Blood Coagulation, Haemostasis & It's Investigation Flashcards
What is haemostasis?
Protective process evolved in order to maintain a stable physiology
Protective process evolved in order to maintain a stable physiology
How does infection relate to haemostasis?
Infection is an important initiator of haemostasis
Infection can change balance of haemostasis to either form clot
How is haemostasis maintained?
Haemostasis maintained in fine balance - microenvironments require clotting and other compartments require it to remain fluid
Describe a condition where infection leads to clotting
E.g. meningococcal septicemia
Causes infarction - dead tissue where blood supply is lost due to thrombus
Clots form in arterial supply of organs => tissue damage
Explain why meningococcal septicemia causes clotting
Coagulation occurs in an attempt to prevent blood flow containing infection to vital organs e.g. heart, liver
What is meningococcal septicemia?
Infarction of skin, blood rash, necrotic hand
What are the role of haemostasis?
Respond to tissue injury
Curtail blood loss
Restore vascular integrity & promote healing
Limit infection
What are the 4 key components of haemostasis?
Endothelium
Coagulation
Platelets
Fibrinolysis
Describe a blood clot blood film
Fibrin mesh - helps strengthen clot
Platelets - v small non nucleated
Red blood cells present
Outline how haemostasis occurs
- Vessel endothelial damage & Blood Loss
- Vascular Spasm causing vasoconstriction to limit blood
flow - Platelet plug forms - platelets run along periphery of
laminar flow, bouncing along endothelial wall and
adhere to site of damage - Coagulation due to fibrin
What are the 3 phases of the haemostatic system?
- primary haemostasis
- secondary haemostasis
- fibrinolysis
Outline the events of primary haemostasis
Primary haemostasis:
- Vasoconstriction (immediate)
- Platelet adhesion (within seconds)
- Platelet aggregation and contraction (within minutes)
What occurs during secondary haemostasis
Secondary haemostasis:
- Activation of coagulation factors (within seconds)
- Formation of fibrin (within minutes)
Describe what happens during fibrinolysis
Activation of fibrinolysis (within minutes)
Lysis of the plug (within hours)
What are the phases of clot formation?
- Initiation
- Amplification
- Stable clot
- Lysis
Why does fibrinolysis occur at the end of haemostasis?
Fibrinolysis occurs at the end because in order to regenerate tissue we want to remove the clot
Describe haemostasis at rest
Triggers and cofactors separated
Lumen of blood vessel containing platelets and clotting factors (VIIa)
What happens when endothelial damage occurs?
When endothelial damage occurs, subendothelial surface is exposed to flowing blood
What is the consequence of exposed subendothelial surface?
Exposed subendothelial surface introduces collagen and tissue factor to flowing blood (is otherwise hidden from blood)
How does subendothelial exposure allow healing and a clot to form?
Platelets recognise damaged area and adhere to exposed underlying collagen
How do platelets initiate clot formation?
Platelets are able to recognise exposed collagen due to presence of VWF
What stimulates thrombosis?
Platelets release lots of prothrombotic substances into microenvironment allowing thrombotic state to occur
Platelets release clotting factors and adhere to other platelets allowing more activation of coagulation factors with one another
What is the most common bleeding disorder?
VW disease most common inherited bleeding disorder
Describe the structure of vWF
VWF has a multimeric structure hidden in the endothelium which is released and unraveled under shear stress
How does shear stress affect vwf?
Stress activates VWF to look for collagen and platelets to form a clot
Describe the structure of activated platelets
Activated platelets form spindles releasing thrombotic factors
Explain why platelets undergo conformational changes when activated
When undergoing adhesion platelets spread to block subendothelial damage and stop blood loss
How do platelets stop bleeding?
