homeostasis and clotting - Atchley Flashcards
homeostasis
vessel spasm –> platelet plug (anchor is vWF**) –> blood coagulation (intrinsic/extrinsic) –> clot retraction –> clot dissolution
vWF**
-tethers the platelets to exposed collagen
secretory granules in platelets
- ADP –> promotes GP2b/3a to be expressed on the surface
- TXA2 –> from arachidonic acid cascade (aspirin irreversibly inactivates COX –> no TXA2)**
- both ADP and TXA2 activate platelets making them sticky and recruit aggregation of other platelets
vascular spasms
- takes <1 min
- triggered by trauma, slows platelets down so they can bind
- vasoconstriction through sympathetic nervous system
platelet plug formation
-vWF attaches to exposed collagen allowing platelets to bind through GP1b**
vWF**
- for platelet aggregation and protect of factor 8**
- need to monitor vWF in Hemophilia A with factor 8 deficiency**
how do platelets cross link?
- through fibrinogen by binding to GP2b/3a** complexes
- ADP and TXA2 increase expression of GP2b/3a** –> targets for anti-platelet drugs
secondary hemostasis
- blood coagulation due to fibrin mesh surrounding platelet plug (thrombus)
- coagulation factors made in liver
- intrinsic (contact factor path) –> activated by sub endothelial collagen** –> activate factor 12**
- extrinsic (tissue factor path) –> activated by release of tissue factor (aka tissue thromboplastin)** –> activated factor 7**
other factors
- factor 4 –> Ca2+ (non protein, chelatable)
- factor 3 –> tissue factor –> starts extrinsic path when cell explodes and activates factor 7**
- factor 13 –> strengthening factor** (cross links fibrin)
vitamin K dependent factors**
- factor 2,7,9,10** (factor 7 is very sensitive)**
- protein C and protein S (natural anticoagulants)**
- protein C more sensitive to vit. K than factor 7**
vit. K required for the synthesis/carboxylation of these factors in liver –> no factors with liver failure
common pathway
- factor 10 down
- converts to thrombin –> takes fibrinogen (soluble) to fibrin (insoluble)
Ca2+ role in coagulation path
- everywhere
- removed to prevent activation in order to test pathways** (reversible)
clot retraction (after 20-60 min)
-squeezes serum from clot and joins separated vessel walls
clot dissolution (fibrinolysis)
- hep reestablish blood flow
- tPA –> converts plasminogen to plasmin to break clots**
- plasmin digest fibrin and certain clotting factors**
lab tests to measure coagulation***
- fibrin split products (D-dimer)
2. fibrin degradation products (FDP)
factors preventing clot formation
1. from healthy endothelial cells: Prostacyclin & nitric oxide: Platelet plug inhibitors Heparan sulfate: Activates antithrombin Thrombomodulin: binds to thrombin Tissue factor pathway inhibitor
- circulating anticoagulants
- antithrombin (enhanced by heparin) neutralized thrombin and inhibits factor 10a**
- protein C (enhanced by protein S) inactivates factors 5a and 8a***
- plasmin degrades fibrin
what is most effect in vit. K deficiency?**
- factor 7 and protein C** (sensitive and have short half-lives)
- extrinsic path more prone to damage if Vit. K deficient**
which path is most sensitive to warfarin/coumadin?**
-extrinsic pathway**
PT (prothrombin time) and PTT (partial thromboplastin time)**
- PT –> measures the extrinsic pathway** (better test for Coumadin)**
- PTT –> measures the intrinsic pathway** (better test for Heparin)**
- measured in seconds needed to form clots
INR
- system for standardizing PT
- used to monitor warfarin/coumadin therapy
- DVT (2-3)
- mechanical heart valve (2.5-3.5)
coagulation disorders - impaired synthesis of coagulation factors
- liver disease: no fibrinogen, prothrombin, or coagulation factors
- vit. K (produced by gut bacteria) deficiency
von willebrand disease (vWF)**
- # 1 genetic coagulation disorder disease
- mild cutaneous, mucosal bleeds**
hemophilia A
- most common SEVERE bleeding disorder**
- serious deep joint/muscle bleeds**
- X-linked in factor 8 deficiency**
- mom will be a carrier (mostly in boys)
- test with PTT**
hemophilia B
- 2nd most common SEVERE bleeding disorder
- serious deep joint/muscle bleeds**
- X-linked in factor 9 deficiency** (Christmas factor)
- mom will be a carrier (mostly in boys)
- test with PTT**
disseminated intravascular coagulation (DIC)
- systemic coagulation and bleeding disorder**
- uncontrolled activation of coagulation cascade –> uses up all the factors/platelets –> sever hemorrhage and organ failure
- PT/PTT are increased due to factor consumption
- low platelets and fibrinogen (used up)
coagulation factors normal in TTP*** (don’t mess with coagulation cascade)
TXA2
-formation prevented by low dose aspirin** due to irreversible inhibition of COX
low dose aspirin**
- targets COX enzyme –> inhibits TXA2 formation –> no platelet aggregation**
- reduces inflammation, fever, pain
- stop 2-3 days before surgery so platelets can build up
endothelial cells can replace TXA2 (have their own COX), but platelets can’t bc they don’t have a nucleus
COX pathway
- form TXA2 (thrombotic) and PGI2 (antithrombotic)
- also form PGD2,E2,F2
- PGE2 is fever modulator**
phospholipase A2/PLA2
inhibited by steroids - blocks everything downstream
LOX pathway
-important for asthma**
heparin***
- activates antithrombin (factor 2a)**
- inhibits factor 10a just as much/if not more than factor 2a**
- also inhibits factors 12,11,10,9,2
- monitor with PTT**
- infused
warfarin/coumadin
- depletes vitamin K by depleting epoxide reductase, which recycles vit. K after it carboxylates factors 2,7,9,10
- inhibits synthesis of vit. K dependent factors
- monitor with PT/INR**
- inhibits vit. K absorption in GI
- taken orally
