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Chapter 32 - Targets for Molecular Therapy: The Biology of Haemostasis
- from SECTION 3 - MOLECULAR THERAPEUTICS
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- By Marion Münster, BSc (Med), MB BCh, DTMH, MMed (Haematology), is Pathologist in Charge, Coagulation Laboratory, Division of Molecular Medicine and Haematology, National Health Laboratory Service and University of the Witwatersrand., Nanthakumarn Chetty, BSc, BSc (Hons), MSc, PhD, Associate Professor, University of the Witwatersrand and National Health Laboratory Service, heads the Platelet Research Unit in the Division of Molecular Medicine and Haematology, School of Pathology, at the University of the Witwatersrand.
- Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
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- Book:
- Molecular Medicine for Clinicians
- Published by:
- Wits University Press
- Published online:
- 04 June 2019
- Print publication:
- 01 October 2008, pp 383-390
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- Chapter
- Export citation
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Summary
INTRODUCTION
Some of the early candidate molecules identified as having potential therapeutic value included proteins involved in the promotion or inhibition of the normal clotting mechanisms, for use in inherited or acquired bleeding or clotting disorders, respectively. In order to understand the rational use of such molecules, which could be produced as recombinant proteins or incorporated into gene therapy strategies, it is necessary to have a thorough understanding of the molecular and cellular mechanisms of the normal physiological haemostatic (‘stopping of bleeding’) process. The primary principle of haemostasis is to minimise blood loss at sites of vessel injury by forming a thrombus (clot) and at the same time maintaining blood flow (Figure 1). In order to achieve this there is a highly regulated, fine-tuned interaction of multiple processes, involving the blood vessel wall, principally the endothelium, plate lets and noncellular blood constituents.
The core elements of haemostasis include vasoconstriction, platelet activation, the pro cess of coagulation and fibrinolysis (clot break - down). All of these processes are initiated simultaneously, triggered by a breach in blood vessel integrity. Endothelial cell damage results in exposure of collagen, which triggers platelet adhesion and activation, while tissue factor expression activates the coagulation cascade resulting in the formation of a fibrin meshwork.
Platelet adhesion and activation is conventionally known as ‘primary haemostasis’ and the process of coagulation and fibrin formation as ‘secondary haemostasis’. In simplistic terms, the platelet plug can be considered to be the ‘bricks’ and the fibrin meshwork the ‘cement’, both being required for the formation of a stable thrombus.
PLATELET ADHESION AND ACTIVATION
Platelets play a critical role in the normal physiology of haemostasis. At sites of endothelial cell injury, platelets adhere to a variety of subendothelial matrix structures via a multitude of platelet surface receptors.
Chapter 33 - Cellular Targets of Antiplatelet Agents
- from SECTION 3 - MOLECULAR THERAPEUTICS
-
- By Nanthakumarn Chetty, BSc, BSc (Hons), MSc, PhD, Associate Professor, University of the Witwatersrand and National Health Laboratory Service, heads the Platelet Research Unit in the Division of Molecular Medicine and Haematology, School of Pathology, at the University of the Witwatersrand., Marion Münster, BSc (Med), MB BCh, DTMH, MMed (Haematology), is Pathologist in Charge, Coagulation Laboratory, Division of Molecular Medicine and Haematology, National Health Laboratory Service and University of the Witwatersrand.
- Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
-
- Book:
- Molecular Medicine for Clinicians
- Published by:
- Wits University Press
- Published online:
- 04 June 2019
- Print publication:
- 01 October 2008, pp 391-395
-
- Chapter
- Export citation
-
Summary
INTRODUCTION
Platelets are anuclear and circulate in the bloodstream as discoid, smooth-surfaced cells about 1–3 μm in diameter. They have a circumferential band of microtubules and two membrane systems, the endoplasmic reticulum or dense tubular system and the plasma membrane-derived surface-connected canalicular system. They also contain alpha granules, dense granules, lysosomes and peroxisomes. The alpha granules contain various poly - peptides including fibrinogen, fibronectin and platelet-derived growth factor (PDGF). Dense granules contain adenosine triphosphate (ATP), adenosine diphosphate (ADP) and calcium ions. Platelets play a major role in thrombosis (formation of a blood clot) and haemostasis (arrest of bleeding) after injury.
The platelet membrane has receptors that are poised for immediate interaction with specific adhesive proteins when an area of vascular damage is encountered. These receptors mediate adhesion to subendo thelium, followed by platelet activation, aggregation with other platelets and formation of a firm platelet plug at the site of the vascular leak. When platelets moving along the vessel wall encounter an area of denuded endothelium, they adhere to the subendo thelial matrix, undergo a change in shape to a sphere with multiple pseudopods, and spread to increase their area of surface contact. Agonists in the microenvironment interact with specific receptors on the platelet surface. The agonist-receptor binding transmits signals from outside the cell to the interior, generating second messengers that induce protein phosphorylation and ion channels. As a result, there is activation of the contractile proteins, secretion of granule contents, an increase in adhesion, recruitment of additional platelets by aggregation, thrombus formation and haemostasis.
RECEPTOR-MEDIATED ADHESION
The platelet membrane contains a number of glycoproteins (GPs) that are receptors for adhesive proteins present both in the vessel wall and in plasma. These GPs have been named from GPI to GPIX. The platelet adhesion receptors include GPIa/IIa for colla gen, GPIc/IIa for fibronectin, GPIb for von Willebrand factor (vWF), GPIIb/IIIa fibrin ogen, vWF, fibronectin and vitronectin. The inter action of platelet GPIb with vWF induces intracellular signalling, resulting in a conformational change and activation of the integrin GPIIb/IIIa. vWF then binds irreversibly to the activated GPIIb/IIIa, producing firm adhesion of the platelet to the vessel wall.