9. Hemostasis (Physiology and Lab Tests)

Question 1

hemostasis definition

Answer 1

processes that stop blood flow after injury

Question 2

define: thrombus, coagulopathy, hypercoaguability (thrombophilia)

Answer 2

• thrombosis: presence of a blood clot in a BV (thrombus vs embolus)
  ○ Thrombus is formed when clotting is activated
  ○ Embolus is a thrombus that has broken free and carried towards brain thanks to bloodstream
  
  • Coagulopathy: condition re: impaired blood clotting

Hypercoaguability (thrombophilia): increased clot tendency

Question 3

hemostasis (general)

Answer 3

• Damaged BVs (arteries) constrict and form activated surfaces which bind platelets and stimulate plasma coagulation
  ○ Slow bloodflow and decrease pressure
• Platelets adhere, release procoagulant materials, aggregate
  ○ Substrates for platelet adhesion include collagen and vWF (impt for high shear rates of arteries)
  ○ Aggregate following sufficient [1+ of thrombin, ADP and/or collagen]
• Plasma coag leads to activation of thrombin
  ○ Cleaves peptides from fibrinogen to allow it to polymerize spontaneously into fibrin by noncovalent bonding
  ○ Formation of covalent crosslinks catalyzed by factor XIIIa
  § 10 grams of fibrinogen and 10 mL of platelets in blood re: normal circumstances
  § People with 1/2 ^ clot normally under most circumstances
• Clot Limitation and Fibrinolysis (tertiary hemostasis)
  
  • Downstream BV express molecs to deactivate activated proteins to limit clot size
  • Proteins dissolve clot around the edges

Question 4

substrates for platelet adhesion

Answer 4

collagen, Von Willebrand Factor (arteries w/high shear rates)

Question 5

platelet lab tests

Answer 5

§ CBC : # of platelets
§ Peripheral smear (look for abnormalities, or to safeguard vs machine counting clotted platelets wrong)
§ Platelet aggregation studies
□ Add agonists to cause platelet activation and measure light transmission
® Less light passes through a gel than the liquid

Question 6

von willebrand testing

Answer 6

§ Von Willebrand antigen level
§ vW activity (ristocetin cofactor activity)
□ Causes platelets to aggregate and good measure of platelet action
§ Factor VIII level (because protected by vWF)
§ Multimer assay
□ Normal patients have lots of different size vW proteins
□ Type 1 vW disease
® Same pattern as normal patient, but not as much protein
□ Type 2A vW disease
® Only high molec wt proteins inactive and these are most involved in clotting
◊ Bleeding probs for pts

Question 7

intrinsic vs extrinsic pathway

Answer 7

intrinsic activated by contact w/surface (like test tube), extrinsice active by tissue damage (shorter, starts with TF:VII)
share common pathway at TF:X to cleave prothrombin into thrombin (activates factor XIII [which helps fibrin form a stable clot] and fibrinogen to fibrin)

Question 8

what is the amplification step of the coagulation cascade?

Answer 8

thrombin activates TF:XI (intrinsic pathway)

Question 9

coagulation cascade proteins - need to know facts

Answer 9

§ Most are enzymes (serine proteases), synth as inactive zymogens
§ Almost all made in liver
§ Factor VII (a/w hemophilia) made in endothelial cells
§ 4 proteins are Vit-K dependent: II, VII, IX, X

Question 10

what proteins does thrombin activate in the coagulation cascade?

Answer 10

TFs: V, VII, XI, XIII (cross-links fibrin and stabilizes clot)
platelets
fibrinogen to fibrin

Question 11

thrombin, the inhibitor

Answer 11

Binds to protein thrombomodulin (modulates thrombin) and protein C
Protein S is a cofactor
Thus inhibits cascade (inactivates V and VIII)

Question 12

thrombin and fibrinolysis

Answer 12

§ Thrombin causes release of plasminogen activator inhibitors (PAI)
□ Inhibit tissue plasminogen activator (tPA) and urokinase
□ Thus fibrinolysis

Question 13

antithrombin

Answer 13

antithrombin III is older name
○ Inhibits all serine proteases (Xa, Xia, Ixa, XIIa, VIIa) and esp thrombin
§ Mediates effects of heparin
□ Heparin has little effect on its own, but it binds to antithrombin and makes it much more potent!
® So pts with antithrombin deficiency you have to tx w/anticoagulant other than heparin

Question 14

TFPI

Answer 14

(tissue factor pathway inhibitor)

○ Inhibits Xa and VIIa

Question 15

PT and PTT

Answer 15

• Results reported in seconds
  
  • Protime
    ○ ~12 secs
    ○ Abnormal w/ defect in factor VII
    ○ Extrinsic pathway
  • Prothrombin time
    ○ ~30 secs
    ○ Abnormal w/ defect in factor VIII, IX, XI, or XII
    ○ Intrinsic pathway
  • Abnormal PT & PTT
    ○ Defect in factor II, V, X, or fibrinogen
  • INR = standardizes the PT testing
    ○ Normal ~1
  • 50% level of coagulation factor gives a normal result

Question 16

mixing study

Answer 16

• Patient’s blood + normal blood (50% each), combine
  ○ If patient is TF deficient, new sample will be corrected with normal PT/PTT (because only need 50% for normal studies)
  ○ If patient has inhibited/prob with factor, new sample will be not corrected
  § Pt has inhibitor to TF

Question 17

TEG

Answer 17

• Mechanical test of clotting strength development
  
  • Provides good assessment of ability of platelets to pull the fibrin clot into a tight mesh and of its subsequent desolution
    ○ More tension or of liquid with more clot!
    ○ Hemophlilia
    § Thrombin generation is delayed and slow
    ○ Thrombocytopenia
    § Not enough platelets to pull the fibrin mess tight
    ○ Fibrinolysis
    § Clot laid down then dissolved
    ○ Hypercoagulation
    § Rapid and overactive coag.