27. Homeostasis and Inherited Bleeding Disorders Flashcards
Define haemostasis.
What happens in primary haemostasis?
Bleeding through leision/defect in vascular wall.
Platelets adhere to the margins of the lesion and aggregate, forming a primary platelet plug. NB: only slows flow; 20 haemostasis stops it.
Describe platelets.
How long do they live, and what happens after they have exceeded this time?
Non-nucleated cytoplasmic fragments derived from bone marrow megakaryocytes. 1-4 um diameter, adequate numbers required for normal haemostasis.
Live 8-14 days, removed from circulation by the reticuloendothelial system
Label A-C of this platelet.
A: lipid bilayer cell membrane, and glycoprotein receptors
B: dense body
C: alpha granule
Describe the 2 features of a platelet cell membrane
1. Glycoprotein molecules: receptors for agonists, adhesive proteins, coagulation factors, other plateets, most abundant: GpIIb/IIIa heterodimer complex, GpIb
2. Phospholipid: associated with prostaglandin synthesis, calcium mobilisation, localisation of coagulant activity to platelet surface
Describe platelet specific granules.
Describe alpha granules.
Dense osmophilic granules (dense bodies, delta-granules), contain neucleotides (ADP)
Series of different proteins, carry lots of things e.g. VWF, platelet factor 4, factor V, fibrinogen, fibronectin, platelet derived gowth factor, tissue plasminogen activator inhibitor-1
What is the role of Von Willebrand factor?
Multidomain protein found freefloating in blood, and in platelets.
Primary function is binding to other proteins, esp. factor VIII. It binds to collagen that’s exposed on endothelial cells due to damage occuring in the BV (endothelium also releases vWF which forms additional links between platelets glycoprotein Ib/IX/V and the collagen fibrils via vWF binding to platelet gplb when it forms a complex with gpIX and gpV, and to other platelet receptors when activated by e.g. thrombin.
Describe primary haemostasis.
Vessel wall injury -> subendothelial matrix exposed -> platelets escape - contact with and adhere to collagen and subendothelial bound vWF via GpIb.
GP IIb/IIIa exposed via vWF binding -> forms second binding site for vWF -> fibrinogen bound to promote platelet aggregation
= localised crosslinking of platelets and vWF! (vWF unfurls and crosslinks beween platelets)
Describe 2 serious inherited platelet disorders.
Serious: both autosomal recessive and rare. severe bleeding disorder risk
- Lack GpIb - Bernard Soulier Syndrome
- Lack GpIIb/IIIa - Glanzmann’s
Likely to need platelets or Novoseven to boost 20 haemostasis
NB: Less Serious: weak against response defects, storage pool disorders
What is von Willebrand disease?
What are the 3 types?
How is it treated?
Autosomal inheritance, males and females, deficient or defective vWF.
Type 1: mild - moderate deficiency
Type 2: protein present but defective
Type 3: Total absent protein
Treat mild with DDAVP (boosts supply of vWF), tranexamic acid, vWF containing concentrate
What is tissue factor?
Present on subendothelial tissue and expressed by cells which are normally not exposed to flowing blood, but are by injuries. Needed for coagulation initiation via factor VII
Describe secondary haemostasis
(requires phospholipid membrane surface)
TF activates coagulation factors in the blood at injuy site -> coag factors adhere to platelet surfaces and form catalytic complexes -> CC cause thrombin formation -> thrombin converts fibrinogen to fibrin -> fibrin polmers form long chains between platelets and platelet plug, are crosslinked and form stable clot.
What are the 3 tests used to test clotting?
APTT (measure activity from XII -> VIII)
PT (measures prothrombin)
TT (thrombin time, measures fibrinogen)
What happens in initial activation after injury?
And following that?
12a and TF activate 10 -> 10a and 5a converts to prothrombin -> thrombin, which can then convert fibrinogen -> fibrin.
Then needs to be amplified to stop the bleeding: thrombin activates 11, 9 and 8 and these create more fibrin to strengthen the clot but e.g. activating 10
Thrombin activates ‘breaks’ in system - inactivates 7 to slow the process.
What is disseminated intravascular coagulopathy (DIC)?
If lots of endothelial damage, may have lots of TFs released - can run into consumption tissue/form clots in small BVs = damaged clotting parameters
What stage of the clotting process does haemophilia A affect?
At point of amplification step, thrombin made to speed up = but no 8 to activate 10, so small amount of 10a and small amount of thrombin = primary working but not secondary.
What is the fibrinolytic pathway?
Tissue plasminogen activator (tPA) converts plasminogen -> plasmin which causes fibrin degradation into products - soluble
