04: Principles of Hemostasis

Question 1

Hemostasis

Answer 1

• 3 components: platelet aggregation, clotting cascade, vasoconstriction
• Steps:
  
  1. Damage to vascular endothelium initiates hemostatic plug to which platelets bind
  2. Primary hemostatic plug encased by fibrin deposition
  3. Contracted clot forms, with beginning fibrinolysis

Question 2

Tissue factor

Answer 2

• Subendothelial protein released during vascular damage
• First clotting factor in extrinsic pathway
• Activates VII –> VIIa

Question 3

Factor VII

Answer 3

• Part of extrinsic pathway
• Vitamin K-dependent hepatic synthesis
• As Factor VIIa, binds TF to form activated tenase complex:
  
  • Converts X –> Xa
  • Converts IX –> IXa (intrinsic pathway)
• Shortest half-life of all clotting factors

Question 4

Factor IX

Answer 4

• Part of intrinsic/contact pathway
• Vitamin-K dependent hepatic synthesis
• As Factor IXa:
  
  • Combines with VIIIa to form tenase complex
  • Activates Factor X –> Xa
• X-linked inheritance deficency: hemophilia B

Question 5

Factor VIII

Answer 5

• Part of intrinsic pathway
• Endothelial synthesis
• Protected by spontaneous degradation by vWF
• Once converted to Factor VIIIa by thrombin (IIa), becomes part of **tenase complex **(with IXa)
• X-linked inheritance deficiency –> **hemophilia A **(80% of all hemophilias)

Question 6

von Willebrand Factor

Answer 6

• Massive multimeric protein (cleaved by ADAMTS13)
• Endothelial and megakaryocytic synthesis
• Binds:
  
  • Collagen in damaged vascular bed
  • Factor VIII
  • Activated platelets via glycoprotein Ib receptor (Gp1bR)

Question 7

Factor X

Answer 7

• Start of common pathway
• Activated to Xa by tenase complex
• Vitamin K-dependent hepatic synthesis
• Converts **prothrombin (II) **–> thrombin (IIa) as part of the **prothrombinase complex **(Xa, Va, phospholipid)

Question 8

Prothrombin (Factor II)

Answer 8

• Key positive upregulator of coagulation
• Vitamin K-dependent hepatic synthesis
• **Thrombin (IIa) **converts:
  
  • Fibrinogen –> fibrin
  • V –> Va
  • VII –> VIIa
  • VIII –> VIIIa
  • XI –> XIa
  • XIII –> XIIIa
  • Protein C – activated protein C (aPC)

Question 9

Fibrinogen (I)

Answer 9

• Non-vitmin K-dependent hepatic synthesis
• Fibrin forms protein meshwork around platelet plug that strengthens clot
• Clot is further stabilized when **Factor XIIIa **crosslinks fibrin strands (also activated by thrombin)

Question 10

Factor XI

Answer 10

• Part of intrinsic/contact pathway
• Activated by **XIIa **or thrombin
• Non-vitamin K-dependent hepatic synthesis
• Hereditary deficiency often noted only as post-operative bleeding (hemophilia C)

Question 11

Protein C

Answer 11

• Natural anticoagulant
• Vitamin K-dependent hepatic synthesis
• Activated protein C (aPC) inactivates:
  
  • Factor Va
  • Factor VIIIa

NB: C is 3rd in alphabet; 8-5 = 3

Question 12

Protein S

Answer 12

• Natural anticoagulant
• Vitamin K-dependent hepatic synthesis
• A co-factor which potentiates aPC activity

Question 13

Antithrombin

Answer 13

• Natural anticoagulant
• Hepatic synthesis
• Inactivates **Factor Xa **and thrombin (IIa)

Question 14

Fibrinolysis

Answer 14

• Intrinsic activation: **Factor XIIa **& kallikrein
• Extrinsic activation: **tPA **& urokinase-like A
• Also **streptokinase **from bacteria.
• All activate **plasminogen **to plasmin, which degrades **fibrin **(releasing fibrin degradation products [FDPs]).

Question 15

D-Dimer

Answer 15

• Not a coagulation factor
• By-product of fibrinolysis (“smoke”)
• Elevated when XS coagulation, renal failure
• Sensitive but not specific

Question 16

Platelet counts

Answer 16

• 180-400K: normal
• >100K: safe for neurosurgery
• >50K: safe for most other surgeries
• <20K: spontaneous bleeding
• <10K: CNS bleeding

Question 17

Thromboxane

Answer 17

• Produced by platelets, inhibit cAMP formation
• High levels of cAMP lead to low free calcium ions, thus preventing aggregation and adhesion
• Positive feedback of platelet aggregation: leads to more clotting, vasoconstriction
• cAMP inhibited by prostacyclin

Question 18

Partial Thromboplastin Time (aPTT)

Answer 18

• Time to complete coagulation starting at intrinsic/contact pathway –> fibrin production
• Normal = 23-35 seconds
• Prolonged by deficiency of any involved factor (XII, XI, IX, VIII, X, V, II, I)
• Longer times do not necessarily reflect bleeding risk!

Question 19

Prothrombin Time (PT)

Answer 19

• Addition of tissue factor to plasma allows measure of time needed to complete coagulation via *extrinsic pathway *(VII, X, V, II, I)
• Normal = 10-13 seconds
• Also expressed as international normalized ratio (INR)
• Most sensitive to Factor VII deficiency

Question 20

Hemostatic dz w/ normal aPTT & PT

Answer 20

• Platelet disorders (medications, uremia, inherited)
• Factor XIII deficiency
• Hyperfibrinolysis

Question 21

Hemostatic dz w/ ↑PT, normal aPTT

Answer 21

• Vitamin K deficiency
• Warfarin effect

Question 22

Hemostatic dz w/ ↑aPTT, normal PT

Answer 22

• Hemophilias
• von Willebrand disease
• Heparin effect
• Lupus anticoagulant
• Contact factor deficiency

Question 23

Hemostatic dz w/ ↑aPTT and ↑PT

Answer 23

• Disseminated Intravascular Coagulation (DIC)
• Extreme warfarin effect
• Rare common pathway facor deficiency

Question 24

Mixing studies

Answer 24

• Determine if prolonged PT and/or aPTT 2/2:
  
  • Factor deficiency
  • Inhibitory Ab to part of cascade
• Step 1: Mix 50% pt and 50% pooled plasma
• Step 2: Recheck PT and/or aPTT
  
  • Normal: Factor deficiency
  • Prolonged: Ab inhibitor