Week 7 - Haemostasis and Coagulation

5 Steps of Haemostasis

Vessel Spasm

• Initial response involves constriction of blood vessels to reduce blood flow.

• Smooth muscle contraction occurs, which helps minimize blood loss.

Platelet Plug Formation

• Adhesion: Platelets adhere to the exposed collagen in damaged vessel walls. Transient tethering signals the start of activation.

• Activation: Platelets become activated, undergoing morphological changes and releasing granules (e.g., alpha granules, dense granules).

  • Release substances such as VWF (von Willebrand factor) and fibrinogen.

• Aggregation: Platelets aggregate through receptors (e.g., GPIV, GPlb) interacting with VWF and fibrinogen, forming a primary platelet plug.

Coagulation

• Fibrin Formation: Thrombin converts fibrinogen into fibrin threads that stabilize the clot. Essential for creating a stable thrombus.

• Clot Retraction: Clot contracts to approximate edges of vascular injury, promoting healing.

• Clot Dissolution (Fibrinolysis): Plasminogen is converted to plasmin, which breaks down fibrin and dissolves the clot after healing.

Coagulation Pathways

Extrinsic Pathway

• Triggered by tissue injury and the exposure of tissue factor (TF) found in cells outside of the blood vessels.

• Key Components:

  • Tissue Factor (TF): A glycoprotein that initiates the pathway upon vascular injury.

  • Factor VII: Upon activation (to VIIa by TF), it forms a complex with TF, which rapidly activates Factor X, leading to thrombin generation.

• This pathway is essential for the immediate response to injury, producing thrombin quickly to facilitate clot formation. The extrinsic pathway is typically the primary pathway for initiating coagulation after vascular injury.

Intrinsic Pathway

• Activated by collagen exposure when blood vessels are damaged, starting a cascade of events within the blood itself.

• Key Components:

  • Factor XII: Triggered upon contact with damaged surfaces, activates Factor XI.

  • Factor XI: Activates Factor IX.

  • Factor IX: In conjunction with Factor VIII, activates Factor X.

• This pathway takes longer to activate than the extrinsic pathway, playing a significant role in sustained haemostasis.

• Key Phases:

  • Initiation: Small amounts of thrombin are generated, which accounts for approximately 4% of the total thrombin production.

  • Propagation: The main production phase where thrombin generation increases significantly (approximately 96%), leading to enhanced clot formation.

Thrombin Production Sequence

• Stepping Stones: Begins with the activation of factor VII and its interaction with TF, leading to the activation of factor IX.

• Thrombin Functions: Converts fibrinogen to fibrin and activates further factors to enhance clot stability (e.g., TAFI, FXIII).

Pathologies of Haemostasis

• Risks:

  • Thrombosis: Caused by inappropriate activation of coagulation leading to blood clots in blood vessels. It consists of arterial thrombosis (e.g., myocardial infarction, stroke) and venous thrombosis (e.g., DVT).

  • Bleeding Disorders: May result from insufficient haemostasis (e.g., thrombocytopenia, coagulation factor deficiencies).

Investigation of Haemostatic Disorders

• Key Tests:

  • Full Blood Count: To assess platelet numbers.

  • Bleeding Time: Normal range 3-8 minutes, indicating primary haemostasis function.

  • Coagulation Tests:

    • Prothrombin Time (PT): Assesses the extrinsic pathway, used for warfarin monitoring. Normal values: 11-16 seconds.

    • Activated Partial Thromboplastin Time (aPTT): Assesses the intrinsic pathway. Normal values: 30-40 seconds.

    • Thrombin Time (TT): Assesses final stages of common pathway; normal values: 15-19 seconds.

Interpretation of Coagulation Assays

• Normal Results: Normal PT, aPTT, TT indicates no hemophilia or platelet functional disorders.

• Prolonged PT: Indicates extrinsic pathway deficiencies or warfarin treatment.

• Prolonged aPTT: May indicate intrinsic pathway deficiencies such as hemophilia or von Willebrand's disease.

Treatment Considerations

• Medication: Aspirin is commonly used to reduce platelet activity and is monitored using thromboxane assays. Recent guidelines suggest caution in prescribing for primary prevention of thrombotic events.

• Future Trends: Ongoing evaluation of newer anticoagulant therapies like FXa inhibitors (e.g., Rivaroxaban, Apixaban) is vital.

Key Takeaway Questions

• What causes bleeding disorders?

• What might lead to thrombotic conditions?Consider lifestyle, genetic factors, and existing medical conditions in assessment.