Exam 7 L.5 Flashcards
Secondary hemostasis
1) end result: generation of thrombin which forms a cross-linked fibrin clot
2) consists of: series of enzymatic reactions (coagulation cascade) involving:
- coagulation factors
- calcium
- surface membranes of platelets
Pathways of secondary hemostasis
1) extrinsic: tissue factor and factor VII
2) intrinsic: factors XII, XI, IX, and VIII
3) common: factors X, V, II, I, and XIII
4) culminates in the generation of thrombin:
- cleaves fibrinogen to form fibrin
- fibrin is cross-linked to form the fibrin clot
PTT time
Assesses intrinsic and common pathways
PT time
Assesses extrinsic and common pathways
Common pathway
Fibrinogen is cleaved by thrombin ==> fibrin, which is then cross-linked to form a clot by FXIIIa
Remember
1) Extrinsic pathway starts the intrinsic pathway!
- Extrinsic is initiated via tissue factor (i.e. vascular injury)
2) factor 12 doesn’t do anything to stimulate clotting in the animal, it only stimulates clotting in the test tube*
3) IT’S ALL ABOUT THROMBIN
4) the coagulation cascade is initiated by TISSUE FACTOR
5) the intrinsic pathway amplifies the coagulation cascade
6) the coagulation cascade is propagated by the platelet
Keeping secondary hemostasis in check
1) physiologic:
- extrinsic pathway: tissue factor pathway inhibitor (TF PI)
- intrinsic and common pathway: anti-thrombin, protein C and S (vitamin K -dependent)
2) therapeutic: heparin- acts via anti-thrombin; warfarin-vitamin K antagonist
Note: thrombin is self-limiting, when activated it also starts a negative feedback pathway on itself
Inherited coagulation disorders
1) F VIII deficiency: hemophilia A
- most common CF deficiency
2) F IX deficiency: hemophilia B
3) vitamin K recycling enzymes: Devon Rex cats
Acquired coagulation disorders
1) toxicity: anticoagulant rodenticides (vitamin K antagonism)
2) DIC: inflammation, bacterial sepsis, cancer (clotting factors get used up)
3) liver disease: decreased production of clotting factors
4) drugs
The vitamin K -dependent clotting factors
Clotting factors II, VII, IX, X
-note: anticoagulant rodenticides antagonize vitamin K
Heparin-how does it work?
Heparin binds to anti-thrombin, allowing it to inhibit FII and FX
Coagulation disorders due to disruption of inhibition
1) consumption of inhibitors: sepsis, DIC
2) loss: protein losing disorders (loss of anti-thrombin)
- anti-thrombin is a similar size as albumin (if you are losing or not absorbing albumin, the same is likely happening with anti-thrombin)
3) decreased production: liver disease/failure
remember: any time you lose albumin you likely lose anti-thrombin!
- - Thus, you are predisposed to forming clots!!
How to identify a disorder of secondary hemostasis
1) clinical signs:
- bleeding into body cavities
- large bruises/hematomas
- joint bleeds
- prolonged bleeding after surgery or trauma
2) screening tests
- coagulation assays: PT, PTT
Hemophilia A
1) inherited factor VIII deficiency
2) X-linked (males affected)
3) most common hereditary coagulopathy
Tertiary hemostasis
Fibrinolysis
-goal is to reestablish blood flow through vessels
Fibrinoysis
1) fibrin clot breakdown
2) by plasmin
3) plasmin is activated by tPA
4) endpoint is release of degradation products
- D dimers: from cross-linked fibrin (if present, D dimers mean there were clots)
- fibrin(ogen) degradation products (FDP’s): from soluble fiber or fibrinogen
Fibrinolysis
Injury to endothelial cells activates tPA (tissue plasminogen activator), tPA activates plasminogen to plasmin, and the plasmin then breaks down cross-linked fibrin to D-dimers (and fibrin/fibrinogen to FDPs)
Inhibitors of fibrinolysis
1) physiologic:
- anti-plasmin (inhibits plasmin)
- plasminogen activator inhibitor (inhibits tPA)
2) therapeutic:
- aminocaproic acid, tranexamic acid ==> they both promote clot formation!!!
What happens in DIC?
Excessive activation of hemostasis (likely via tissue factor!! - Too many cells showing tissue factor!**) ==> Too much thrombin ==> excessive clotting (thrombosis)
1) consumes platelets
2) consumes coagulation factor
3) consumes inhibitors
AND
Loss of control/restriction
==== Systemic, uncontrolled thrombin generation ==> thrombosis ==> hemorrhage (end-stage, as all clotting factors are used up)
Diagnosis of diagnosis of DIC
Defects in tests of all pathways of hemostasis
1) primary hemostasis: low platelets
2) secondary hemostasis: coagulation tests prolonged, fibrinogen may be low or normal
3) Fibrinolysis: D dimers or FDP (high)
4) inhibitors: anti-thrombin (low)
Most common inherited coagulation disorders
1) vWD: primary hemostasis
2) hemophilia A: secondary hemostasis
Most common acquired coagulation disorders
1) thrombocytopenia: primary hemostasis
- counts <30,000/uL at risk of spontaneous hemorrhage
2) rodenticide toxicosis (secondary hemostasis)
3) DIC (all hemostatic components)
