelet globulins caused a greater release of prostaglanding-like material and 5-hydroxytryptamine as well as larger inflammatory lesions. Thus, platelet integrity is not necessary for the induction of lesions by antiplatelet globulins and the mediators in the sponge exudates must have originated from leucocytes or damaged tissues. Mast cells seem no to be involved in the production of 5-hydroxytryptamine in this inflammatory reaction. It is suggested that in idiopathic thrombocytopenic purpura (ITP) an Arthus-type hypersensitivity reaction, rather than the thrombocytopenia itself, is the cause of the vascular lesions and their manifestations.This article published in Agents and Actions 5, 534 (1975) required a second publication due to heavy misprintings.     

Platelets,Arthus-type reactions and inflammatory mediators

The release of inflammatory mediators and the appearance of necrohaemorrhagic lesions induced by subcutaneous implantation of sponges containing antiplatelet serum globulins were studied in control and thrombocytopenic rats. In thrombocytopenic animals, antiplatelet globulins caused a greater release of prostaglanding-like material and 5-hydroxytryptamine as well as larger inflammatory lesions. Thus, platelet integrity is not necessary for the induction of lesions by antiplatelet globulins and the mediators in the sponge exudates must have originated from leucocytes or damaged tissues. Mast cells seem no to be involved in the production of 5-hydroxytryptamine in this inflammatory reaction. It is suggested that in idiopathic thrombocytopenic purpura (ITP) an Arthus-type hypersensitivity reaction, rather than the thrombocytopenia itself, is the cause of the vascular lesions and their manifestations.     

Immunogenicity, parturition and the prostaglandins

Immunologists have long suspected that maintenance of pregnancy (viable placentation) is contingent upon the suppressed maternal immune response. Curiously, it has never been suggested that the termination of pregnancy at term might in some way be triggered by the un-blocking of this maternal immune suppression. It is the hypothesis of this paper that maintenance and termination of pregnancy are contravening expressions of a maternal-fetal immunologic regulatory response. The role of the prostaglandins in parturition, and the immune response, is discussed.     

Platelets and bronchospasm

The intrathoracic accumulation of radiolabelled platelets and concomitant changes in airway resistance have been recorded continuously in anaesthetised guinea pigs. Platelet-activating factor (PAF-acether) and antigen (in sensitised animals) elicited dose-related intrathoracic accumulation of platelets that could be associated with an increase in airway resistance. Maximal increases in airway resistance preceded maximal increases in platelet accumulation. Low doses of antigen could elicit substantial platelet accumulation, without detectable changes in lung function. It is concluded that physical obstruction of the pulmonary vasculature is not the sole determinant of platelet-dependent bronchoconstriction.     

Platelets and inflammation

Besides their functions in the haemostatic process and in thrombus formation after an endothelial injury, blood platelets also take part in the processes of inflammation and tissue repair that follows. For this purpose, they closely collaborate with all types of leukocytes. Activated platelets secret chemotactic substances, they facilitate the binding of leukocytes to the endothelium and their subsequent extravasation, and they may influence the inflammatory responses of leukocytes in both stimulating and inhibiting ways. However, platelets themselves also contain an array of potent proinflammatory substances, and therefore they are regarded as mediator and effector cells in inflammation. Their capability to interact with bacteria, parasites, and other foreign materials is possibly a phylogenetic vestige and may explain the existence of IgE-dependent killing mechanisms of platelets. On the other hand, the connection between IgE and platelets, besides the platelet-induced eosinophil infiltration, offers a functional basis for the involvement of platelets in allergic processes, particular in the skin and the airways.     

Platelets and infection

The primary function of platelets is to patrol the vasculature and seal vessel breaches to limit blood loss. However, it is becoming increasingly clear that they also contribute to pathophysiological conditions like thrombosis, atherosclerosis, stroke and infection. Severe sepsis is a devastating disease that claims hundreds of thousands of lives every year in North America and is a major burden to the public health system. Platelet surface receptors like GPIb, αIIbβ3, TLR2 and TLR4 are involved in direct platelet-bacteria interactions. Plasma proteins like fibrinogen and vWF enable indirect interactions. Furthermore, platelet granules contain a plethora of proteins that modulate the immune response as well as microbicidal agents which can directly lyse bacteria. Bacterial toxins are potent platelet activators and can cause intravascular platelet aggregation. Platelets contribute to the antibacterial response of the host involving Kupffer cells, neutrophils and the complement system. In this review we summarize the current knowledge about platelet-bacteria interactions and highlight recent advances in the field.     

Platelets, von Willebrand factor, and prostaglandin I2

Depending on the time of addition, prostaglandin I2 (PGI2; greater than or equal to 10(-9) M) either inhibits or reverses platelet agglutination mediated by human factor VIII-related von Willebrand factor activity (FVIIIvWF) and ristocetin, or bovine FVIIIvWF alone. 6-Keto-PGF1 alpha, the inactive metabolite of PGI2, is without effect, PGI2 inhibition is potentiated by the phosphodiesterase inhibitor, theophylline, and is not the result of PGI2 suppression of ADP release. PGI2 (+/- theophylline) does not inhibit ristocetin-induced binding of purified human 125I-FVIIIvWF multimers to washed platelets or to platelets treated with PGI2 and then formalin fixed (although subsequent agglutination of these platelets is impaired). Washed platelets treated previously with 2-aminoethylisothiouronium bromide (AET), an agent that reduces disulfide bonds and alters platelet membranes, also bind human 125I-FVIIIvWF multimers without agglutinating. We conclude that FVIIIvWF-mediated agglutination requires both functional platelet FVIIIvWF binding sites and platelet-platelet cohesion sites, and that platelet surface cohesion sites are altered by AET and PGI2. PGI2 from adjacent intact endothelial cells may prevent excessive platelet accumulation on exposed subendothelium without suppressing an essential hemostatic process--the binding of platelets to subendothelial FVIIIvWF.     

Platelets: preparations, transfusion, modifications, and substitutes.

OBJECTIVE: To summarize current knowledge and recent progress pertaining to platelet concentrate preparations, modifications, and future prospects for platelet substitutes. METHODS: Current publications identified through a search of an electronic literature database were evaluated and reviewed. Relevant data were abstracted into this article. Abstractions of the data were made depending on their relevance. This review starts with standard methods of platelet preparation and goes on to describe different modifications intended to optimize the product and increase its safety. The article concludes with a discussion of the use of hematopoietic growth factors and novel kinds of platelet components for future use. CONCLUSIONS: Many modifications in the preparation of platelet transfusions have occurred in recent years. Platelets prepared by standard techniques contain significant numbers of donor leukocytes, which are responsible for several adverse effects. Awareness of this problem has lead to the development of effective means for their removal. Several methods to reduce the risk of viral and bacterial transmission through platelet transfusions are emerging. New technologies in the use of platelet substitutes have attempted to prolong the platelet storage potential and prevent the development of recipient alloimmunization. As the biological activities of growth factors become better understood, the clinical applications of novel recombinant products may redefine the concept of future platelet transfusions. It is important that research continues into the optimal methods for the preparation and use of platelet transfusions to provide maximal clinical benefits with minimal risk of complications.