Anticoagulants, Antithrombotics And Thrombolytics

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*** PLEASE SEE SUPPLEMENTAL PACKET FOR PICTURES, DIAGRAMS AND STUDY QUESTIONS RELATED TO THIS LECTURE***

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Oral Anticoagulant (prototype)

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Warfarin

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Therapeutic Uses for Heparin

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DVT-deep vein thrombosis
PE-pulmonary emboli
MI-myocardial infarction
Prophylaxis Thrombosis

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Contraindications for Heparin

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Hypersensitivity
Active bleeding
Hemophiliacs
Severe hypertension

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Mechanism of action for Warfarin

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Inhibits the synthesis of vitamin K dependent factors (II, VII, IX, X, protein C and S)

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Pharmacokinetics of Warfarin

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Onset of action is delayed 5-7 days in order to synthesize new factors

Orally active

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Warfarin

Drug Interactions

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Drugs which stimulate metabolism: reduce anticoagulation

-Chronic alcohol ingestion
-Barbiturates
-Griseofulvin

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Platelet
(function)

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Provide initial hemostatic plug at site of vascular injury

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Dissolution of clots (#3)
--after plasmin is formed--

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3. plasmin digests fibrin to soluble degradative products; phagocytic WBCs remove the debris

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Pharmacokinetics of Heparin

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Parenterally administered (IV or SB)
*onset is immediate

IV administered in acute case phase of thromboembolic event

given at hospital or with home health

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Adaptations/Modification of Heparin

examples: Enoxaparin (LOVENOX)
Delteparin (FRAGMIN)

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Low molecular weight heparins are derived from chemicl of natural product-now available in U.S. and are given subcutaneously

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Warfarin Treatment

Monitor...

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1. PT-prothrombin time
2.INR-Internal Normalized Ratio-standard assessment developed by WHO; allows comparison of values from different labs

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Side Effects of Warfarin

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Increased bruising and tendency towards hemorrhaging

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Therapeutic Uses of Warfarin

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Treatment, prevention and recurrence of thromboembolism in patients with prosthetic heart valve, chronic artrial fibrillatio, patients undergoing moderate to high risk surgical procedures and as adjunct to coronary artery occlusion

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Warafin

General Info

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Structurally similar to Vit. K

acts over time

O.T. handle pt carefully b/c of side effects; watch out for bleeding

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Warfarin

Drugs which inhibit metabolism

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potentiate anticoagulation

-Cimetidine (TAGAMET)
-Disulfiram
-Metronindazole (FLAGYL)

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Warfarin

Drugs which inhibit platelet aggregation

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potentiate anticoagulation

Asprin->b/c it is an anti-platelet drug

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Antiplatelet Drugs

NSAIDs

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e.g. Aspirin

-Inhibit COX enzyme, thereby inhibiting synthesis of the thromboxane A2 in platelets

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Antiplatelet Drugs

Dipyridamole

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Thought to impair adenosine metabolism
to interfere with platelet function; exact mechanism not well understood

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Antiplatelet (antithrombotic drugs)

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Inhibit platelet function. Prevent thrombus formation in arteries

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Antiplatelet Drugs

Glycoprotein (GP) IIb-IIIa inhibitors

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e.g. Ticlopidine

Antagonize GP receptor on the platelet membrane that is stimulated by fibrinogen; fibrinogen is therefore unable to bind platelet;
platelet activation is decreased to reduce platelet-induced clotting

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Thrombolytic Drugs

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All act directly or indirectly to convert plasminogen to plasmin, which in turn, cleaves fibrin to cause lysis of thrombi

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Thrombolytic Drugs

Examples

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Alteplasse (tissue-type plasminogen activator, tPA)

Streptokinase
Anistreplase
Urokinase

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Function of Alteplasse

(tissue-type plasminogen activator, tPA)

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-Produced by recombinant techniques
-Converts plasminogent to plasmin
-Selective for formed clots, therefore only affects fibrin in clots not in circulation

Given in acute conditions

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Therapeutic Uses

for Altepasse

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Emergency treatment of MI

Deep vein thrombosis

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Toxicity of Altepasse

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Bleeding (intracranial)

Allergic Reaction

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Occupational Therapy Implications

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Be aware that anticoagulant therapy is associated with increased tendency for bleeding and bruising

May affect ADLs

Thrombolytic drugs usually given in acute situations

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Physiology of Hemostasis


SEE PICTURES OF PHYSIOLOGY ON pg. 2

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A clot that adheres to vessel wall

versus

an intravascular clot that floats
within the blood

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Thrombus

vs

Embolus

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How are fibrin clots formed?