They form complexes with fibrin, collagen and vWF with glycoproteins on their surface
Outline the role of platelets in haemostasis
- Damaged endothelium exposes, TF, collagen etc. to
flowing blood - Allows adhesion: vWF binds extracellular collagen and
Gp1b-IX-V complex (glycoprotein 1b) - Activation Gp2b-III undergoes conformational change
- Platelets activated and secrete thrombotic mediators
- Recruit more platelets to form a bigger platelet clot
- Aggregates formed and produce contraction to
strengthen platelet clot - Contractile proteins and fibrin formed on top form a
platelet plug at site of injury
Give an overview of the haemostatic plug formation
> response to injury
- Vessel constriction
- Formation of an unstable platelet plug, platelet
adhesion, platelet aggregation
> primary haemostasis - Stabilisation of the plug with fibrin blood coagulation
- Dissolution of clot and vessel repair fibrinolysis
> secondary haemostasis
What is the role of fibrin in haemostasis?
Fibrin mesh binds and stabilises platelet plug and other cells
Describe events of secondary haemostasis
- Extrinsic - tissue damage pathway TF will form a
complex with factor 7a - This complex activates factor 10a
- Activation of 10a induces the THROMBIN BURST
- The thrombin burst results in fibrin formation and further
platelet activation - Intrinsic pathway occurs when blood activated by
coming into contact with a foreign surface/ non
physiological surface
Where are clotting factors produced?
Vast majority of clotting factors produced by liver
Describe the consequence of haemophilia A
Severe Haemophilia A (FactorVIII (8)) deficiency
Large thrombin burst doesn’t occur
Can lead to bleeding in joints = toxic: initiates early onset arthritis
What is the effect of haemophilia b?
Haemophilia B (Factor IX (9)) deficiency
No continuation of reaction = no thrombin burst
What allows the formation of fibrin?
Tissue factor and Factor VIIa allow the formation of thrombin from prothrombin
A huge thrombin burst is formed which can now produce fibrin from fibrinogen
What is fibrinolysis?
The process of clot dissolution
What are the main functions of fibrinolysis?
- clot limiting mechanism
- repair and healing mechanism
Describe the steps involved in firbinolysis
Series of tightly regulated enzymatic steps
- Feedback potentiation & inhibition
What are the components of firbinolysis?
- Plasminogen
- Tissue plasminogen activator (t-PA) & urokinase (u-PA)
- Plasminogen activator inhibitor -1 and -2
- α2-plasmin inhibitor
What are the products of fibrinolysis?
D dimers are generated when cross-linked fibrin is degraded.
FDP (Fibrin degradation products) are generated if non-cross linked fibrin or fibrinogen is broken down.
Describe the enzymatic reaction that causes fibrinolysis
Plasminogen activated by tissue plamsinogen activator to produce plasmin
plasmin degrades fibrin clot
How are D dimers used to identify if a patient has a clot?
When patients have a clot we can measure their D dimer levels which will be significantly higher as fibrinolysis occurs at the same time
What therapeutics are used to induce fibrinolysis in myocardial infarction?
tPA and a bacterial activator, streptokinase, are used in therapeutic thrombolysis for myocardial infarction (Clot busters)
Describe the balance between haemostasis and thrombosis
Normal haemostasis: a state of equilibrium
Balance between coagulation factors and platelets and anticoagulant proteins and fibrinolytic factors
When does thrombosis occur?
If balance is tipped in favour of coagulation factors and platelets, get thrombosis
What causes thrombosis?
Can be due to excess production or polymorphism causing hyperactivation
What are the signs and symptoms of thrombosis?
red , swollen painful leg →
Classic DVT
With elevated D dimer levels
What are the consequences of prolonged DVT?
prolonged DVT causes: Atrophic changes Hyperpigmentation Ulceration Infection
Describe the loss of balance leading to bleeding
Balance lost towards excess fibrinolysis and anticoagulation makes patients unable to form a clot
⇒ excess bleeding
What causes excessive bleeding?
Can be due to a lack of coagulation factors (haemophilia) and platelets (thrombocytopenia) → deficiencies are common
Or an excess of fibrinolytic factors and anticoagulant proteins
What is ecchymosis?
ecchymosis: easy bruising very large in unusual sites
Virtually all bleeding disorders and often in normal
