BIOLOGY 2F03 Lecture Notes - Lecture 10: Fibrinolysis, Bradykinin, Thrombin
19 May 2018
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HMWK is a source of bradykinin and may be anti-thrombotic
• HMWK binds to -ve surface with the help of Zn via their D5 domains. When doing so it displaces
fibrinogen
• HMWK can cleave PK & F11 via its D6 domains
• When bradykinin is released, HMWK binds to surfaces more tightly and prevents other
cells/molecules from doing so
• Apart from releasing bradykinin, HMWK inhibits neutrophil adhesion, enhances fibrinolysis
• Kininogens tend to have a number of antithrombotic domains and can achieve this function by:
o Preventing thrombin binding to and activating platelets
o Inhibiting calpain, which is a molecule released by thrombin
o Inhibiting cleavage of PAR1 by thrombin
• HMWK is upregulated in pregnancy/ HRT
1. The CAS has a number of biological functions but it is unclear how far its role in coagulation is in
humans
a) Bradykinin formation
a. Inmportant for vasodilation, platelet inhibition, inhibition of SMC proliferation, pain.
(?excessive CAS → shock)
b. Promotion of tPA release from endothelial cells (fibrinolysis)
b) Complement activation
a. Pro-inflammatory
b. C1 esterase deficiency = excessive complement activation = heridtary angioedema
c) Thrombin inhibition by HMWK
d) Fibrinolysis
a. Cleavage of plasminogen by F12a and K
e) Anti-adhesive
a. HMWK inhibits protein/cell binding
f) Angiogenesis
a. HMWK & F12 bind to the uPA receptor on endothelial cells
g) ?coagulation
a. F12, HMWK & PK deficiencies both increase APTT but are not associated with bleeding
b. F12 deficient mice taken longer to form clots but this is not seen in humans. (This could
be because humans lack the PAR3 receptor which 12a otherwise activates)
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Document Summary
Hmwk is a source of bradykinin and may be anti-thrombotic: hmwk binds to -ve surface with the help of zn via their d5 domains. Inhibiting calpain, which is a molecule released by thrombin. Inhibiting cleavage of par1 by thrombin: hmwk is upregulated in pregnancy/ hrt, the cas has a number of biological functions but it is unclear how far its role in coagulation is in humans, bradykinin formation. F8 physiology: synthesised in hepatocytes and in some groups of endothelial cells. Like f8, thrombin activates f5 by cleaving the b domain. Low levels = haemophilia a: ca(cid:374) (cid:271)e (cid:858)(cid:373)i(cid:373)i(cid:272)ked(cid:859) (cid:271)y type 3 (cid:448)wd, high levels are associated with increased risk thrombosis. Lo(cid:449) le(cid:448)els = (cid:858)parahae(cid:373)ophilia(cid:859) (cid:894)rare(cid:895: high levels are not associated with increased risk of thrombosis, fv leiden = apc resistance = pro-thrombotic. Thrombin cleavage of b domain heterotrimer thrombin cleavage heterodimer.
