lecture 3 - blood: platelets & haemostasis Flashcards
what is haemostasis?
the arrest of bleeding from the broken blood vessel
the bodies haemostatic mechanisms are normally able to stop loss of blood through small damages capillaries arterioles and venues
what are platelets?
- thrombocytes
- small anucleur cell fragments
- stored in the spleen, released by contraction of the spleen activated by sympathetic nervous system
- short lifespan: 7-10 days
- don’t have a nucleus
what is thrombopoiesis?
platelet synthesis
occurs in red bone marrow
what happens in thrombopoiesis?
1) hematopoeitic stem cells differentiate into committed precursor cells: megakaryoblasts
2) megakaryoblasts develop into megakaryocytes
what does thrombopoitin do?
stimulates megakaryocytes to extend arms (cytoplasmic arms) through bone marrow sinusoids into blood vessels
small fragments break off as platelets
produce about 1011 a day
structure of platelets
exterior coat - rich in glycoproteins
dense tubular system - thromboxane A2 synthesis and release
microfilaments and microtubules - maintains shape
dense body and granules
2 types of dense bodies in platelets
alpha:
• contain clotting mediators including von Willebrand factor, factors V, VIII and fibrinogen
delta:
• contain ADP, Ca++ and serotonin, required for platelet activation and clotting
what is a platelet disorder?
thrombocytopenia - low number of platelets
causes of thrombocytopenia
autoimmune disease
drug induced - inhibition of platelet synthesis, immunological destruction of platelets
symptoms of thrombocytopenia
- easy bruising
- petechial rash
- mucous membrane bleeding
- excessive bleeding after minor trauma
what is petechiae?
pin-point haemorrhages, resulting from blood leaking from intact capillaries due to increases vascular permeability or failure of platelet function
usually occur in clusters
what is thrombotic thrombocytopenic purpura?
platelet disorder
caused by formation of small clots in circulation resulting in low platelet numbers
rare but serious disorder can be: • cognitive defect • autoimmune disease • caused by toxins
what are the 7 stages in haemostasis?
1) vascular spasm - blood flow through the injured vessel decreases
2) platelet plug formation
3) coagulation - intrinsic and extrinsic pathways produce factor Xa
4) coagulation - common pathways produce thrombin
5) coagulation - thrombin converts fibrinogen to fibrin, glues platelet plug together
6) clot retraction
7) thrombolysis - plasmin degrades fibrin and clot dissolves
what happens in vascular spasm?
- smooth muscle layer surrounding cut constricts to slow blood flow to minimise blood loss
- damaged cells and platelets release potent vasoconstrictors such as serotonin and ADP
- as the ends of the endothelial surfaces are pushed together they become sticky and adhere to each other
what happens in platelet plug formation?
1) prostacyclin stops platelets sticking to the cell wall
2) endothelial cells produce von Willeband factor
3) exposed collagen and vWF binds and activates platelets
4) release of platelet factors (ADP, serotonin, thromboxane A2)
5) platelets release granule contents
6) this attracts more platelets
7) these aggregate into platelets plug
what does the platelet plug do?
seals the bark in the vessel lining and performs 3 other functions
• compaction/strengthening
• further vasoconstriction
• stimulation of the clotting cascade
what is prostacyclin important?
inhibits platelet aggregation at the normal vessel singing so that the platelet plug is limited to the defect and doesn’t spread to normal tissue
what is coagulation?
- complex cascade of reactions involving a series of factors
- the process by which liquid blood changes to a solid gel (clot or thrombus)
- formation of the clot on top of the platelet plug strengthens and supports the plug
what does thrombin (factor IIa) do in coagulation?
converts fibrinogen to fibrin monomers by proteolytic cleavage causing stick pends
how do fibrin monomers stick together?
by factor 8a and Ca++
makes a fibrin polymer which forms the clot
overall process of coagulation
1) thrombin converts fibrinogen to fibrin monomers
2) fibrin monomers made into polymer by factor 8a and Ca++
3) this forms the clot
what are the 2 pathways that stimulate thrombin activity?
INTRINSIC
EXTRINSIC
what happens in the intrinsic pathway?
- initial stimulus is collagen exposure
- glass can substitute for collagen - why blood coagulates in a test tube
- all the necessary factors are present in the blood
what happens in the extrinsic pathway?
