Antihaemostasis mechanisms – to prevent clotting in normal physiology
Vascular endothelium produces a variety of factors to stop clotting in these 3 ways:
- Inhibit platelet adhesion
- Natural anticoagulants
- Fibrinolytic effects
Inhibit platelet adhesion:
- Nitric oxide
- Prostacyclin (PGI2)
- Adenosine diphosphatase which degrades ADP, an essential compound for platelet activation
Heparan sulphate (similar to heparin) activates antithrombin III -> inactivates thrombin (Factor IIa) and factor Xa
Thrombomodulin binds thrombin directly and removes it from circulation. The thrombomodulin + thrombin complex activates protein C, which with protein S cofactor inactivates factor Va and VIIIa.
Plasminogen is a beta globulin proenzyme synthesised by the liver. It is interwoven into the fibrin clot as it is formed.
Tissue plasminogen activator (t-PA) released by endothelial cells cleaves plasminogen to form plasmin. Plasmin degrades fibrin clots from the endothelial cell surface = fibrinolysis.
Fibrin degradation products are formed from fibrinolysis, including d-dimer, used to detect VTE, as clots forming would lead to a rise in fibrinolysis.
Fibrinolysis is much slower than coagulation, because the time lag allows healing to take place.
Haemostatic mechanisms – to prevent bleeding in normal physiology
3 key steps:
- Platelet aggregation
The platelet plug is too soft to stand on its own for very long – a high cardiac output rushing by will just knock the entire plug off the damaged endothelium. A strong clot has to be made using a fibrin net.
Cell based model of coagulation:
The classical cascade is an in vitro explanation, not sufficient to explain how clotting can be achieved quickly in vivo. In vivo, the following mechanisms help produce a massive amount of thrombin quickly: Initiation, amplification and propagation
- Damaged endothelial cells expose plasma to tissue factor .
- Nearby factor V and VII become activated.
- Nearby clotting factors get activated and form more thrombin.
Further activation of clotting factors and platelets by thrombin, TF, vWF, ADP and PAF, preparing for large scale thrombin generation.
Surface of activated platelet is loaded with activated clotting factors, can form large amounts of thrombin.
How do you measure clotting and coagulation?
Point of care vs lab tests
Point of care:
- Activated clotting time (ACT)
- Thromboelastography (TEG)
- Platelet function analyser
- Point of care PT, INR, aPTT
- Point of care fibrinogen
- Bleeding time
- Prothrombin time (PT)
- Activated partial thromboplastin time (APTT)
- Fibrinogen level
- Factor Xa level (and specific factor 8,9 levels for haemophilia)
- International normalised ratio (INR)
- Thrombin time
- Advanced platelet function assays
- Platelet count
- von Willebrand factor levels
Applications of knowing haemostatic mechanisms:
Pharmacology – antiplatelets, anticoagulants, fibrinolytics and antifibrinolytics
Physics – measurement of coagulation and comparison of methods
Specific equipment – TEG and ACT
Clinical – Heparinisation in cardiac bypass/interventional radiology/ interventional cardiology, warfarin reversal or loading, management of acute severe haemorrhage and disseminated intravascular coagulation, thromboprophylaxis, management of VTE including life threatening PE and stroke, perioperative management of anticoagulants, regional anaesthesia and anticoagulants/antiplatelets