Hemostasis II Flashcards
Thrombin activity is determined by __ and __
activation and inactivation
Name the Inhibitors of the coagulation cascade in each color
R: B, Serpins
G: A, non Serpins
B: C, TM- protein C system
What is the inhibitor type of A, non-serpins?
Kunitz-type inhibitor:
Describe structure of A, non-serpins inhibitor?
red: AAs which fit into the active site of the protease
Enzyme-Inhibitor Complex: reversible, Key-lock-model-
No conformational change
An example of non-serpins inhibitor?
TFPI is such an inhibitor
The role of Tissue Factor Pathway Inhibitor (TFPI)
1/ Inhibits the initiation of the cascade
2/ The only inhibitor which can also inhibit membrane-bound proteases
Kunitz-type Inhibitor, released from __ and ___
endothelial cells and platelets
Kunitz-type Inhibitor is reversible
-> There are ionic interactions between __ and __
the Kunitz-Domains (K) and the proteases
Kunitz-type Inhibitor
-> The role of Protein-S-binding
Protein S-binding enhances FXa-binding, which enhances FVIIa-binding, and both FXa and FVIIa will be inactivated in the TF/FVIIa/FXa-Complex
Does Kunitz-type Inhibitor have a high or low affinity?
HIGH
Kunitz-type Inhibitor is present in low or high concentration?
LOW CONCENTRATION
A, non-Serpins, No2: a2-Macroglobulin stericly hinders protease activity
-> Structural features?
-inhibits thrombin, plasmin, kallikrein
What are Serpins?
Serine-protease-Inhibitors
The role of Serpins
regulate many Ser-Proteases, and thereby many processes: Hemostasis, digestion, complement system- inflammation, ECM remodelling in embryonal development, cancer metastasis, tissue repair, apoptosis
Serpins cause reversible or irreversible inhibition.
-> Why?
Irreversible inhibition: enzyme cleaves the inhibitor, just like a substrate, but the hydrolysis of the acyl-enzyme intermediate is rather slow (weeks…)- irreversible
The role of Serpins in hemostasis:
Antithrombin – Thrombin, (FXa, (FIXa)) – target of heparin therapy Heparin cofactor II – Thrombin
a1-Protease Inhibitor – Trypsin, elastase, thrombin
3 steps of The TM-protein C-pathway
1, thrombomodulin (TM) on the surface of healthy endothelial cells
2, Thrombin binds to TM-via exosite I – specificity of thrombin changes: cleaves Protein C to activated Protein C (APC), instead of the other substrates
3, APC inactivates Va and VIIIa to Vi and VIIIi
What is the most important endogenous anticoagulant mechanism?
Membrane-bound enzyme complexes in hemostasis
-> The TM-protein C-pathway
Symtomps of Deep venous thrombosis/DVT
Most frequently in the legs,
-swelling, blocked venous blood flow
-lung emboli
– severe complication multifactorial
-Virchow-Triad
What is Virchow-Triad?
1, enhanced blood clottability,
2, disturbed blood flow,
3, endothelial cell damage
Anticoagulants applied in DVT
-> What are Anticoagulants for indirect inhibition?
Heparins: UFH, LMWH, fondaparinux
Vitamin K-antagonists (VKA):
Anticoagulants applied in DVT
-> What are Anticoagulants for Direct inhibition?
- Hirudin et al: block the active site of thrombin
- DOAC/(NOAC): direct/(novel) oral anticoagulants
Anticoagulants applied in DVT
-> What is the role of Heparins: UFH, LMWH, fondaparinux?
Work with Antithrombin together, accelerate the inactivation of thrombin by antithrombin
Anticoagulants applied in DVT
-> What is the role of Vitamin K-antagonists (VKA)?
Inhibit the formation of Gla-domains, and thereby the assembly of membrane- bound activation complexes – slower thrombin generation
