Wk 2 Hemostasis & Coagulation Flashcards
What are the 4 main steps in hemostasis?
Vascular injury occurs ->
1. vasoconstriction
2. primary hemostasis = platelet plug formation
3. secondary hemostasis = fibrin formation/polymerization
4. thrombus and antithrombotic events
What happens with primary hemostasis?
- platelet adhesion to vascular injury. Collagen most IMP for this, vWF has role too
- platelet shape change
- granule release, promoted by platelet agonists like ADP, TxA2, which bind to the platelet surface receptors to promote the release
- recruitment of more platelets by granules
- aggregation (hemostatic plug): fibrinogen binds platelet GPIIb/IIIa receptors, connecting adjacent platelets
What are the 3 primary tasks of primary hemostasis?
- platelet adhesion
- platelet activation
- aggregation
Main overall goal = form platelet plug
Main goal of secondary hemostasis
Make fibrin (and deposit it around the platelets in the plug)
-stabilizes the plug
Analogy for primary and secondary homeostasis
platelets = bricks
fibrin = mortar
4 steps in secondary hemostasis
- tissue factor
- phospholipid complex expression
- thrombin activation
- fibrin polymerization
What is the coagulation cascade?
Sequential enzymatic reactions -> formation of fibrin
-process is diff in lab (in vitro) and in body (in vivo)
What are the two pathways for activation of secondary homeostasis in vitro?
- intrinsic
- extrinsic
What components does each step of the coag cascade include?
- enzyme (activated coagulation factor)
- substrate (inactive coag factor - “pro-enzyme”)
- cofactor (helps rxn proceed)
- (-) charged phospholipid surface provided by platelets
- calcium (for steps w/ factors II, VII, IX, X)
What is the first step of the extrinsic pathway of secondary homeostasis?
Tissue injury ->
1. tissue factor (thromboplastin) activates F VII
2. FVII -> FVIIa
How is the extrinsic pathway measured?
By the prothrombin time (PT) = time to fibrin clot formation
A long PT -> consider low FVII
What are the steps of the intrinsic pathway?
Starts w/ contact factors: prekallikrein, high molecular weight kininogen collagen (HMWK collagen) and FXII
Includes F XII, XI, IX, VIII
How is the intrinsic pathway measured?
By partial thromboplastin time (aPTT)
Long aPTT -> consider low intrinsic pathway factors
Time to fibrin clot formation measured and reported as aPTT
What are components of the common pathway?
Starts w/ FX from either intrinsic or extrinsic pathway
Includes F X, V, II (prothrombin) and FI (fibrinogen)
How is blood prepared for testing in the lab for coag factors?
- Pt whole blood sample collected in tube w/ anticoagulant (sodium citrate)
- Tube centrifuged to separate cells (RBC, WBC and platelets) from plasma
*Plasma = liquid portion of blood + coag factors, formed from centrifuged whole blood that did not clot in tube
*serum = liquid portion of blood -coag factors, formed from centrifuged whole blood that clotted in tube if not anticoag was added to tube
WHich sample is used for coag testing?
Plasma is used for PT and aPTT testing - need to have coag factors present to make fibrin from the sample
What is a mixing study?
Can be done w/ aPTT or PT
If pt has long aPTT or PT, mix equal parts of the pt plasma and normal pooled plasma (has 100% of all coag factors) and then perform aPTT or PT on the mixture
2 possible outcomes:
1. corrects & shortens time to clot
2. fails to correct, clot formation still slow -> s/t other then coag factors is limiting clotting time
How is a mixing study interpreted?
- Correction = factor deficiency
- No/partial correction or prolongation w/ incubation = factor inhibitor
*usually, sometimes inhibitors are not directed at one clotting factor and are non-specific
What is a factor inhibitor?
An antibody directed against a clotting factor
In vitro vs in vivo clotting
What does thrombin do to the coag cascade?
Enhances it a several points
What happens during in vivo clotting?
- Initiated most importantly by exposing TF at sites of endothelial damage
- TF activates FVII to FVIIa
- TF/FVIIa complex is the most IMP activator of FIX (FIX->FIXa) in vivo
- Thrombin enhances the cascade through feedback activation in vivo
What are 5 roles of thrombin?
- converts fibrinogen to fibrin
- stabilizes fibrin clot
- activates platelets
- pro-inflammatory
- anticoagulant
What are 3 causes of bleeding disorders?
- vessel problems
- platelet problems (ie ITP)
- clotting factor problems (von Willebrand disease, hemophilia A and B, DIC)
INCOMPLETE
Compare hemophilia A and B
-inherited factor deficiencies tend to affect only one factor
-acquired factors tend to affect multiple factors
How are hemophilia A and B diagnosed?
- Prolonged aPTT
- Normal PT and platelet count
- Diagnostic tests: Factor VIII activity or Factor IX activity
What factors are vitamin K dependent?
II, VII, IX, and X
What factors do hepatocytes make
All except VIII
What factor would help distinguish b/w liver disease and vitamin K deficiency?
Factor V activity b/c it’s not vitamin K dependent
What are 4 bleeding disorders w/ norm APTT and PT?
- von Willebrand Disease (usually) 2. Factor XIII deficiency
- Quantitative platelet disorder
- Thrombocytopenia - Qualitative platelet disorder
–Acquired- Uremia, myeloproliferative neoplasms, antiplatelet drugs, post-cardiopulmonary bypass
–Inherited- Glanzmann thrombasthenia, Bernard- Soulier syndrome, others
How to interpret coag tests in a bleeding patient
Reference range for PT and APTT
The reference range of the aPTT is 30-40 seconds. The reference range of the PTT is 60-70 seconds.
