Pharm Summer Final - Anticoags

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Coagulation cascade

Intrinsic & Extrinsic pathways

Back 1

Intrinsic Pathway - occurs by physical chemical activation

Intrinsic Pathway begins w/ trauma to the blood vessel, exposure of blood to a wetable surface such as glass. In response to these stimuli 2 events occur.

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First Factor XII is converted from its inactive form to an active form Factor XIIa . 2nd platelets are activated .

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Factors IX converts factor X into factor Xa. Activation of factor X is also greatly accelerated by factor VIIIa.

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Factor X functions as a protease to convert inactive molecule prothrombin => to thrombin.

Thrombin => cleaves fibrinigen to fibrin. Which then forms fibrin strands.

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Deficiencies is Factor VIII & IX lead to hemphelia .

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Extrinsic Pathway = initial step is traumatized vascular wall exposes plasma to TISSUE FACTOR.

Factor VII binds to tissue factor => Factor VII + Ca++ acitvates => factor X => factor Xa.

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Te remainder of the cascade is similar to the intrinsic pathway!

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An anticoagulant is a substance that prevents coagulation; that is, it stops blood from clotting. :

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Heparins
Coumarin compounds

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Heparins

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Heparin binds to the enzyme inhibitor antithrombin (AT) . The activated AT then inactivates thrombin and other proteases involved in blood clotting, most notably factor Xa. The rate of inactivation of these proteases by AT can increase by up to 1000-fold due to the binding of heparin.

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Coumarin compounds: WARFARIN

act by antagonizing the effects of vitamin K.

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warfarin inhibits the production of gamma-carboxyglutamic acid residues, slowing the activation of the coagulation cascade.

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Prothrombin is produced in the liver and is post-translationally modified in a vitamin K-dependent reaction that converts ten glutamic acids on prothrombin to gamma-carboxyglutamic acid (Gla).

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Deficiency of vitamin K or administration of the anticoagulant warfarin inhibits the production of gamma-carboxyglutamic acid residues, slowing the activation of the coagulation cascade.

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Coumarin = ORALLY given

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HEPARINS = not IM

Sub Q or IV

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Heparins increase antithrombin activity by 1000 fold.

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inhibit factors IX, X , XI

Heparin = 30, 000 daltons

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Heparin is very highly protein bound.

If you increase plasma proteins = decr in effectiveness of heparin

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High molecular weight
Poor lipid solubility

DOES NOT CROSS PLACENTA( ok for mom & baby )

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Heparin how do we monitor :aPTT & ACT

activated partial thromboplastin time (aPTT) which measures the intrinsic pathway. 25-35 Normal

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Activated clotting time (ACT) is test effectiveness of high dose heparin therapy. measures the intrinsic clotting activity of the whole blood.

Normal range = 90-120

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You use Heparin to prevent thombus & pulmonary embolism

Embolism = when piece of thrombus breaks off and travels to pulmonary system

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Use for:

HIP patients, Vascular sx, CPB sx = b/c at risk for DVT

300-400 units per kg for bypass

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ASA + HEPARIN = BAD= coag issue

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Heparin side effects:

Thrombocytopenia
Ocular sx(eye)
Bleeding
proceed with caution near big artery

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Thrombocytopenia

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platelet count < 100K = mild

<50K = Severe!!! Stop & reverse

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HITT =

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Heparin Induced thromocytopenia & Thrombosis

Heparin MUSt be discontinued!

Heparin can be reveresed much faster than coumarin

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Reversal of Heparin :

salmon sperm

1 mg of protamine/100 units of heparin

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give protamine slowly = b/c it can cause HYPOtension from histamine release if given too fast

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protamine side effects:

hypotension
allergic rx
pulmonary hypertension

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Low weight molecular weight Heparin =
ENOXAPARIN

4-5000 daltons
binds less to plasma protein
More bioavailable = can be dosed once daily

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Alternatives to Protamine :

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Platelet factor 4 (PF4)

Heparinase -I

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Oral Anticoagulants: Coumarin

Warfarin -

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- diffficult to reverse

- DOES cross placenta = bad for baby. Fetus can develop hematoma

- does NOT cross breast milk- okay for mothers

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Oral Anticoagulants: Coumarin

Warfarin - how it works

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Vitamin K depletion

factors II, VII, IX, X affected

(2 + 7 = 9 & 10) way to remember

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prothrombin time (PT) and international normalized ratio (INR)

= normal range for the INR is 0.8–1.2.

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They are used to determine the clotting tendency of blood, in the measure of warfarin dosage, liver damage, and vitamin K status.

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Onset of coumarin = 8-10 hours

peaks => 36- 72 hours

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Stop taking 3-4 days before sx.

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Surgical patients in emergency that are on Anticoagulants :

Give vitamin K or FFP

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Patients who are anticoagulated with warfarin are deficient in vitamin K dependent coagulation factors II, VII, IX, and X,

FFP is efficacious for treatment of deficiencies of factors II, V, VII, IX, X, and XI

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Antithrombotic Drugs : PLAVIX (Clopidogrel) , ASA, & Hirudin

(Clopidogrel) :
Prodrug with slow onset
Dose: 75mg/day

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(Clopidogrel) inhibits platelet aggregation

is an oral antiplatelet agent to inhibit blood clots in CAD, peripheral vascular diz, and cerebrovascular diz

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Hirudin = Direct thrombin inhibitor

Alternative to heparin in HITT pts

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Suppresses platelet function

Clinical uses:
Prevention of DVTs in hip replacement surgery

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Aspirin

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For prevention of arterial thrombosis
Inhibit platelet aggregation
Inhibits COX1
Blocks production of Thromboxane