Disorders of Blood Coagulation Flashcards
What is haemostasis?
life preserving process designed to maintain blood flow:
- respond to tissue injury
- curtail blood loss
- restore vascular integrity & promote healing
- limit infection
Effect of infection on haemostasis
Infection is an important initiator of haemostasis. Coagulation therefore not only stops blood loss, but can act as a mechanism against infection.
Meningococcal septicaemia
Bacterial infection initiates haemostasis, forming excessive clots which occlude blood vessels and specific areas lose their blood supply, resulting in disseminated intravascular coagulation (DIC)
Key components of haemostasis
Endothelium
Coagulation
Platelets
Fibrinolysis
What is a blood clot made of?
- fibrin mesh (end point of coagulation)
- platelets
- red blood cells
Phases of the Haemostatic system
1) Primary haemostasis
2) Secondary haemostasis
3) Fibrinolysis
Primary haemostasis
Formation of platelet plug:
- Vasoconstriction (immediate)
- Platelet adhesion (within seconds)
- Platelet aggregation & contraction (within minutes)
Steps of primary haemostasis
1) The endothelium continuously releases small amounts of vWf which circulates in the blood.
2) Endothelial cells also store vWF in Weibel-Palade bodies for release when approximately stimulated
3) If collagen becomes exposed to blood (through damage), vWF binds to it.
4) Platelets express receptors for both collagen and vWF and become activated when these proteins bind to them
5) Activated platelets express functional fibrinogen receptors, which are required for aggreagation.
Where does vWF reside?
When is vWF released and unravelled?
lies in the endothelium
when there is increased stress during blood vessel injury
why are blood clots localised?
To prevent systemic blood clots
Function of vWF
attaches to collagen in the subendothelium and acts as an anchor for platelets to attach to it and form a platelet plug (platelet aggregation)
-this prevents excessive blood loss at site of injury
Secondary haemostasis
Formation of the fibrin clot:
- activation of coagulation factors (within seconds)
- formation of fibrin (within minutes)
Steps of Secondary haemostasis
1) Tissue factor, expressed by nearly all sub-endothelial cells activates the coagulation cascade to which initiates a minor burst of thrombin
2) Factor FVIIa binds to TF, which leads to the conversion of prothrombin to thrombin.
3) Thrombin activates receptors on platelets as well as the endothelium, amplifying platelet aggregation and initiating release of stored vVF from endothelial cells
Steps of the amplification stage
1) Thrombin activates two cofactors: Factor VIIIa and Factor Va which form calcium-ion dependent complexes on the surface of platelets with Factor IXa (tenase complex) and Factor Xa (the prothrombinase complex).
2) These complexes greatly accelerate the production of Factor Xa and thrombin, respectively.
3) The greatly increased production of thrombin via tenase and prothrombinase contributes considerably more to the process. Thrombin will convert fibrinogen to the fibrin mesh.
How many clotting factors are there?
Where are the majority of clotting factors produced?
13 clotting factors
liver
-hence people with liver disease sometimes have bleeding disorders due to deficiencies in clotting factors
Coagulation pathways
1 - extrinsic pathway
2 - intrinsic pathway
3 - common pathway (convergence of 1 and 2)
Intrinsic pathway of coagulation
Extrinsic pathway of coagulation
Pathway involving surface contact
Factors released by damaged tissues begin cascade (e.g. tissue factor)
-primary way in which we form a clot
What does each reaction in the coagulation pathways (intrinsic and extrinsic) require?
Ca2+
Phospholipid
+/- Specific co-factors
FVII deficiency
FXII deficiency
causes bleeding
not associated with bleeding
What initiates coagulation?
when sub-endothelial tissue is exposed to the circulation at the site of injury
Fibrinolysis
dissolution of a clot
-clot limiting mechanism
> activation of fibrinolysis (minutes)
lysis of the plug (within hours)
Key substances in fibrinolysis
- plasminogen
- tissue plasminogen activator (t-PA) & urokinase plasminogen activator
- ⍺2-plasmin inhibitor
What is plasminogen?
