Exam 4 - Coagulation Disorders Flashcards
What are the phases of platelet formation?
- Adhesion
- Aggregation
- Secretion
- Cross-linking of adjacent platelets
What are red and white thrombi?
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
Describe the role PGI2 in thrombogenesis?
What drugs are noted here?
“Prostacyclin” - sits in endothelial cell wall and normally inhibits platelet aggregation
NSAIDS, except aspirin,inhibit formation of PGI2 and are therefore “pro-clot”
What is collagen and vWF role in thrombogenesis?
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
What is the role of ADP, TXA2, and 5-HT during thrombogenesis?
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
How does aspirin effect platelet aggregation?
Inhibits COX-1, inhibiting production of TXA2, preventing platelet activation
What is fibrins role in platelet aggregation?
Creates a web-like structure that holds the platelets together, allowing them to aggregate
Describe what the common pathway does?
Activates thrombin which leads to fibrin formation
Describe the extrinsic pathway?
- Tissue damage exposes tissue factor (TF)
- TF activates factor VII
- TF facilitates conversion of factor VII to factor X
- Factor X converts prothrombin to thrombin
- Thrombin converts fibrinogen to fibrin
Describe the common pathway?
- Factor X is activated by the extrinsic and intrinsic pathway
- Factor X converts prothrombin to thrombin with the help of factor V
- Thrombin converts fibrinogen to fibrin
- Fibrin becomes cross linked with the help of factor XIII
Describe the intrinsic pathway?
- Damage to endothelial cells activates factor XII
- Activating factor XI
- Activating factor IX
- Activating factor X
Factor VIII aids in activation of factor X
12, 11, 9, 10, common pathway
What does thrombin activate?
Activates: factors V, VIII, XI, XIII, and protein C
What are the inhibitors in the coagulation cascade and their effects?
- Protein C - inhibits factors VIII and V
- Antithrombin - inhibts factor X and thrombin
Draw the coagulation cascade.
What 3 factors can lead to DVT + what is the name of this group of symptoms?
Virchow’s Triad
* Stasis
* Endothelial injury
* Hypercoagulability
What are the risk factors for DVT?
- Can be inherited like coagulation factor deficency
- Acquired like being bedridden, trauma, obesity, estrogen use, cancer, venous insufficiency
What is DIC?
- Overstimulation of the blood clotting mechanism resulting in excessive consumption of factors and platelets leading to spontaneous bleeding
What are the causes and treatments for DIC?
- Causes: massive tissue injury, malignancy, bacterial sepsis, placental abruption
- Treatments: Plasma transfusion, correct the underlying cause
Has a high mortality rate
Define TTP and HIT?
Causes and treatments?
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.
Draw the fibrinolysis pathway, including mediators involved.
- t-PA, urokinase, and streptokinase activates plasminogen to plasmin
- Plasmin will induce breakdown of fibrinogen and fibrin
What are the 4 classes of coagulation modifiers?
- Anticoagulants
- Antiplatelets
- Thrombolytics
- Hemostatics/Antifibrinolytics
What drugs are anticoagulants?
Heparin, Fondaparinux, Hirudin, Warfarin, Rivaroxaban, Apixaban, Dabigatran, Argotroban
What drugs are antiplatelets?
Aspirin, clopidogrel, abciximab
What drugs are thrombolytics?
Streptokinase and t-PA
What drugs are hemostatics/antifibrinolytics?
What are the indirect thrombin inhibitors and their MOA?
- 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.
What are the direct thrombin inhibitors and their MOA?
- Hirudin: bind to both the active and substrate sites on thrombin, derived from leech saliva
- Argatroban, dabigatran: bind only to the thrombin active sites
What are the toxicities and contraindications for HMWH?
Treatments?
- 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.
Describe the lab tests used for coagulation and their normal values?
- 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
What is the MOA of Warfarin?
- 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
Treatment considerations and pharmokinetics of Warfarin?
- 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
Reversal for Warfarin?
- Large dose of Vitamin K
- FFP
- Stop drug
- Factor IX concentrates
What are the non-warfarin oral anticoagulant drugs and their targets?
- Apixaban, rivaroxaban- inhibit factor Xa
- Dabigatran, argatroban - inhibts thrombin
What are the fibrinolytic drugs?
t-PA, urokinase, streptokinase
List the antiplatelet drugs and their MOA?
- 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
Describe the use and mechanism of vitamin K?
- Found in leafy green vegetables
- Reverses warfarin by increasing the clotting factors that warfarin inhibits (II, VII, IX, X)
Describe the use of plasma fractions?
- Used for deficiencies in plasma clotting factors
- Can be derived from plasma or recombinant
Describe the uses and MOA of desmopressin?
- Increases factor VIII activity
- Used in mild hemphilia A and von Willebrand disease
Desctibe the uses and MOA of aminocaproic acid?
- Competitvely inhibts plasminogen activation
- Used for hemophila treatment, bleeding from fibrinolytic therapy, intracranial aneurysms, post surgical bleeding
Describe the uses and MOA of transexamic acid (TXA)?
- Decreases the risk of death in major bleeding
- It is an antifibrinolytic that inhibits conversion of plasminogen to plasmin
