Exam 4 - Coagulation Disorders

Question 1

What are the phases of platelet formation?

Answer 1

1. Adhesion
2. Aggregation
3. Secretion
4. Cross-linking of adjacent platelets

Question 2

What are red and white thrombi?

Answer 2

Red: contain RBC and occur in slow moving vessels, can detach and lead to PE
White: contain only fibrin and platelets in fast moving vessels, causes downstream ischemia

White thrombi

Question 3

Describe the role PGI2 in thrombogenesis?
What drugs are noted here?

Answer 3

“Prostacyclin” - sits in endothelial cell wall and normally inhibits platelet aggregation
NSAIDS, except aspirin,inhibit formation of PGI2 and are therefore “pro-clot”

Question 4

What is collagen and vWF role in thrombogenesis?

Answer 4

Collagen: Exposed during endothelial cell injury and binds to GP Ia in platelets
vWF: Exposed during endothelial cell injury and binds to GP Ib in platelets
Both of these binding lead to release of soluble mediators from platelets

Question 5

What is the role of ADP, TXA2, and 5-HT during thrombogenesis?

Answer 5

5-HT: causes vasoconstriction of smooth muscle and binds to other platelets, activating them
ADP, TXA-2: Bind to receptors on other platelets activating them
* Activation of other platelets causes release of more of these mediators in a positve feedback system

Question 6

How does aspirin effect platelet aggregation?

Answer 6

Inhibits COX-1, inhibiting production of TXA2, preventing platelet activation

Question 7

What is fibrins role in platelet aggregation?

Answer 7

Creates a web-like structure that holds the platelets together, allowing them to aggregate

Question 8

Describe what the common pathway does?

Answer 8

Activates thrombin which leads to fibrin formation

Question 9

Describe the extrinsic pathway?

Answer 9

1. Tissue damage exposes tissue factor (TF)
2. TF activates factor VII
3. TF facilitates conversion of factor VII to factor X
4. Factor X converts prothrombin to thrombin
5. Thrombin converts fibrinogen to fibrin

Question 10

Describe the common pathway?

Answer 10

1. Factor X is activated by the extrinsic and intrinsic pathway
2. Factor X converts prothrombin to thrombin with the help of factor V
3. Thrombin converts fibrinogen to fibrin
4. Fibrin becomes cross linked with the help of factor XIII

Question 11

Describe the intrinsic pathway?

Answer 11

1. Damage to endothelial cells activates factor XII
2. Activating factor XI
3. Activating factor IX
4. Activating factor X

Factor VIII aids in activation of factor X

12, 11, 9, 10, common pathway

Question 12

What does thrombin activate?

Answer 12

Activates: factors V, VIII, XI, XIII, and protein C

Question 13

What are the inhibitors in the coagulation cascade and their effects?

Answer 13

• Protein C - inhibits factors VIII and V
• Antithrombin - inhibts factor X and thrombin

Question 14

Draw the coagulation cascade.

Answer 14

Question 15

What 3 factors can lead to DVT + what is the name of this group of symptoms?

Answer 15

Virchow’s Triad
* Stasis
* Endothelial injury
* Hypercoagulability

Question 16

What are the risk factors for DVT?

Answer 16

• Can be inherited like coagulation factor deficency
• Acquired like being bedridden, trauma, obesity, estrogen use, cancer, venous insufficiency

Question 17

What is DIC?

Answer 17

• Overstimulation of the blood clotting mechanism resulting in excessive consumption of factors and platelets leading to spontaneous bleeding

Question 18

What are the causes and treatments for DIC?

Answer 18

• Causes: massive tissue injury, malignancy, bacterial sepsis, placental abruption
• Treatments: Plasma transfusion, correct the underlying cause

Has a high mortality rate

Question 19

Define TTP and HIT?
Causes and treatments?

Answer 19

Heparin Induced Thrombocytopenia (HIT) is caused by HMWH use. The body creates antibodies against platelets and destroys them.
Can be treated with protamine, platelet transfusions, and stopping heparin use.

Question 20

Draw the fibrinolysis pathway, including mediators involved.

Answer 20

• t-PA, urokinase, and streptokinase activates plasminogen to plasmin
• Plasmin will induce breakdown of fibrinogen and fibrin

Question 21

What are the 4 classes of coagulation modifiers?

Answer 21

• Anticoagulants
• Antiplatelets
• Thrombolytics
• Hemostatics/Antifibrinolytics

Question 22

What drugs are anticoagulants?

