Combined Hemostasis Flashcards
Extrinsic pathway
tissue factor pathway
intrinsic pathway
contact activation pathway
extrinsic tenase
7a, TF –> 10 or 9 + anionic phospholipid + Ca
Intrinsic tenase
9a, 8a –> 10 + anionic phospholipid + Ca
Prothrombinase
5a, 8a –> prothrombin + anionic phospholipid + Ca
Protein C complex
thrombin, thrombomodulin –> protein C + anionic phospholipid + Ca
Initiation
1) Tissue injury exposes TF
2) Circulating 7 binds to TF and becomes activated
3) TF/7a complex (extrinsic 10ase) activates 10 or 9
4) 10a binds to 5a (prothrombinase) activates prothrombin
Amplification
1) Thrombin activates 5, 8, 11 while 7a/TF activates 9
2) 9a binds to 8a (intrinsic 10ase) activates 10 to make more thrombin
Propagation
1) Thrombin convert fibrinogen → fibrin which undergoes polymerization
2) Thrombin activates 13
3) 13a crosslinks and strengthens overlapping fibrin strands
Antithrombin
SERPIN; inactivates 7a, 9a, 10a, 11a
Heparin is co-factor
Protein C pathway
1) thrombomodulin induces conformational change in thrombin
2) altered thrombin not able to activate platelets or convert fibrinogen to fibrin but can activate protein C
3) activated protein C with protein S (cofactor) inactivates 5a and 8a
TFPI
single chain polypeptide reversibly inhibit 10a and 7a-TF complex
Fibrinolysis
1) plasminogen (proenzyme) activated by conversion to plasmin by either
a. t-PA secreted from vascular endothelial cells
b. u-PA secreted from many cells
2) Plasmin cleaves fibrin at multiple sites releasing fibrin degradation products (D-dimer) → 2 D domains from adjacent fibrin monomers
1) PAI-1
inactivates t-PA and u-PA
2) Alpha 2 antiplasmin
inactivates plasmin
3) TAFI
acts on fibrin by cleaving terminal residues reducing binding sites for plasminogen
Heparin and LMWK
activate antithrombin → inhib 10a and thrombin
tPa and streptokinase
activate plasmin → break up fibrin
Warfarin
vitamin K reductase inhibitor → cannot recycle vitamin K → inhib 2, 7, 9, 10, S, C
Hemostasis
forms thrombus (clot) to repair vessel injury
Primary hemostasis-
FORMATION OF WEAK PLATELET PLUG Adhesion Activation Aggregation Forms a platelet plug
Steps in Primary hemostasis #1: Vessel wall injury
1) Vessel wall injury- exposes subendothelium + collagen
2) Transient vasoconstriction of vessels, decr blood supply
Steps in Primary hemostasis #2: Platelet adhesion
3) vWF binds subendothelial collagen
4) Platelet bind vWF using Gp1b receptor
5) vWF derived from Weibel Palade bodies of endothelial cells and alpha granules
Steps in Primary hemostasis #3: Platelet Activation
6) Adhesion induces shape change in platelets
7) Degranulation releases ADP (dense grnaules to expose Gp2b/3a receptor) and TXA2 for platelet AGGREGATION
Steps in Primary hemostasis #4: PLATELET Aggregation
8) Platelets aggregate at site of injury via Gp2b/3a using fibrinogen as linking molecule → forms platelet plug
Secondary hemostasis
Fibrin is crosslinked yielding a stable fibrin-thrombus
What is required to activate zymogens?
Requires phospholipid surface (SURFACE OF PLATELETS) and calcium
PT
measures extrinsic + common pathway (LESS #s)
better for measuring effect of Warfarin
PTT
measures intrinsic + common pathway (MORE #S)
better for measuring effect of Hep
What activates factor 12
lupus anticoagulant:
How to test for it?
subendothelial collagen
What activates factor 7
tissue thromboplastin
Hemophilia A
Factor 8 deficiency
X linked recessive; mostly affects males
Incr PTT; normal PT;
decr Factor 8;
normal platelet count
Hemophilia B; Christmas disease
Factor 9 deficiency
Coagulation factor inhibitor
Acquired antibody against coag factor → so can’t be involved in coag cascade
Explain how a 1:1 mixing study can distinguish a clotting factor deficiency from an inhibitor of coagulation.
• A 1:1 mixing study of normal plasma with patients plasma can indicate if disease is due to a clotting factor deficiency or from an inhibitor of coagulation.
○ If PTT is not corrected after two hours of incubation–> disease is due to inhibitor.
○ If PTT corrects, clotting factor deficiency.
lupus anticoagulant:
How to test for it?
Q
• Detect by:
- greatly prolonged PTT,
- no bleeding tendency,
- can have thrombotic syndromes (DVT, PE, thrombotic strokes, or recurrent miscarriages).
(more likely to clot, but slower to clot)
vWF Disease
most common inherited coagulation disorder
Increased bleeding time (poor platelet adhesion so can’t seal off blood vessel quickly); incr PTT (because can’t stabilize factor 8 so simil to hemophilia A); normal PT
Abnormal ristocetin- Ristocetin normally causes platelets to aggregate
treatment of vWF
DDAVP
Increases vWF release from Weibel-Palade bodies of endothelial cells
Vitamin K purpose in coag cascade
gut → liver → activated by epoxide reductase → gamma carboxylate 2, 7, 9, 10, C, S
Liver failure
Decreased production of coat factors
Decreased activation of vit K by epoxide reductase
Test using PT
DIC
Widespread microthrombi result in ischemia and infarction
Consumption of platelets and factors
Lab tests for DIC
Decr platelet count
Incr PT/PTT (b/c forming thrombi)
Decr fibrinogen (using up linker proteins btwn platelets)
Microangiopathic hemolytic anemia (RBC sheared as cross frags of platelets → forming schistocytes)
Elev fibrin split products (D-dimer)
Crosslinked with fibrinogen → when get cut in blood vessel → lyse crosslinked fibrin = D-dimer
Fxn of plasmin
(1) cleaves cross-linked fibrin and serum fibrinogen (prevent future thrombus production)
(2) destroys coag factors to shut down formation of thrombus
(3) blocks platelet aggregation
Purpose of fibrinolysis
Fibrinolysis = after form thrombus, must remove thrombus to heal wound site