Function of plasmin
How is plasminogen converted to plasmin?
precursor to the active enzyme plasmin
breaks down fibrin clots
tPA converts plasminogen to plasmin
D dimers
Fibrin Degradation Products (FDPs)
products generated when cross-linked fibrin is degraded
*D dimer levels used clinically to detect for clots
products generated when non-cross linked fibrin or fibrinogen is broken down
Therapeutic thrombolysis for myocardial infarction
tPA and streptokinase (bacterial activator)
The process of fibrinolysis
- Plasminogen is converted to plasmin by tissue plasminogen activator (t-PA).
- Plasmin degrades the fibrin mesh to fibrin degradation products which can be cleared.
Thrombosis vs Bleeding
There needs to be a state of equilibrium between factors which break down clots (fibrinolytic factors, anticoagulant proteins) and factors which promote clotting (coagulation factors, platelets) to maintain normal haemostasis
Cause of thrombosis
- High coagulation factors and platelets
- Low fibrinolytic factors and anticoagulant proteins
Consequence of thrombosis
Chronic venous insufficiency:
- atrophic changes
- hyperpigmentation
- ulceration
- infection
Cause of bleeding
Consequence of bleeding
- High fibrinolytic factors and anticoagulant proteins
- Low coagulation factors and platelets
Easy bruising (ecchymosis)
Natural anticoagulants (I)
Antithrombin (AT) is a serpin (serine protease inhibitor) Activity greatly enhanced by binding heparan binding sites on endothelial cells Major checkpoint to inhibit coagulation (thrombin), IXa, Xa) Its heparan binding domain is the basis of the anticoagulant activity of heparin which increases the activity of ATIII
Protein C and protein S are natural anticoagulant plasma proteins Protein C is activated by thrombin bound to thrombomodulin (TM) on endothelial cells to form activated protein C (APC) Protein S is an APC cofactor which helps binding to cell surfaces APC degrades cofactors FVa and FVIIIa
Haemophilia - failure to clot leading to haemorrhage
- Mutations in coagulation factors (haemophilia A and B)
- Platelet disorders (von Willebrand disease)
- Collagen abnormalities (fragile blood vessels and bruising)
Haemophilia A (80%)
Mutated FVIII
Haemophilia B (20%)
Mutated FIX
Thrombophilia – excessive clotting leading to thrombosis
- Inherited: mutations in coagulation factors (DVT)
* Acquired: malignancy increases clotting factors (DVT)
Disseminated intravascular coagulation (DIC) – whole body clots
- Infection
- Depletion of clotting factors and platelets leads to bleeding
As in sepsis (body’s response to an infection injures its own tissues and organs)
Depletion of clotting factors and platelets leads to bleeding
Excessive clotting
Factor V Leiden mutation
Resistance to APC
FVa is not inactivated
Antithrombin deficiency
Thrombin, IXa and FXa are not inactivated
Protein C deficiency
Protein S deficiency
Increases risk of DVT
Prothrombin Time (PT)
test to measure activity of prothrombin in the blood:
- sensitive to extrinsic pathway and to a lesser extent common pathway
- tissue factor driven
Activated Partial Thromboplastin Time (APTT)
- sensitive to intrinsic pathway and to a lesser extent common pathway
- contact activated
*normal= 30-45 seconds
Thrombin Time (TT)
Determines if adequate fibrinogen is present for normal coagulation:
-sensitive to defects in conversion of fibrinogen to fibrin
Haemophilia
von Willebrand disease
Bleeding into joints
Affects mucous membranes.
Mostly mild, but bleeding can vary in severity
Inherited defect/deficiency in vWF
Virchow’s Triad
Development of a venous thrombus depends on:
• Alterations in the constituents of the blood
• Changes in normal blood flow
• Damage to the endothelial layer
Management of VTE
Investigations pre-treatment • Clotting screen – Prothrombin time – Partial thromboplastin time – Thrombin time • Full blood count • Renal screen • Liver function tests – If clinical suspicion of liver disease
Treatment • DVT: Anticoagulate • Immediate anticoagulant effect • Heparin or warfarin • DOACs – Rivaroxaban, apixaban (FXa inhibitors) – Dabigatran (thrombin (FIIa) inhibitor) • PE: Thrombolysis • Alteplase (tissue plasminogen activator) • Streptokinase • Followed by anticoagulant to prevent recurrence
Deep Vein Thrombosis clinical features
• Pain & tenderness of veins • Limb swelling • Superficial venous distension • Increased skin temperature • Skin discoloration All reflect obstruction to the venous drainage Increased risk of pulmonary embolism