Answer 22

Heparin, Fondaparinux, Hirudin, Warfarin, Rivaroxaban, Apixaban, Dabigatran, Argotroban

Question 23

What drugs are antiplatelets?

Answer 23

Aspirin, clopidogrel, abciximab

Question 24

What drugs are thrombolytics?

Answer 24

Streptokinase and t-PA

Question 25

What drugs are hemostatics/antifibrinolytics?

Answer 25

Question 26

What are the indirect thrombin inhibitors and their MOA?

Answer 26

* **Unfractionated heparin:** Enhances the activity of antithrombin by 1000X which irreversibly binds thrombin AND factor Xa - most effective * **LMWH**: Enhances antithrombin specifically to factor X, not effecting thrombin - less effective * **Fondaparinux**: Specific for only enhancing antithrombin- least effective.

Question 27

What are the direct thrombin inhibitors and their MOA?

Answer 27

* **Hirudin:** bind to both the active and substrate sites on thrombin, derived from leech saliva * **Argatroban, dabigatran:** bind only to the thrombin active sites

Question 28

What are the toxicities and contraindications for HMWH? Treatments?

Answer 28

* **Bleeding, HIT** (heparin induced thrombocytopenia, 7-10 days after exposure) * **Any state with increased bleeding risk**: active bleeding, hemophilia, thrombocytopenia, severe HTN, intracranial hemorrhage, infective endocarditis, active TB, GI ulcers, advanced hepatic disease * **Treatment:** Protamine sulfate. Its positive charge binds to heparin's negative charge to inactivate it.

Question 29

Describe the lab tests used for coagulation and their normal values?

Answer 29

* **Prothrombin Time (PT)** *Time to clot*. Assesses function of *extrinsic* system and common pathway of coag cascade. * **INR** = (PT test / PT normal) -Normal = 0.8 - 1.2 -Warfarin Target = 2 – 3 * **Activated Partial Thromboplastin Time (aPTT)**: Assess function of *intrinsic* system and common pathway. -Normal = 35 – 45 sec

Question 30

What is the MOA of Warfarin?

Answer 30

* **MOA:** blocks gamma-carboxylation of glutamate residues via inhibition of vitamin K reductase, inhibiting production of *factors II, VII, IX, X*. * Blocks REDOX cycle of vitamin K

Question 31

Treatment considerations and pharmokinetics of Warfarin?

Answer 31

* 100% bioavailibility, 99% protein bound * Can cause birth defects and fetal hemorrhage * Metabolism depends on genetic based enzyme induction or inhibition * Vitamin K levels can alter function

Question 32

Reversal for Warfarin?

Answer 32

* Large dose of Vitamin K * FFP * Stop drug * Factor IX concentrates

Question 33

What are the non-warfarin oral anticoagulant drugs and their targets?

Answer 33

* Apixaban, rivaroxaban- inhibit factor Xa * Dabigatran, argatroban - inhibts thrombin

Question 34

What are the fibrinolytic drugs?

Answer 34

t-PA, urokinase, streptokinase

Question 35

List the antiplatelet drugs and their MOA?

Answer 35

* **Aspirin:** COX-1 inhibitor preventing formation of TXA2 preventing platelet aggregation * **Clopidogrel:** Irreversably inhibits ADP receptors on platelets * **Abcixamab:** inhibits receptors IIb/IIIa preventing cross linking by fibrin

Question 36

Describe the use and mechanism of vitamin K?

Answer 36

* Found in leafy green vegetables * Reverses warfarin by increasing the clotting factors that warfarin inhibits (II, VII, IX, X)

Question 37

Describe the use of plasma fractions?

Answer 37

* Used for deficiencies in plasma clotting factors * Can be derived from plasma or recombinant

Question 38

Describe the uses and MOA of desmopressin?

Answer 38

* Increases factor VIII activity * Used in mild hemphilia A and von Willebrand disease

Question 39

Desctibe the uses and MOA of aminocaproic acid?

Answer 39

* Competitvely inhibts plasminogen activation * Used for hemophila treatment, bleeding from fibrinolytic therapy, intracranial aneurysms, post surgical bleeding

Question 40

Describe the uses and MOA of transexamic acid (TXA)?

Answer 40

* Decreases the risk of death in major bleeding * It is an antifibrinolytic that inhibits conversion of plasminogen to plasmin