Term 2 Lecture 6: Haemostasis/ haemorrhage Flashcards
Haemostasis and haemorrhage greek meaning
Haemo - blood
Stasis - stoppage
Rrhage - abnormal flow
Phases of haemostasis
(Primary/secondary/fibrinolysis)
Primary: reaction of blood flow, formation of temporary plug in wall of damaged vessel ( by platelet/endothelial interaction)
Secondary: coagulation phase,
conversion of soluble Fibrinogen to insoluble fibrin (requires many enzymes), strengthens initial haemostatic plug, due to soluble plasma proteins (most of which are made in liver)
Fibrinolysis: degredation of Fibrin plug after repair of wound
Platelets (thrombocytes)
Have no nuclei and infact aren’t cells, they are just fragments of megakaryocyte cells.
Small membrane bound packets of granular cytoplasm (clotting proteins and cytokines)
Circulating platelets have a 1-4 micrometre diameter and are 0.5-1micrometre thick - v. Tiny
Contain many membrane bound organelles like mitochondria, smooth ER and lysosomes
Originate in bone marrow, produced by pinching off and shedding of megakaryocytes (which are polyploidal - cells that have a nucleus containing multiple copies of DNA) parts of the megakaryocyte face onto the lumen of the blood vessel into which platelets break off.
Megakaryocytes are derived from multipotent progenitors in bone marrow which becomes lineage restricted to megakaryocyte production
Platelets coagulate to form a plug and prevent blood loss.
Platelet features
See drawing in physiology notebook 2
Central portion of platelet aka the granulomere, contains granules and lysosomes
Alpha granules contain:
Protein w/haemostatic functions- fibrinogen, thrombospondin, plasminogen
Growth factors-
PDGF platelet driven growth factor activates cell division e.g. of fibroblasts and endothelium
TGF alpha/beta, beta secretes a lot of collagen
Dense core granules contain:
Mediators of vascular tone - Ca²+, serotonin and ADP.
Peripheral microtubules and microfilaments constitute the hyalomere membrane region
Glycoproteins on outer membrane allow platelet to communicate with the external environment
Alteration of cytoskeletal proteins during platelet shape change
(Disc>sphere>spread)
Disc - resting platelet, long actin filaments, rough due to membrane invaginations, actin binding proteins present: filamin - forms link between filaments, gelsolin cuts filaments, Cap2 caps ends of filaments, profilin aids polymerisation of actin as does ARP 2/3
> Increase of Ca²+ causes increase in gelsolin and cofilin and decrease in filamin leading to filament fragmentation and recycling
Resulting in:
Sphere- calcium changes arrangement of actin filaments as the majority of the proteins are regulated by Ca. Gelsolin level increases and fragments existing filaments. Cofilin activity increases so cross-linking is reduced. Cytoskeleton shape changes to become rounder and expands in vol.
> Increase in PPI phospho inositols causes GTPase increase, Arp2/3 increase and profilin increase leading to actin filament assembly
Resulting in:
Spread - proteins are activated to polymerise actin fibres, long actin fibres form changing the shape of the platelet
See diagram physiology notebook 2
Platelet plasma membrane
Glycocalyx - surface coat
Contains glycoproteins that have a role in adhesion and aggregation
Receptors for coagulation factors
l (fibrinogen), V, Vlll, X, XL, Xll, Xlll
All enhance coagulation
Plasma membrane
ADP receptor
Platelet factor Vlll (binds Von Willebrand factor)
Platelet granules contain
Ca & Mg
ADP & ATP for platelet aggregation
5HT (serotonin) & Thromboxane for vasoconstriction
PDGF platelet driven growth factor
Mitogen for fibroblasts
Chemokines for neutrophils
Steps of primary haemostasis
1) exposed collagen detected and coagulation cascade activates, binds and activates platelets to area.
(Intact endothelium releases prostacyclin and NO to prevent binding and dilate vessel)
2) release of platelet factors
3) attracts more platelets
4) aggregates to form a plug
Vascular phase (vasoconstriction)
After injury to a blood vessel vasoconstriction occurs as a neurogenic response to restrict blood flow
The injury breaks the endothelial lining of the vessel exposing collagen to which the platelets adhere
Contraction further exposes the basement membrane and collagen causing further platelet recruitment
Activation of platelets causes release of vasoconstriction
Endothelium
Produce Von Willebrand factor
Synth basement membrane (damage repair)
Normally synth and release PGI2 aka prostacyclin but reduce their secretion when damaged
Prostacyclin inhibits platelet aggregation and causes vasodilation
Involved in binding and extravasation of immune cells - aids neutrophils moving into surrounding damaged tissues
Synthesises tissue factor which is exposed when endothelium is damaged - an important factor in secondary haemostasis
Prostacyclin and Thromboxane
Similar in structure and synthesis pathway
Thromboxane (produced by platelets) suppresses cAMP synth and elevates Ca²+ levels
Prostacyclin (produced by healthy endothelial cells) activates cAMP synth and reduces Ca²+ levels
NO additionally inhibits platelet activation and promotes vasodilation by raising cAMP levels
Aspirin function
Aspirin inhibits cyclo oxygenase enzyme. It is known as a “thinning agent” because without this enzyme platelets cannot aggregate and as they have no nuclei they have no ability to regenerate the enzyme unlike epithelial cells that can replace the inhibited enzyme.
Platelet phases 1-4
1) Adhesion: adhesion of platelets to exposed basement membrane. Requires Von Willebrand factor Vlll which acts as a bridge between platelet and membrane
2) Adhesion triggers shape change: change from disc to irregular “spread” shape with pseudopodia projections, adhere to other platelets. Receptors for ADP, collagen & thrombin increase on platelet membrane.
3) Activation: activation of receptors for ADP, Thromboxane A2 and thrombin cause granule release. Eicosanoids released - Thromboxane A2 and prostaglandins.
4) Aggregation: ADP and Thromboxane A2 act as platelet chemoattractants. Platelets aggregate - further recruitment/activation. Primary homeostatic plug formed in minutes - fragile requires the further stabilisation provided in secondary haemostasis.
Primary haemostasis summary
Haemostasis involves interaction of blood vessels, platelets and soluble serum proteins
Primary haemostasis is quick (secs-mins) forming a weak repair
Blood vessels respond to damage by vasoconstriction which causes contraction through the endothelium
Platelets adhere to the exposed basement membrane and each other to form a temporary plug changing shape from smooth to spiky.
