Hemostasis

Question 1

Stages of hemostasis

Answer 1

1. vascular spasm/vasoconstriction 2. platelet plug formation/1° hemostasis
2. blood coagulation/2° homeostasis 5. disolution of fibrin clot/3° homeostasis

Question 2

Vascular spasm

Answer 2

• trauma to vessel wall results in smooth muscle contraction caused by:
• local myogenic spasm
• endothelin and serotonin released from vessel wall
• nervous reflexes

-transient effect

Question 3

Platelet adhesion (general)

Answer 3

• first step in plug formation
• normally prevented by negative charges on platelets and endothelial cells
• mediated by platelet receipts glycoprotein Ib/Ia
• receptors bind to components of exposed subendothelial matrix (basement membrane) eg: collagen, vWF
• platelets change shape and release granule contents (ADP, Ca2+) that activate other platelets
• binding of ADP to recepor facilitates release of Ca2+ adn decreases cAMP
• increased intracellular Ca2+ activates PLA2 nd leads to TXA2 release

Question 4

Platelet adesion steps

Answer 4

1. Plately GpIa binds collagen-development of pseudopods promote platelet-platelet interactions
2. vWF bind GpIb
3. binding exposed GPIIb/IIa for binding of fibrinogen

Question 5

von Willebran factor

Answer 5

• bridge between GpIb and collagen fibbers
• complexes with factor VIII
• defect associated with platelet plug formation defect (1° homeostasis) and coagulation devect (low factor VIII, 2)

Question 6

Platlet Aggregation

Answer 6

• mediated by fibrinogen
• binds to GpIIb/IIIa on adjacent platlets
• GpIIb/IIIa defect: thrombastenia of Glanzman and Naegeli

Question 7

Lab tests for platelet plug formation

Answer 7

• bleeding time up–>defect leads to this
• vWF down
• platelet # down
• GpIb down
• GpIIb/IIIa down

Question 8

Extrinsic Clotting Pathway

Answer 8

1e. Tissue injury—>release tissue factor (factor III)
2e. Tissue factor III: Factor ViII—>VIIa
3e. Factors III & VIIa & Ca2+ (IV): X—>Xa

Question 9

Intrinsic Pathway

Answer 9

1i. Rough endothelial surface and exposure of collagen: XII–>XIIa
2i. XIIa: XI—>XIa; (also activates kallikrein for what its worth)
3i. XIa: IX—>IXa
4i. Thrombin (IIa): VIII—>VIIIa
5i. IXa, VIIIa, platelet phospholipids and Ca2+: X–>Xa

Question 10

Common Pathway

Answer 10

1c. Thrombin (IIa): V–>Va
2c. Xa and Va and Ca2 form prothrombinase complex
3c. Prothrombinase complex: II–>IIa (prothrombin to thrombin)
4c. Thrombin (Ca2+): Fibrinogen (I)—>Fibrin (Ia) (soft clot as monomers aggregate linked by H-bonds)
5c. Thrombin (Ca2+): XIII—->XIIIa
6c. XIIIa: Crosslinks fibrin monomners (hard clot)

Question 11

XIIIa

Answer 11

• crosslinks fibrin to form hard clot

- highly specific transglutaminase

Question 12

Actions of thrombin

Answer 12

• Convert fibrinogen to fibrin
• Activate XIII to XIIIa which crosslinks fibrin
• Activation of factor V
• Activation of factor VIII

Question 13

Extrinic pathway uses;

Answer 13

III, VII (injury)

Question 14

Intrinsic pathway uses:

Answer 14

XII, XI, IX, VII (pathological processeses like atherosclerosis)

Question 15

Components of prothrombinase comples

Answer 15

Xa, Va, Phospholipid, Ca2+

Question 16

Components reqiring phospholipids

Answer 16

prothombinase complex, intrinsic tenase complex

Question 17

Test for extrinsic coagulation pathway defect:

Answer 17

• Increased prothrombin time (INR) (PT) (also in common pathway))
• sensitive indicator of vitamin K deficiency (Factor VII very senstive to this)

Question 18

Test for intrinsic coagulation pathway defect:

