Haemostasis Flashcards
To understand the key elements of the haemostatic mechanism. To be able to relate these elements to the essential functions of the control of bleeding and the prevention of thrombosis . To appreciate, in broad terms, the way in which problems may arise as a result of inherited or acquired pathology. To be aware of the categories of drug which may be used for therapeutic purposes to modify haemostasis.
What is haemostasis?
The cessation of bleeding at a vascular injury site via thrombus formation.
What is a thrombus made up of?
platelet plug
fibrin clot
What is primary haemostasis?
Aggregation of platelets
What is secondary haemostasis?
fibrin clot formation
What is the role of thrombin?
Production of fibrin monomers that then cross link to form mesh around platelets for fibrin clot to form
What are platelets derived from?
Megakaryocytes
What is the proportion of platelets to RBCs?
1-2 platelets per 20 RBCs
What is thrombopoietin?
hormone which regulates megakaryocyte and platelet production
What is thrombocytopenia?
A platelet count below 150 x 109
What is the normal platelet count?
150-400* x 109
What is thrombocytosis?
A platelet count over 450 x 109 per litre.
What is the diameter of platelets?
1-4 um
What is the survival rate of platelets?
8.5-10 days
Half life of 4 days
What produces thrombopoietin?
kidneys and liver
How is platelet adhesion prevented in normal conditions?
Endothelial lining is intact and release NO and prostacyclin (PGI2)
What is platelet adherence?
Endothelial damage means NO production stops and collagen from underneath is exposed to VWF in the blood which binds to it with platelets forming a bridge.
What is the role of GP1b receptors?
platelets receptors which help the binding of collagen to VWF
What is the role of Gp1a and Gp6 receptors?
Allow platelets to bind directly to collagen
What is the problem with Gp1a and Gp6 receptors?
As they allow the platelets to bind directly to collagen but without VWF binding is weak and platelets are dislodged easily.
What is the role of GP2b/3a receptors?
Expressed by adherent platelets and bind to fibrinogen to bind even more platelets.
What happens in platelet aggregation>
Adherent platelets express GP2b/3a receptor which binds fibrinogen to bind to even more platelets to form a meshwork.
What happens when platelets become activated?
Become spiky and entangled
What is the platelet release reaction?
Activated platelets release ADP, thromboxane A2 (TXA2) and serotonin (5-HT) from granules
What is a platelet plug?
ADP and TXA2 attract more platelets to the site which aggregate
What does 5-HT do?
Acts on local SM to increase local vasoconstriction
How is there a positive feedback system?
Spiky platelets release cytokines to attract even more platelets until a large enough plug can stop the bleeding
What is the bleeding time?
The time to form an effective platelet plug and stop the initial haemorrhage
What is the bleeding time test?
Make a puncture wound in a superficial area of skin and monitor time needed for bleeding to stop
What should bleeding time normally be?
1-9 minutes
What should bleeding time in children normally be?
1-13 minutes
How does bleeding time differ between males and females?
Slightly longer in females
What stops the positive feedback system to stop platelets forming giant clots?
healthy endothelium releases prostacyclins and NO to prevent platelet plug spreading beyond damage area
What is the role of endothelin?
Released by endothelial damage and is a powerful vasoconstrictor resulting in reduced local blood flow so helps to form the primary haemostatic plug
What does thrombin do for platelet plug?
Released by the coagulation cascade and stabilises and strengthens the platelet plug
What is factor VII?
A plasma protein
How is factor VII converted into factor VIIa?
Factor VII is exposed when a vessel is injured to tissue factor III and they react forming VIIa
How is VIIa converted into factor Xa.
VIIa reacts with calcium and factor X in the blood
What does factor Xa do?
Factor Xa and calcium converts a small amount of prothrombin to thrombin
What is the role of thrombin?
Polymerises soluble fibrinogen into insoluble fibrin in the platelet plug to then form a stable clot
What does a stable clot consist of?
Matrix of fibrin, platelets and trapped erythrocytes
How does a small amount of thrombin activate a positive feedback loop in the extrinsic pathway?
Thrombin convers converts three other factors ( V, VIII, XI) into their active forms (Va, VIIIa & XIa). VIIIa & IXa the increase conversion of X to Xa and Va increases effectiveness of increased Xa. This loop quickly forms a large amount of thrombin.
What is factor XII also activated by apart from thrombin?
Factor XII (as well as factor VII) is also activated by exposure to collagen on sub-endothelial tissue, and by polyanions released from platelets when they are activated.
What is the intrinsic pathway?
Factor XIIa converts factor XI to XIa and thus IX to IXa. IXa forms Xa and a small amount of thrombin.
What is the purpose of the intrinsic pathway?
It can activate clotting when blood is stagnant often in atria or leg veins (during DVT for example)
What coagulation test assesses extrinsic and common pathways?
Prothrombin Time (PT)
What coagulation test assesses intrinsic pathway?
Activated Partial Prothrombin Time (APPT)
What is INR?
A standard value which compensates for the different results for prothrombin time that different manufactures give
What is the normal INR range?
0.8-1.2
What is INR commonly used to assess?
The coagulability of blood in patients taking warfarin or heparin as at risk of abnormal clot formation
What is the last stage of coagulation?
Factor XIIIa increases crosslinking in the fibrin fibrils to form a mechanically stable clot.
What is haemophilia A caused by?
deficiency of factor VIII.
What is haemophilia B caused by?
Deficiency of factor IX.
What is the role of plasmin?
responsible for the removal of clots (fibrinolysis) when the damaged tissue has healed.
How does plasmin do its role?
inactive precursor plasminogen circulates in blood, binds to platelet plugs and gets incorporated into final clot
What holds plasminogen in its inactive form?
Alpha-2 antiplasmin
What converts plasminogen to plasmin?
Tissue plasminogen activator which is released from normal endothelial cells
What is D-Dimer?
A product of fibrin breakdown, protein, circulates in blood
Why is vitamin K so important?
Modifies proteins to allow them to bind to calcium ions
What are the 2 forms of vitamin K?
Vitamin K1 and K2
Where is vitamin K1 found?
green leafy vegetables
How is vitamin K2 produced?
K1 converted into K2 by animal or bacteria in the gut flora
What are the risk factors for vitamin K deficiency?
Liver disease, poor diet, poor absorption, antibiotics
How do you treat bleeding caused by overdose of warfarin? (anticoagulant)
Give vitamin K
What are the 2 classic anticoagulants?
Heparin
Warfarin
How does heparin work?
Binds and activates anti-thrombin which inhibits thrombin and factor Xa
How is heparin given?
Subcutaneous not absorbed
How does warfarin work?
Competes with sites that bind Vit K so reduces effectiveness of clotting factors
What are some modern anticoagulants?
DOACs/NOACs
How do DOACs and NOACs work?
Direct thrombin inhibitor and factor Xa inhibitor
WHy are modern anticoagulants better than classic?
Less serious side effects, rapid onset action, short half life, less routine monitoring needed
Why are modern anticoagulants worse than classic?
more expensive, use with care with patients with kidney problems, no antidote so difficult to stop effect in emergency
