Regulation of Fibrin Clot Structure and its Role in Thrombosis-Extra Reading Flashcards
Undas, ATVB, 2011
-Clots with compact, highly branched networks and thin fibres are resistant to lysis i.e the type of clot seen with Y’
-Factors able to increase clot permeability and susceptibility to lysis= low dose aspirin, lowering of homocysteine, diabetes control, smoking cessation and suppression of inflammatory response-so all indicate that CVD risk factors may cause changes to clot structure
-Evidence indicates that abnormal fibrin properties is a novel risk factor for arterial and venous thrombosis
-Thin, highly branches fibres=less permeable, more rigid and more resistant to lysis
-thick fibres with large pores are permeable and show accelerated fibrinolysis
GENETIC FACTORS
-heritability of fibrin characteristics is 10-40% (not that much! shows environmental factors must play a large role)
VAL34LEU
- There is evidence to suggest that the protective effects of Val34Leu against MI, DVT, PE, VTE etc only occur in certain situations
- Activation of Leu34 FXIII occurs more rapidly than Val34 FXIII (2.5x quicker) which means that the clots produced have thinner fibres and smaller pores because the clot has been stabilised before there has been time to accumulate thicker networks of protofibrils
- BUT in plasmas with high fibrinogen concentrations, Leu34 FXIII produces clots with thicker fibres, increased permeability and susceptibility to fibrinolysis
- SO:
- at low fibrinogen concentrations Leu34 protects against thromboembolic conditions because dense/stable clots can’t throw off emboli
- but at high fibrinogen concentrations Leu34 confers protection against the likes of MI because the clots are more susceptible to fibrinolysis by Plasmin
-High thrombin concentrations result in thin fibres and small pores because of increased FXIII activity
- Oxidative stress reduces clot formation
- Air pollution studies show reduced clot formation in an oxidative manner
- however, antioxidant therapies have failed to demonstrate any benefit
DIABETES
- T2DM patients show blood clots that are dense and resistant to fibrinolysis
- This is thought to be attributed to FIBRINOGEN GLYCATION which interferes with fibrinogen binding
SMOKING
- Smoking increases thrombosis risk by RAISING fibrinogen levels
- the high fibrinogen levels produces clots that are dense and composed of thinner fibres resistant to lysis
- Thromboelastography of whole blood before and after smoking two cigarettes showed lower lysis efficiency following the smoking
- Smoking >5years showed: 22% lower clot permeability and 35% slower clot lysis
CAD
- 50% of CAD patients have clot permeability below the 10th percentile of control
- denser-than-usual fibrin is a consistent component of atherosclerotic plaques and the presence of this fibrin may promote plaque growth
ISCHAEMIC STROKE
-plasma obtained following ischaemic stroke shows clots with 20% increased density
VTE
- Several studies have demonstrated reduced efficiency of clot lysis in VTE
- there is a 2 fold increase in risk of VTE for those with clot lysis times above the 90th percentile
Bridge, Thrombosis and Haemostasis, 2014
- Dense clots with smaller pores are more resistant to lysis and so present a bigger risk of cardiovascular events
- this means that therapies aimed at normalising clot structure may be of benefit in the prevention of cardiovascular events
- Fibrinogen expression is rapidly upregulated in response to IL-6 and other cytokines-because fibrinogen is an acute phase protein and these cytokines indicate that inflammation is present
- low thrombin concentrations result in fibrin clots with thick, loosely woven fibres because not much fibrinogen is converted to fibrin
- high thrombin concentrations result it thin, tightly compact fibrin clots because lots of fibrinogen is converted to fibrin
- So high thrombin concentrations are responsible for denser clots that are resistant to lysis
- Aspirin affects blood clots because it causes ACETYLATION OF FIBRINOGEN
- this results in a looser fibrin clot structure with larger pores, thicker fibres and less resistance to lysis
- Twin studies have shown a significant heritability of 40-45% for the complex fibrin clot phenotype
- The effects of cardiovascular risk factors on clot structure seem to be additive as patients with CAD and DM show denser, more resistant clots than patients with solo disease
- Aspirin, Statins, LMWH, NOACs and Fondaparinux all show improvements to clot structure with larger pores and decreased resistance to lysis
- However specific therapies aimed at normalising clot structure are still sought
Walton, Thrombosis and Haemostasis, 2015
-Venous thrombosis is the 3rd most common cause of mortality
-Venous thrombi have a high red cell and fibrin content
-VT is initiated by endothelial dysfunction, and inappropriate expression of plasma and cellular procoagulant activity under low blood flow/stasis (VIRCHOW’S TRIAD)
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- FXIII deficient clots seen in vivo and also in FXIII knockout mice show reduced retention of RBCS
- This finding challenges the paradigm that RBCs are simply ‘trapped in the fibrin network’ ; it indicates that the retention of RBCs may be an active process that is mediated by FXIII
- Y’ is affected more by inflammation
- IL-6 causes a much bigger increase in the expression of Y’ than YA
- A reduced Y’ to YA total fibrinogen i.e less Y’ is associated with an increased risk of VT showing that Y’ is protective against VT?
- Y’ is thought to be protective against VT because Y’ reduces plasma thrombin generation through its Y’-carboxyl-terminal peptide which via various cascades reduces sensitivity to Protein C and thus reduces coagulation
- Studies have found that the precise timing at which FXIII is activated is crucial to its effects on clot structure
- FXIII only alters clot morphology marginally i.e fibre and pore size, but it has a PROFOUND effect on clot integrity-it massively increases the elastic modulus of the clot
- Platelets cause retraction of a thrombus which massively compresses RBCs to form Polyhedrocytes
- This compression of RBCs reduces the permeability of clots and restricts access of fibrinolytic agents
- Means that polyhedrocytes could be a potential novel therapeutic target
