Haemostasis Flashcards
what are endothelial cells
layer of cells lining the inner surface of all vessel walls (huge total surface area)
what do endothelial cells do in blood vessels
Control blood fluidity and flow (controls size, when intact contributes to preventing clots and when injured promotes local clotting on exposed basement membrane)
Signals inflammatory cells to areas needing defence and repair
Gate keeper between blood and tissues (nutrients, hormones, waste, actively controls extravasation of fluid, cells and molecules)
what is Haemostasis
Process that causes bleeding to stop
Opposite is haemorrhage
what is the function of Haemostasis
Clotting and stopping blood escaping
Keeps blood in damaged vessels
First stage of healing
what can the endothelium do when injured
Endothelium secretes inhibitors of haemostasis (injured, stops secretion, instead secretes von Willebrand factor)
what are 3 platelet based pathways to repair blood vessels
form primary haemostatic plug
Coagulation meshwork on clot
vasoconstriction
why do platelets form a primary haemostatic plug
vessel wall injury (via platelet adhesion, activation and aggregation)
how does coagulation make a meshwork on a clot
(enzyme cascade, part of coagulation requires platelets membrane)
how do platelets cause vasoconstriction
platelets release pro thrombotic agents (serotonin, adp and thromboxane a2)
what is Virchow’s triad
risk factors for each 3
what are megakaryocytes
Found in bone marrow Prod 4000 platelets (20x less than rbcs, platelet size = 3x0.5um)
what are thrombocytes
Thrombocyte = platelet Thrombocytopaenia = low platelet count
how are platelets activated for Haemostasis
exocytose (secrete chemicals) + change shape + increase respiratory rate (O2 consumed)
what activation is required for Haemostasis
Activation required for haemostais, aggregation of platelets, some coagulation steps (phosolipids)
how do platelets covers wounds
Adhesion (to exposed collagen)
Activation (exocytose dense granules, serotonin, adp, calcium)
Aggregation (stimulated by adp, blocked by prasugrel, via fibrinogen)
how does ADP link to activation
Secrete adp > activate P2Y receptor > cation flow
Platelets release thromboxane A2 (TXA2)
ADP > positive feedback on platelets
how are clotting factors found
circulate as inactive precursors
how are activated clotting factors represented
Factor X is activated to be Factor Xa
what are clotting factors
enzymes, cleave other factors to activate them
what clotting factors are not enzymes
Factor V AND VIII (necessary co factors allowing enzymes to function, inactive initially)
how does activation only happen when needed
Initial activating factor is segregated
Eg tissue factors behind endothelial cells, while clotting factor precursors in blood (hard to get together but need to too work, activated when endothelial cell is damaged)
how does thrombosis occur spontaneously
blood flow is slow
Eg atrial fibrillation > thrombosis (can travel via BVs) > to brain, stroke
Blood left standing clots (lab stops this with citrate or heparin)
what is plasma and serum
Plasma =fluid portion of blood
Serum =fluid left after clotting
what is thrombosis and embolism
Thrombosis = abnormal function of clot locally Embolism = abnormal migration of a clot (or other intravascular object)
what is the goal of Haemostasis
activate thrombin (normally inactive, prothrombin)
what does thrombin do
turns fibrinogen into fibrin (cross linked to form a stable clot by XIII and Ca2+)
what are the two coagulation cascades
Extrinsic and Intrinsic (contact activation) pathway
All factors/ proenzymes are already in place, amplification of process through positive feedback
what is the extrinsic pathway
tissue factor pathway
Requires secretion of tissue factor to occur, initiation of coagulation
what is the intrinsic pathway
contact activation pathway
All factors/ proenzymes are already in place, amplification of process through positive feedback
how can thrombin be activated
Activated poorly by Factor Xa
Factor Va, cofactor to Xa, together activate well
how can factor X be activated to Xa
Extrinsic Xase, intrinsic Xase, thrombin also activates it (positive feedback)
what is intrinsic and extrinsic Xase
Extrinsic Xase = tissue factor (under endothelium) + factor VIIa
Intrinsic Xase = factor Viiia + factor IXa
what do the extrinsic and intrinsic pathway lead to
combine into common pathway
leads to clotting
what are the types of coagulation factors of the common pathway
Prothrombin group
Thrombin group
Enzymes
what factors are in the prothrombin group
factors II, VII, IX, X
what factors are in the thrombin group
factors I, V, VIII
Thrombin activates them