Answer 18

Increased APTT (partial thromboblastin time)

Question 19

γ-Carboxylase

Answer 19

• performs vitamin K depended carboxylation of Prothrombin (Factor II), VII, IX, X, and Proteins C, S, and Z
• form mature clotting factors capable of activation, contain γ-carboxyglutamate
• γ-carboxylation facilitates Ca2+ binding by introducing 2 adjacent negative charges to coordinate calcium ions and allows complex to bind to phospholipids on platelete membrane
• factor VII (which is extrinsic) is most sensitive to Vit K deficiency
• inibited by warfarin

Question 20

Warfarin

Answer 20

Inhibits epoxide reductase in liver, necessary for the regeneration of the active form of Vitamin K

(inhibits γ-Carboxylase, preventing production of mature Prothrombin (Factor II), VII, IX, X and Proteins C, S, and Z (but those are more anticoagulants))

Question 21

Fibrinolysis

Answer 21

Inactive plasminogen incorporated into developing clot

• activated by tissue plasminogen activator, urokinase, or streptokinase to plasmin
• can be inibited by plasminogen activator inhibitor 1 & 2
• α2-antiplasmin inhibits Plasmin
• fibrin broken down to fibrin degredation products/D-dimers–>elevated in DVT, measured to estimated rate of fibrinolysis and follow up on thrombosis patients

Question 22

Contorl of hemostasis

Answer 22

• normal endothelia are anti-throbotic
• put out PGI2 and NO that prevent platelet aggregation
• PGI2-increases cAMP in platelets and hihibits platelet activation–>thromboxane antagonist
• coagulation automatically initiates fibrinolysis

Question 23

Antithrombin III

Answer 23

• bind and inhibits factor Xa and IIa (thrombin)
• anticoagulent
• activated by Heparin

Question 24

Heparin

Answer 24

Activates antithrombin III (bind and inhibits factor Xa and IIa (thrombin))

Question 25

Protein C and S

Answer 25

- require vit K and γ-Carboxylase - inactivate cofactors Va and VIIIa - Protein C is activated by binding of thombomodulin to thrombin - S is a cofactor for C

Question 26

Streptokinase

Answer 26

Thrombolytic agent, activates plasminogen to plasmin to break down clots

Question 27

Hemophilia A

Answer 27

- Inherited Factor VIII deficiency - X linked - Intrinsic pathway (increasted clotting time and increased APTT) - similar to hemophilia B

Question 28

Hemophilia B

Answer 28

- Inherited Factor IX deficiency - X linked - Intrinsic pathway (increasted clotting time and increased APTT) - similar to hemophilia A

Question 29

Characteristic Hemophila lab findings/symptoms/signs

Answer 29

- easy bruising - masvie hemorrhage after trauma and surgical procedure - spontaneous hemorrhages, particularly in the joints-->hemarthrosis - Bleeding time=normal (platelet plug) - Platelet count normal - clotting time increased (defect in intrinsic pathway) - PT/INR-normal (tests extrinsic and common) - APTT-increased - Assay indvidual factors to distiguish b/w the two

Question 30

Von Willebrand Disease

Answer 30

- Deficiecny of vWF - most common inherited bleeidng disorder - defect in platelet plug formation - instability of factor VII (may lead to increased APTT) - clinical features similar to hemophila A - increased mucosal bleeding - epistaxis - post op bleeding - bleeding time prolonged - platelt count-normal - APTT-prolonged (factor VII levels low to normal) - vWF levels low

Question 31

Platelet defects

Answer 31

- quatitative-->low platelet count and increased bleeding time-->thrombocytopenia - qualitative-->normal platelet count and increased bleeding time: Bernard soulier syndrome (GbIb defect) or Thrombastenia of Glanzman and Naegeli (defect of GpIIb/IIIa)

Question 32

Bernard soulier syndrome

Answer 32

normal platelet count and increased bleeding time: GbIb defect

Question 33

Thrombastenia of Glanzman and Naegeli

Answer 33

normal platelet count and increased bleeding time: (defect of GpIIb/IIIa)