Drugs Used in Disorders of Coagulation

By

M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science

Drugs Used in Disorders of Coagulation

Stages of Blood Coagulation Nomenclature Thrombus Formation Prothrombotics & Antithrombotics DIC Anticoagulant Drugs Regulation of Fibrinolysis Fibrinolytic Drugs Fibrinolytic Inhibitors Anti Platelet Drugs Plasma fractions Drug Pictures

Stages of Blood Coagulation

Vasospasm Platelet adhesion Platelet aggregation Viscous metamorphosis Activation of coagulation factors Fibrin synthesis Summary of coagulation process

EDTA: Ethylene Diamine Tetraacetic Acid

Blood plasma after the addition of Tissue Factor. The gel-like structure is strong enough to hold a steel ball.

Nomenclature Thrombus: Clot Prothrombotic: Promotes clot formation. Antithrombotic: Inhibits clot formation. Coagulation: The process of clot formation. Procoagulant: Promotes clot formation. Anticoagulant: Inhibits clot formation. Fibrinolysis: The process of dissolving the fibrin. Fibrinolytic: Promotes dissolving the fibrin. Fibrinolytic Inhibitor: Inhibits dissolving the fibrin.

Thrombus Formation

White thrombus: forms in arteries by adherence of platelets

Red thrombus: forms around a white thrombus or in low-pressure

veins Consists of a fibrin network in which red cells are

enmeshed The platelets dominate the arterial thrombus

and the fibrin tail dominates the venous thrombus

Prothrombotics & Antithrombotics

Platelet ADP: a powerful inducer of platelet aggregation

Platelets Thromboxane A2 (TXA2): induces thrombogenesis and vasoconstriction

Platelets Serotonin (5-HT): stimulating further aggregation and vasoconstriction

Endothelial Prostacyclin (PGI2): inhibits thrombus formation

Endogenous anticoagulants: protein C and S.

DIC

Introduction Diagnosis Treatment

DIC Introduction

There are inhibitors that inactivate the coagulation proteins as they escape from the site of vessel injury

They include: α1-antiprotease, α2-macroglobulin,α2-antiplasmin, and antithrombin

If this system is overwhelmed, Disseminated Intravascular Coagulation (DIC) occurs

DIC is seen in: massive tissue injury, abruptio placentae, or bacterial sepsis

DIC. Note the characteristic skin hemorrhage ranging from small purpuric lesions to larger ecchymoses.

DIC

DIC Diagnosis

DIC should prompt a search for the underlying disease if not already apparent.

No single test establishes the diagnosis of DIC. The tests include:

aPTT, PT, thrombin time (TT) Fibrin degradation products (FDP) Platelet and RBC count Blood smear.

DIC Diagnosis (Cont’d)

Common findings include: The prolongation of PT and/or aPTT Platelet counts 100,000/mm3, or a rapid decline in platelet

numbers The presence of schistocytes (fragmented red cells) Elevated levels of FDP.

The most sensitive test for DIC is the FDP level. Because fibrinogen has a prolonged half-life, plasma

levels diminish acutely only in severe cases of DIC.

DIC Treatment The control of bleeding requires replacement

therapy.

FFP is indicated (1 unit of FFP increases most coagulation factors by 3% in an adult without DIC).

Brisk hyperfibrinolysis or low levels of fibrinogen requires cryoprecipitate.

Cryoprecipitate is plasma fraction enriched for fibrinogen, FVIII, and vWF.

DIC Treatment (Cont’d)

The replacement of 10 U of cryoprecipitate for every 2–3 U of FFP is sufficient to correct the hemostasis.

Platelet concentrates 1–2 U/10 kg body weight are sufficient for DIC patients with severe thrombocytopenia.

Clotting factor concentrates are NOT used. Because single factor replacement has limited

efficacy for control of bleeding.