- initial stimulus is contact between blood and damaged tissue outside of the blood vessel that exposes tissue factor (thromboplastin/factor III)
- initiating factor is on the plasma membrane of cells outside the blood vessel
where else can thrombin act as well as converting fibrinogen to fibrin?
can act directly on factor VIIIa
what happens in blood clotting?
1) tissue exposure initially triggers the extrinsic pathway leading to thrombin production, but the amounts produced are too small for sustained coagulation (initiation phase)
2) thrombin produced by the extrinsic pathway feeds back and activates the intrinsic pathway (amplification phase)
what is hemostasis?
clot retraction
what happens in clot retraction?
- occurs as coagulation cascade nears completion
- actin and myosin fibres in platelets contract bringing edges of wounded vessel closer together
- serum (fluid consisting of plasma without clotting proteins) is forced out of the clot
what processes inhibit coagulation?
- anti-thrombin
- tissue factor pathway inhibitor
- thrombin
- thrombomodulin
- fibrinolysis
how does anti-thrombin inhibit coagulation?
inhibits many clotting factors, especially thrombin
how does the tissue factor pathway inhibitor inhibit coagulation?
binds to the factor III/VIIIa complex preventing it from activating factors IX and X
how does thrombin inhibit coagulation?
it binds to its receptor and stimulates production of prostaglandins (PGI), NO and ADP to inhibit further platelet aggregation
how does thrombomodulin inhibit coagulation?
expressed by endothelial cells and binds thrombin, eliminating its coagulant effects and activating protein C which with protein S inactivates factors Va and VIIIa
how does fibrinolysis inhibit coagulation?
breaks down the fibrin clot
process of fibrinolysis
1) aggregated platelets secrete platelet derived growth factor beta (PDGF-beta)
2) PDGF-beta recruits fibroblasts from surrounding tissue
3) fibroblasts form scar tissue at the site of damage
4) simultaneous with healing - clot is dissolved by a fibrinolytic enzyme called plasmin
how is plasminogen activated?
by tissue plasminogen activators (t-PA) secreted by endothelial cells
plasminogen –> plasmin
plasmin degrades fibrin and clot dissolves
disorders of haemostasis
- haemorrhage
- thrombosis
- platelet disorders
- haemophilia
what is a haemorrhage?
haemostasis can only cope with damage to smaller blood vessels
leads to bruising (contusion)
• black/blue marks of a bruise caused by internal bleeding
• colours are due to degradation of haemoglobin to biliverdin, bilirubin and heamosiderin
• eventually removed by plasmid and phagocytosis
what is a thrombus?
blood clot within a vessel or the heart
what is an embolus?
detached mass able to travel in a vessel
solid, liquid or gas
what is an embolism?
the lodging of an embolus
what is a thrombocytopenia-embolism?
blockage by a thrombus that has travelled
what factors contribute to thrombis?
blood stasis - e.g. DVT
changes in the vessel wall - injury/inflammation
thrombogenic changes in the blood
what are some acquired disorder of haemostasis?
hepatic disease
• lack of fibrinogen and thrombopoetin
vitamin K deficiency
• vit K required for Ca++ binding
drug induced
what are anticoagulants?
medicines that help prevent blood clots
used where theres an increased risk of clot formation
where is there an increased risk of clot formation?
- atrial fibrillation
- aortic valve replacement
- recent surgery that limits motility
- autoimmune disease attacking blood vessel walls
what is warfarin?
- most widely prescribed oral anticoagulant
* inhibits vitamin K
what drugs interfere with warfarin action?
potentiators: aspirin, broad-spectrum antibiotics
inhibitors: barbiturates
what is heparin?
- endothelial cell-derived polysaccharide
- given by injection as not absorbed through the gut
- binds to the inhibitor anti-thrombin III
what are some coagulation disorders?
- von Willebands disease
- haemophilia A
- haemophilia B
von Willeband’s disease
- lack of vWF
- leads to poor platelet aggregation
- associated with excessive gum bleeding
- autosomal dominant
- mild
haemophilia A
- deficiency in factor VIII
* X-linked recessive disorder
haemophilia B
- deficiency in factor IX
- also known as ‘Christmas disease’
- excessive bleeding