FACTS

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The clotting (coagulation) cascade

2 semi-independent pathways lead to formation of prothrombin (factor II):

*Intrinsic pathway-all of its components are within the blood; SLOW (2-6 minutes)

*Extrinsic pathway-triggered by extravascular damage; FAST (15 seconds)

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How are fibrin clots formed?

FACTS

THE FINAL COMMON PATHWAY. . .

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In the final common pathway, prothrombin is activated by thromboplastin (factor Xa) to activated prothrombin (thrombin IIa). Thrombin (IIa) then converts fibrinogen to fibrin monomers, which are converted to fibrin polymers. The fibrin polymers cross-linked to form the fibrin clot

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***SEE PAGE 3 FOR DIAGRAM OF CLOTTING CASCADE***

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Plasminogen

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The inactive proenzyme that is plasmin once activated

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Dissolution of clots (#1)

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Plasminogen (inactive proenzyme) is activated and becomes plasmin by:

1. tissue plasminogen activator (tPA)-released from vascular endothelial cells following injury

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Dissolution of clots (#2)

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2. urokinase (produced from epithelial cells as prourokinase to plasmin-to a lesser degree)

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Dissolution of clots (#4)

---after plasmin is formed---

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4. Plasminogen and plasmin are rapidly inactivated by their respective inhibitors
Fibrin
plasminogen-->plasmin |
Soluble Products

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Treating clots

THROMBOEMBOLISM

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Abnormal clot formation

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Treating clots

DEEP VEIN THROMBOSIS

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A.K.A. DVT

Abnormal clots in legs

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Treating Clots

PULMONARY EMBOLUS

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A.K.A. PE

Abnormal clots in lungs

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Treating Clots

Clots can block carotid arteries resulting in O2 deprevation in the CNS

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Stroke
-mental retardation and/or physical disability

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Treating Clots

Clots can form secondary plaque in coronary arteries-compromised delieving of O2 to heart tissues

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Myocardial Infarction

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Anticoagulants

examples: Heparin
Warfarin

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Treatment of overactive clotting

Control function and synthesis of clotting factors-used in venous system (venus thrombosis)

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Thrombolytics

examples: Attepasse (tissue-type plasminogen activator, TPA)
Anistrepiase
Litokinase
Streptokinase

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Facilitate destruction of blood clots

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Definition of Heparin

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An anticoagulant; a glycosaminoglycan found in secretory granules of mast cells (physiological function unknown)

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Mechanism of action of Heparin

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Binds, activates and potentiates the endogenous anticoagulant, Antithrombin III (AT III) to neutralize clotting factors: II, IX, X, XI, XII and kallikrein

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Sources for Heparin

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extracted from porcine intestinal mucosa or bovine lung

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Side effects of Heparin

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Hemorrhage
Thrombocytopenia (low blood platelet count)

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Heparin Treatment

Monitor...

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1. blood components-total blood count

2. aPTT (Partial Thromboplastin Time)-Intrinsic Pathway

3. PT (Prothrombin Time)-Extrinsic Pathway

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Heparin Toxicity

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can be reversed with protamine sulfate

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Physiology of Hemostasis

FACTS

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Impaired hemostasis leads to bleeding

While stimulated hemostasis leads to thrombus formation

***Therefore, you need balance between the 2 systems***

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Physiology of Hemostasis
FACTS (in stages)

STAGE #1

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1. Vascular constriction:

initial phase; reflex response that
limits blood flow

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Physiology of Hemostasis
FACTS (in stages)

STAGE #2

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2. When vessels rupture, platelets are exposed to collagen located outside the blood vessel. Exposure to collagen, platelets release ADP (adenosine diphosphate) & thromboxane which cause the sufaces of nearby platelets to become sticky and as "sticky" platelets accumulate, a 'plug' forms

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Physiology of Hemostasis
FACTS (in stages)

STAGE #3

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3. Formation of a fibrin mesh

-ensures stability of platelet plug. Fibrin mesh is formed via the
coagulation cascade

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Physiology of Hemostasis
FACTS (in stages)

STAGE #4

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4. Dissolution of clot by action of plasmin following repair

-ensures normal blood flow resumes

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A delicate balance between procoagulant, anticoagulant and fibrinolytic processes in the body

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Normal Hemostasis

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Spontaneous arrest of bleeding from a damaged blood vessel (involves blood clotting and subsequent dissolution of clot following repair)

**NOTE: thrombosis is the most common abnormal source of this

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Hemostasis=Blood Coagulation

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What is:

Thrombosis

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Intravascular formation of a blood clot

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Antithrombotics

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Measures that cure or prevent
thrombosis

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Pertaining to disintegration of a
blood clot

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Thrombolytics

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Fibrinolysis

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dissolution of clot