Clotting pathways

Haemostasis and Coagulation

• Haemostasis means the arrest of bleeding. Platelets are activated and aggregate together. However this is weak. if the platelet plug breaks up again, you will begin bleeding again
• So the coagulation cascade produces fibrin cross-links (reinforces) platelets to allow them to bind to each other more strongly, thus decreasing the risk of re-bleeding

The Vascular Phase

• Blood vessel tries to maintain blood flow but also respond to breaches. The inner layer is a single layer of endothelial cells on a basement membrane. The cells secrete von Willebrand factor (VWF) into the plasma and subendothelium.
• Below the basement membrane is a subendothelium rich in collagen, elastin, fibronectin, tissue factor (TF), VWF etc. Below this lies smooth muscle layer. Below the smooth muscle layer is the adventitial layer.
• Endothelium has a negative charge and repels platelets, produces prostacyclin and degrades ADP. Heparan sulphate and antithrombin III inhibit clotting factor activation. The endothelium also causes intrinsic fibrinolysis with a plasminogen activator.
• Smooth muscle can dilate and constricts in response to local NO production and so regulates blood flow and dilatation
• The VWF binds to platelet GPIb-IX and GPIIbIIIa and mediates platelet adhesion to the vessel wall. Also carries FVIII and prevents its early degradation so prothrombotic
• The subendothelial Collagen, elastin if exposed will activate platelets tissues VWF etc and lead to thrombus formation

Platelets

• Platelets are formed from megakaryocytes in the bone marrow. The normal platelet count is 150-450 x10⁹/l. The life span of the platelet is 8 - 9 days.
• The platelet has a phospholipid cell membrane into which are inserted glycoproteins (GP) which act as major cell receptors and antigens of the platelets.
• Platelet Adhesion: if endothelium breached then platelets contact subendothelial tissues and GPIb-IX and VWF form a complex and platelets adhesion occurs.
• Aggregation: Platelets then stick to one another to form the primary platelet plug. Normal platelet number, presence of GPIIb-IIIa complex on the platelet surface (receptor for fibrinogen), plasma fibrinogen and calcium ions are necessary for platelet aggregation. As platelets aggregate they release their a and d granule contents which further sustain the aggregation response.

The Coagulation Phase

• In this phase liquid blood coagulates into a stable jelly-like clot. Blood coagulation takes in a cascade of enzyme reactions, each successive step being catalysed by the active enzyme formed in the previous step.
• The process soon "snowballs" and gathers speed and force. Complexes are formed by Vitamin K dependent factors that help to localise the process. These factors are produced in the liver in their precursor form.
• They bear glutamic (Gla) residues at the amino-terminal end of the molecule which undergoes carboxylation of the Gla residues in the presence of a carboxylase, vitamin K, carbon dioxide and oxygen. These bind calcium ions which then serve as a bridge to bind the proteins to phospholipid surfaces

🔎 Investigations

• Extrinsic and common pathway is tested by Prothrombin Time (PT)
• Intrinsic and common pathway is tested by Activated Thromboplastin Time (APTT)
• Bleeding time measures platelet vessel wall interaction and is a poor predictor of abnormal surgical bleeding
• Thrombin time (TT) measures clottable fibrinogen and normal TT is 12-14 seconds

Bleeding

• Vascular/Platelet defect: skin petechiae and mucosal surfaces ? bruising, epistaxis, gum bleeding, menorrhagia
• Coagulation defect: Bleeding into subcutaneous tissues, haematoma formation and haemarthrosis