VWF Fxn
- Mediates platelet binding to sites of vascular injury by binding to collagen and the platelet GPIb receptor (acts as a bridge)
- Carrier for coagulation factor VIII
VWF Fxn
- Mediates platelet binding to sites of vascular injury by binding to collagen and the platelet GPIb receptor (acts as a bridge)
- Carrier for coagulation factor VIII
What is the inheritance pattern of vWD?
autosomal dominant (most commonly)
1/100 - 1/10k
vWD classifications
Type 1: Partial quantitative deficiency (most common)
Type 2: Qualitative deficiency
Type 3: Total quantitative deficiency
How is vWD diagnosed?
aPTT often normal
* aPTT may be prolonged if FVIII is low enough (this is less common)
* Normal PT and platelet count
* Diagnostic tests- vWD panel
* vWF antigen (VWF:Ag in table in MCQ)
* vWF activity (ristocetin cofactor activity, VWF:Rco in table in MCQ) * Factor VIII activity- why? - often tightly bound to vWF
What is fibrinolysis?
System regulated by activators and inhibitors to counterregulate hemostasis
The active enzyme plasmin breaks down fibrin clot
* Fibrin degradation products (FDPs), such as D-dimer*, are formed
What is fibrinolysis?
System regulated by activators and inhibitors to counterregulate hemostasis
The active enzyme plasmin breaks down fibrin clot
* Fibrin degradation products (FDPs), such as D-dimer*, are formed
What med induces fibrinolysis?
tPA = tissue plasminogen activator
What are 3 forms of fibrolytic therapy?
Streptokinase, urokinase, tissue plasminogen activator (tPA)
-Convert plasminogen to plasmin to break down fibrin clot
What do protein C and S do?
Protein C requires protein S as a cofactor
-together they inactivate factors Va and VIIIa to turn off coag cascade (along with antithrombin, which turns off thrombin, also IXa and Xa)
What would happen w/ deficiency of protein C? S? Antithrombin?
Unregulated coagulation
How does antithrombin work?
Inactivates thrombin, then F IXa and FXa
What is a thrombus?
Results from inappropriate activation of hemostasis in an uninjured vessel or from thrombotic occlusion of a vessel after minor injury
-thrombi can obstruct vessels or form emboli
What is Virchow’s Triad?
3 risk factors leading to thrombosis:
1. endothelial injury
2. abnorm blood flow
3. hypercoaguability
What are 2 causes of hypercoaguability?
- inherited: factor V Leiden
- acquired: disseminated cancer
What are 2 primary causes of endothelial injury?
- hypercholesterolemia
- inflammation
What are 2 primary causes of abnormal blood flow?
- stasis (a-fib, bed rest)
- turbulence (atherosclerotic vessel narrowing)
What are 3 pathological features of thrombi?
- firm
- focally attached to vessel wall
- have lines of Zahn - striped appearance w/ fibrin (differentiates from postmorten thrombi, which are more gelatinous)
Where are 4 locations thrombi are found?
- venous - where there’s stasis
- arterial - where there’s turbulence or endothelial injury
- cardiac (mural thrombi) - turbulent or abnorm flow
- vegetations - thrombi on heart valves
What are 4 fates of a thrombus?
- propagation - accum more platelets and fibrin
- embolization - parts break off, travel elsewhere
- dissolution - shrinkage due to fibrinolysis (recently formed thrombi)
- organization and recanalization - ingrowth of endothelial cells, smooth muscle cells and fibroblasts w/ capillary channels re-establishing the vascular lumen
What are 2 other forms of emboli besides thromboemboli?
- fat embolism - occurs w/ fracture to long bones. Symptoms: pulmonary insufficiency, neurologic symptoms, anemia, thrombocytopenia, fatal in 5-15%
- air embolism = bubbles of gas in circ due to communcation b/w vasculature and outside air or decompression sickness. Can block perfusions or promote cytokine release -> intense inflammation
- amniotic fluid embolism = amniotic or fetal tissue introduced into maternal circ via placental membrane or uterine vein tear. Symptoms: sudden severe dyspnea, cyanosis, shock, severe neurologic impairment, DIC
* 2 to 6 in 100,000 deliveries but up to 80% mortality rate
What is hypercoagulability?
- AKA thrombophilia
- Blood disorder that predisposes to thrombosis
- Can be either
- Primary (inherited)
- Secondary (acquired)
What are 5 inherited thrombotic disorders?
- Factor V Leiden
- prothrombin mutation (increases FII)
- Protein S def
- Protein C def
- Antithrombin def
*FV and mutation are more common, but less risk
What is Factor V Leiden?
- Autosomal dominant
- point mutation in coagulation factor V
- Mutation makes factor V resistant to cleavage and inactivation by activated protein C
- Activated protein C resistance
- Greater risk for thrombosis in homozygotes (50-fold increase) than heterozygotes (5-fold increase)
Is DIC primary? Why or why not?
NOT a primary disease. Associated w/ diseases that cause release of tissue factor or endothelial injury
* Infections, especially bacterial sepsis * Obstetric complications
* Preeclampsia/eclampsia
* Trauma, burns, tissue necrosis
* Venomous bites
* Malignancies
* Leukemia, others
* Severe immunological reactions
* Hemolytic transfusion reactions, transplant rejection
Must know underlying cause for tx
How is DIC dx?
- elevated D-dimer (a fibrin degradation product)
- decreased fibrinogen
- prolonged PT and APTT
- decreased Hct
- Schistocytes
- decreased platelets
What is a D-dimer?
2 D domains in crosslinked fibrin that plasmin has cleaved from the fibrin
What does D-dimer detection imply?
- Fibrin has formed and polymerized * There is a thrombus
- Factor XIIIa has cross-linked fibrin * There is a stable thrombus
- Plasmin has degraded cross-linked fibrin * Fibrinolysis is occurring
