BIOLOGY 2F03 Lecture Notes - Lecture 18: Adamts13, Plasmapheresis, Hemostasis
19 May 2018
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The ADAMTS13-vWF specificity is achieved in 3 ways
• vWF MUST unravel before it can be cleaved
• there are multiple sites of interaction in order to get ADAMTS13 & vWF to fit together properly
• vWF must fit into the active site cleft or it will not by hydrolysed by glutamic acid
1. Aberrant vWF proteolysis correlates to diseases of coagulation
Excessive vWF proteolysis is implicated in Type2a (group II) vWD
• A2 domain mutations = easy unfolding = increased cleavage by ADAMTS13
• The phenotype relates to easy haemorrhage
Impaired vWF proteolysis results in TTP; thrombotic thrombocytopenic prupura
• Rare disease characterised by microthrombi which are rich in platelet and UL-vWF (little fibrin)
o High circulating unstable Ul-vWF → more spontaneous unravelling → inappropriate
primary haemostasis (thrombotic)
o Platelets are used up (thrombocytopenic)
o MAHA occurs because red cells get damaged against micro0thrombi/ occluded
vasculature
• Disease process is seen when ADAMTS13 activity drops to <5-10% of normal
• Congenital TTP:
o Most mutations impair secretion
o Heterozygotes tend to be asymptomatic
• Acquired TTP
o Usually due to IgG antibodies produced against the spacer domain, in particular the
sequence which allows vWF A2 binding
• Untreated = mortality >90%. Principle of treatment lies with plasma exchange every 2-3 weeks
to give a source of ADAMTS13 and remove the auto-antibodies in acquired disease
1.16 - PATHOPHYSIOLOGY OF vWD
1. Diagnosing vWD requires a number of laboratory tests assessing vWF quantity & function
There are a number of problems when it comes to assessing vWF - it is difficult to say what is normal
• It has multiple binding interactions and hence multiple functions; one or many of which may be
lost
• It has a multimeric structure
• There are different pools of human vWF (plasma, WPB, subendothelium, platelets)
• The ABO blood group plays an influence on circulating vWF concentration. In addition vWF
levels increase with age
• Stress induces vWF release from stored WPB
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Document Summary
Excessive vwf proteolysis is implicated in type2a (group ii) vwd: a2 domain mutations = easy unfolding = increased cleavage by adamts13, the phenotype relates to easy haemorrhage. Principle of treatment lies with plasma exchange every 2-3 weeks to give a source of adamts13 and remove the auto-antibodies in acquired disease. 1. 16 - pathophysiology of vwd: diagnosing vwd requires a number of laboratory tests assessing vwf quantity & function. There are a number of problems when it comes to assessing vwf - it is difficult to say what is normal. It has multiple binding interactions and hence multiple functions; one or many of which may be lost. It has a multimeric structure: there are different pools of human vwf (plasma, wpb, subendothelium, platelets, the abo blood group plays an influence on circulating vwf concentration. In addition vwf levels increase with age: stress induces vwf release from stored wpb.
