- • Fundamentals of coagulation and haemostasis
- • Coagulation disorders
- • Platelet function and disorders
- • Laboratory investigations
- • Considerations in dentistry
- • Antiplatelet medications
- • Anti-coagulant medications
- • To understand the process of haemostasis
- • To understand the mechanisms of the coagulation cascade
- • To understand platelet function
- • To identify the most common disorders of haemostasis
- • To know how to order and interpret laboratory tests relevant to haemostasis
- • To be aware of important considerations in dentistry relating to haemostasis
Coagulation disorders and anti-coagulant therapy are increasingly prevalent among patients with complex medical conditions. There are profound implications for the dental management of such patients. This chapter will consider normal haemostasis followed by consideration of abnormalities affecting platelet function and coagulation disorders in turn. There will then be a consideration of appropriate local measures for control of bleeding and a review of individual anti-coagulant drugs.
The physiology of normal haemostasis will be discussed in the next sub-section followed by a review of the laboratory tests used to assess haemostatic function.
Haemostasis refers to the mechanisms by which the body prevents excessive loss of blood from within vessels. There are three major components of haemostasis:
- Local measures such as vasoconstriction
- Primary haemostasis, or formation of a platelet plug
- Secondary haemostasis, known as the coagulation cascade.
Primary haemostasis depends on the presence of sufficient functional platelets to form a platelet plug. Platelets are non-nucleated fragments of megakaryocytes, and are formed in the bone marrow. Their lifespan is 7–10 days and they contain granules filled with hormones, enzymes and other chemicals that are essential for primary haemostasis. The external membrane of the platelet contains glycoproteins, which interact with the vessel wall and other components of the coagulation cascade to assist with haemostasis.
When a vessel wall is damaged, components such as collagen are exposed and platelet glycoproteins contact these surfaces, leading to platelet activation. Following platelet adhesion to an area of damaged vessel either directly or via circulating molecules such as von Willebrand’s factor, the platelets are activated, resulting in a change in shape to a more rounded structure, enabling greater surface interactions between platelets. Activation also results in release of platelet granule contents.
Following degranulation, mediators that promote platelet aggregation and adhesion are released leading to the formation of a stable platelet plug to occlude the defect in the vessel. Key mediators include ADP and thromboxane A2, both of which contribute to further platelet adhesion and aggregation. Glycoprotein GPIIb/IIIa will become exposed on the aggregated platelets, and this molecule interacts with the coagulation cascade via the binding of fibrinogen.
The coagulation cascade refers to a sequence of enzyme activation of proteins, with the endpoint being the generation of thrombin. Thrombin converts plasma fibrinogen into fibrin, which forms the basis of the haemostatic plug via interactions with platelets. The coagulation cascade features a number of amplification reactions leading to the generation of sufficient thrombin in order to cause fibrin polymerization and stabilization of the thrombus.
There are two major pathways in the coagulation cascade, known as the extrinsic and intrinsic pathways (Figure 20.1). These converge on the ‘common’ pathway, which involves the activation of factor X, leading to generation of thrombin, and then the development of fibrinogen. Fibrinogen is hydrolysed by thrombin, releasing peptides that form fibrin monomers, which are then available for polymerization and the formation of a fibrin meshwork, the basis of a blood clot. The initial trigger for coagulation is the interaction of tissue factor (exposed by vascular injury) with clotting factor VII. This starts the extrinsic pathway of coagulation, and leads to activation of factors IX and X, and production of a small amount of thrombin. This pathway is rapidly inactivated by intrinsic anticoagulant functions, so the intrinsic pathway, partially triggered by the small amount of thrombin already produced, takes over and amplifies the coagulation response. This pathway involves a number of coagulation factors and leads to the activation of factors VIII and V. This results in the generation of a larger amount of thrombin, which can then hydrolyse fibrinogen and release fibrin monomers. Polymerization of fibrin, assisted by activated factor XIII, leads to the formation of a stable thrombus.
The coagulation process is limited by a number of intrinsic anticoagulants, including tissue factor pathway inhibitor, anti-thrombin, protein C and protein S. The process of fibrinolysis occurs to limit the size of the thrombus developed at a site of vascular injury, and is mediated by plasmin. Plasminogen is converted to plasmin by activators from the vessel wall or tissues. Plasmin will then break down fibrin and thus limit the size of a thrombus, and assists in healing following the vascular injury.
Initial investigations when a bleeding disorder is suspected include a full blood count with differential and a blood film. This may identify a reduction in the platelet count, and the blood film may demonstrate the reason for this, such as haematological malignancy leading to bone marrow failure. Specialized tests are available to assess platelet function.
Investigation of the coagulation system includes tests to assess both the extrinsic and intrinsic pathways.
The prothrombin time (PT) measures the function of factors VII, X, V, prothrombin and fibrinogen (extrinsic pathway). For ease of interpretation and to account for inter-laboratory differences, PT is usually expressed as the international normalized ratio (INR). The INR is a ratio of the patient’s PT to a mean normal PT, with a correction in order to calibrate the result against a World Health Organization standard.
Activated partial thromboplastin time (APTT) is used to evaluate the intrinsic coagulation pathway, including factors VIII, IX, XI and XII as well as factors X, V, prothrombin and fibrinogen.
Assays are also available to examine for specific clotting factor deficiencies.
As discussed above, platelets are a crucial part of the clotting process and platelet disorders are considered here followed by a discussion of individual antiplatelet drugs.
Platelets are produced in the bone marrow by fragmentation of megakaryocyte cytoplasm. The normal platelet count is 150–400 × 109/L and the average platelet lifespan is approximately 7–10 days.
Platelet disorders encompass abnormalities in the number of platelets as well as their function. Excessive numbers of platelets (thrombocythaemia/thrombocytosis) may be due to a myeloproliferative disorder, or can be reactive following major haemorrhage, as well as in malignancy, chronic infection or connective tissue disorders. Patients who have had their spleen removed may also have elevated platelet counts.
Insufficient platelets (thrombocytopenia) may be due to a failure of production secondary to bone marrow disorders, increased consumption of platelets due to autoimmune disease or other disorders, or sequestration of platelets in the spleen in severe liver disease.
Disorders of platelet function may occur due to hereditary abnormalities of platelet function, in myelodysplastic and myeloproliferative disorders, in patients with renal failure or most commonly, secondary to medications such as aspirin, dipyridamole or clopidogrel.