Cofactors are V and VIII, factor I is fibrinogen, increased in inflammation, pregnancy and oral contraceptives
what are needed for enzyme cofactors
vitamin K needed for synthesis, require Ca2+ for activation, stable
what is coagulation based on
positive feedback loop, thrombin activates upstream clotting factors
what is vitamin k
A class of related fat soluble vitamins
Required to synthesis enzyme coagulation factors (prothrombin (11), VII, IX,X (calcium dependant proteases)
Vitamin K is essential for gamma carboxylation of clotting enzymes
what can liver dysfunction lead to
Clotting factors made by liver (liver dysfunction cirrhosis or hepatitis) can lead to clotting deficiency
what is fibrinolysis and inhibition of coagulation used for
To balance with clot formation
Imbalance can lead to BV accumulating damage and haemorrhage or clot obstructing vessel lumen
what does plasmin do
Lyses fibrin – stops or destroys clots
Starts as inactive plasminogen (plasma protein made by liver)
Requires tissue plasminogen activator (tPA) to mature (tPA is on the surface of endothelial cells)
what is protein c
a coagulation inhibitor
Inactive enzyme made by liver, activated on surface of endothelial cells
Inactivates factor Va and VIIIa (works with cofactor protein s to inactive Va)
what is antithrombin III
works with heparin
Peptide in blood made by liver
Blocks activity of thrombin (also of Xa and IXa)
is the action of heparin reversible
Heparin is reversible by protamine sulfate
what happens with an anti thrombotic III deficiency
AT III deficiency = risk of thrombotic disease
Recombinant form used medically for thrombotic disorders
what happens with a vitamin k deficiency
Clotting insufficiency
Rare b/c vitamin K is made by large intestine bacteria (also found in leafy green veg)
Caused by GI disease or no fat absorption (liver disease > no bile salts)
Warfarin prevents recycling of vitamin K
what is haemophilia A
Clotting disorder
Affects large BVs, affects joints and muscles, wounds bleed for a few days
Due to congenital lack of clotting factor VIII
X linked
Treat with purified factor VIII (expensive and rare)
Christmas disease (defect in factor IX, aka haemophilia B, symptoms as per Haemophilia A)
what is haemophilia B
Christmas disease (defect in factor IX symptoms as per Haemophilia A
how does atherosclerosis occur (by inflammation)
Monocytes enter lesion, become macrophages (consume cholesterol esters), can become foam cells), can die and release contents (attract more monocytes, cytokines, chemo-attractants)
Inflammation leads to Haemostasis, vice versa (Synergistic)
how is atherosclerosis caused by lipids
LDL deposits lipids in lesion, cholesterol esters non-aqueous (make them solid or hard), cholesterol esters are oxidised (O2 radicals) making them immunogenic, oxidised lipids are consumed by macrophages (become foam cells, explode and attract more monocytes)
how is atherosclerosis caused by the endothelium
Expresses chemo attractants (for monocytes to find and enter lesion), endothelium lost so collagen stimulates coagulation (normally covers collagen and basement membrane)
Endothelium lost, vessel cannot control its dilation (normally provides NO)
how can pharmacology be used to control blood clotting
Anti-platelet agents (block platelet activation, good for treating arterial disease)
Anti-coagulants (block production or activity of clotting factors, used for venous disease)
Fibrinolytics (primarily used to dissolve fibrin in arterial disease)
how do anti-platelet agents act
Prevent clotting in arteries (have limited effects, used in acute coronary syndrome)
what are examples of anti-platelet agents
Aspirin (cyclo-oxygenase (COX) inhibitor, blocks formation of thromboxane A2 in platelets, lengthens bleeding time, doesn’t increase coagulation time, prophylaxis for myocardial infarction)
ADP receptor inhibitors (prasugrel/ clopidogrel)
what do anti-coagulants do
Prevent clotting in veins (in low pressure pulmonary circulation, prophylactic for deep vein thrombosis and pulmonary embolism)
what are examples of anti-coagulants
Heparins (inhibit coagulation (with AT III) by inhibiting factor Xa, different types)
Novel Oral Anti Coagulants (NOACS) – dabigatran (thrombin inhibitor) and rivaroxaban (factor Xa inhibitor)
Warfarin (vitamin K antagonist, slow onset and requires monitoring)
what do fibrinolytics do
Clotting in arteries (high pressure) used in acute coronary syndrome eg AMI
what are examples of fibrinolytics
Tissue plasminogen activator (tPA)
Streptokinase ad urokinase
Aka thrombolytic drugs
what does adp, serotonin, thromboxane A2 do when secreted by activated platelets
adp activates platelets further
serotonin vasoconstriction
txa2 vasoconstriction and aggregation
