Clotting Cascade

Question 1

Clotting Cascade

Answer 1

Question 2

Extrinsic v. Intrinsic pathway

Answer 2

Extrinsic: starts with TF; due to vessel injury

Intrinsic pathway: starts wtih XI = due to contact

Question 3

Tissue Factor

Answer 3

Subendothelial protein released during vascular damage

First clotting factor in extrinsic pathway

Activates Factor VII to VIIa

Question 4

Factor VII

Answer 4

Part of extrinsic pathway

Vitamin K dependent hepatic synthesis

VIIa converts X to Xa, IX to IXa
- connects intrinsic and extrinsic pathways

VIIa as shortest half-life of all clotting factors

Question 5

Factor IX

Answer 5

Part of intrinsic pathway

Vitamin K dependent hepatic synthesis

IXa combines with VIIIa to form “tenase complex,” which converts X to Xa

X linked inheritance –> hemophilia B

Question 6

Factor VIII

Answer 6

Part of intrinsic pathway

Endothelial syntheesis: it releases VIII when damaged

Protected by spontaneous degradation by vWF

Thrombin converts it to VIIIa & it becomes part of tenase complex

X linked inheritance –> hemophilia A

Question 7

von Willebrand Factor

Answer 7

Massive multimeric protein cleaved by ADAMTS13

Endothelial and megakaryocyte synthesis (platelets produce it)

Binds collagen in damaged vascular bed

Carries factor VIII

Binds activated platelets via glycoprotein Ib receptor

Question 8

Factor X

Answer 8

Activated to Xa by ‘Tenase complex’

Vitamin K dependent hepatic synthesis

Converts prothrombin to thrombin as a part of the prothrombinase complex (Factor Xa, Va, and phospholipid

Question 9

Factor II

Answer 9

Prothrombin is cleaved to form Thrombin (IIa)
Thrombin is Two

Key positive upregulator of coagulation

Vit K dependent hepatic synthesis

It converts fibrinogen to fibrin

Also converts V to Va, VII to VIIa, VIII to VIIIa, XIII to XIIIa, XI to XIa, Protein C to activated Protein C

Question 10

Factor I

Answer 10

Fibrinogen
“Fibrinogen is First”

Forms protein meswork around platelet plug that strengthens clot

Cloth is further stabilized when Factor XIIIa crosslinks fibrin strands

Question 11

Factor XI

Answer 11

Part of intrinsic pathway

Can be activated to XIa by: XIIa or thrombin

Non-vitamin K dependent hepatic synthesis

Hereditary deficiency often noted only as post-operative bleeding (Hemophilia C)

Question 12

Two major ways to turn off coagulation

Answer 12

Protein C: thrombin turns on protein C to activated protein C, which turns of VIIIa and Va

Protein S: makes Protein C more efficient

Question 13

Protein C

Answer 13

“Natural anticoagulant”

Vitamin K dependent hepatic synthesis

aPC inactivates Va and VIIIa

aPC activity potentialted by Protein S

Question 14

Antithrombin

Answer 14

“natural anticoagulant”

Non-Vitamin K dependent hepatic synthesis

Incativates Factor Xa and Thrombin

Question 15

Protein S

Answer 15

Vitamin K dependent hepatic synthesis

Potentiates Protein C

Question 16

Fibrinolysis

Answer 16

Breaking up of the fibrin clot

Plasmin chews up the fibrin clot and breaks it into fragments (fibrin degradation products)

Question 17

D-Dimer

Answer 17

Not a coagulation factor

Biomarker of clotting: tells you clotting is happening

By-product of fibrinolysis

Elevated when there is excessive coagulation and in renal failure

Question 18

Vitamin K dependent factors

Answer 18

II, VII, IX, X, Protein C, Protein S

2+7=9, 10 comes after + C and S

Question 19

Normal platelet count?

How low can you go for neurosurgery, most other surgeries, spontaneous bleeding, CNS bleeding?

Answer 19

Normal = 180,000-400,000

>100,000 = safe for neurosurgery

>50,000 = safe for most other surgeries

<20,000 = spontaneous bleeding

<10,000 = CNS bleeding

Question 20

What are the 2 ways that platelets unite the pathways & do clotting?

Answer 20

(1) They are sticky, bind vWF, endothelium, and ahve granules (fibrinogen, factor V, etc.) = one way to get the pathway bc all the factors are packed in one

(2) Platelets produce thromboxane = potent vasoconstrictor and a second way to do clotting
(remember that aspirin inhibits thromboxane)

Question 21

Which 2 tests can you use to assess pt’s coagulation systems? What are the pros/cons to this system?

Answer 21

Prothrombin time (PT): extrinsic pathway

Partial Thromboplastin Time (PTT): intrinsic pathway

This is what happens in tests tubes, not what happens in people; sometimes you can get tests that don’t reflect their risk for bleeding

Question 22

PTT

Answer 22

Partial thromboplastin Time

Measures intrinsic pathway: time needed to complete coagulation starting at top of intrinsic pathway through prouduction of fibrin

Normal 23-35 seconds

Prolonged by deficiency of any involved factor; then go back and check the levels of each protein to see which protein they are deficient in

Longer times do not necessarily reflect bleeding risk

Question 23

PT

Answer 23

Addition of tissue factor to patient plasma allows measurement of time needed to complete coagulation via the extrinsic pathway

Typically 10-13 seconds

Also expressed as international normalized ratio (INR)

Most sensitive to Factor VII deficiency

Question 24

Which disorders have normal PT and PTT?

Answer 24

Platelet disorders (meds, uremia, inherited)

Factor XIII deficiency

Hyperfibrinolysis

Question 25

Which disorders have long PT & normal PTT?

Answer 25

Vitamin K Deficiency

Warfarin effect

Question 26

Which disorders have long PTT only?

Answer 26

Hemophilias (VIII, IX, XI)

von Willebrand dz

Heparin effect

Lupus anticoagulant

Contact factor deficiency

Question 27

Which disorders have prolonged PT and PTT?

Answer 27

DIC: disseminated intravascular coagulation

Extreme warfarin effect

Rare common pathway factor deficiency

Question 28

What is a mixing study? What can you learn from it?

Answer 28

To determine if prolonged PT and/or PTT is secondary to factor deficiency or inhibitory antibody to part of clotting cascade

Mix 50% pt and 50% pooled plasma

Recheck PT and PTT

• if normal: factor deficiency present (check which)
• if prolonged, inhibitor present (antibody is binding to the factors)