Anticoagulant Drugs

Parenteral: Heparin Hirudin

Oral: Warfarin

Heparin Antithrombin inhibits thrombin (II), VIIa, IXa, Xa,

XIa and XIIa (2 7 9 10 11 12) Heparin accelerates the reaction 1000 fold Heparin is not consumed and after reaction binds to

more antithrombin It is extracted from porcine intestine and bovine lung LMW heparins for thromboembolism include:

Enoxaparin Dalteparin

Heparin Toxicity

The major adverse effect is bleeding Elderly women and patients with renal failure

are more prone to hemorrhage It causes transient thrombocytopenia in 25% of

patients The heparin-induced antibody, causes platelet

aggregation and thromboembolism

Heparin Contraindications Hypersensitivity to the drug Active bleeding & hemophilics Thrombocytopenia & purpura Severe hypertension, intracranial hemorrhage Infective endocarditis & active tuberculosis Ulcerative lesions of the GI tract Threatened abortion Visceral carcinoma & advanced hepatic or renal disease Recent surgery of the brain, spinal cord or eye Patients undergoing lumbar puncture or regional

anesthesia

Heparin Administration & Dosage

Heparin should prolong the activated partial thromboplastin time (aPTT) 2–2.5 times

Must never be administered intramuscularly (hematoma at the injection)

Reversal of Heparin Action

Discontinuance of the drug

Protamine sulfate (heparin antagonist)

Excess protamine must be avoided; it also has an anticoagulant effect

Hirudin

Hirudin is a thrombin inhibitor from the leech (Hirudo medicinalis) now available as Lepirudin

Its action is independent of antithrombin so inactivates fibrin-bound thrombin in thrombi

Is monitored by the aPTT

(Hirudo medicinalis)

Warfarin

Found in spoiled sweet clover silage causing bleeding in cattle

It prevents activation of vitamin K Blocks synthesis of prothrombin (II), VII, IX, and

X as well as the anticoagulant proteins C and S There is an 8 to 12 hour delay in its action Inhibition of coagulation is dependent on the half-

lives of inhibited factors

Warfarin toxicity

Warfarin crosses the placenta readily and can cause a hemorrhagic disorder in the fetus

The drug can also cause abnormal bone formation Warfarin should NEVER be administered during

pregnancy

Administration & Dosage of Warfarin

The adjustment of the prothrombin time (PT) takes 1 week

The prothrombin time should be 25% of normal If prothrombin time < 20%, the warfarin should be

reduced or omitted The therapeutic range for warfarin is now defined as

International Normalized Ratio (INR) Dosage is adjusted to achieve an INR of 2.5 – 3.5

Warfarin drug interaction

The most serious are those that increase the risk of bleeding and include: Phenylbutazone, also inhibits platelet function and

may induce peptic ulcer Metronidazole, fluconazole, and trimethoprim-

sulfamethoxazole Aspirin, hepatic disease, and hyperthyroidism The third-generation cephalosporins Heparin

Warfarin drug interaction Cont,d

Drugs that decrease warfarin effect: Vitamin K Hypothyroidism

Drugs with no effect on warfarin: Benzodiazepines Acetaminophen Opioids Indomethacin Most antibiotics

Warfarin Reversal of Action Stopping the drug Fresh-frozen plasma (FFP) Vitamin K

Vitamin K1 (Phytonadione) is found in food Vitamin K2 (Menaquinone) is synthesized by intestinal

bacteria Vitamin K3 (Menadione) should NEVER be used. It is

ineffective in warfarin overdosage Onset of effect is delayed for 6 hours Rapid infusion of vitamin K1 can produce dyspnea,

chest and back pain, and DEATH

Regulation of Fibrinolysis

Fibrinolysis is fulfilled by conversion of plasminogen to plasmin

Injured cells release activators of plasminogen Plasmin limits thrombosis by digestion of fibrin Fibrinolysis is therapeutic for thrombotic disease Heparin and the oral anticoagulant drugs do not

affect the fibrinolytic mechanism

Fibrinolytic Drugs

Fibrinolytic drugs activate formation of plasmin Usually both protective and target thrombi are

broken The drugs include:

Streptokinase & Urokinase Alteplase & Anistreplase (plasminogen+streptokinase) Tissue plasminogen activator (t-PA)

Indications of Fibrinolytic Drugs

Multiple pulmonary emboli

Central deep venous thrombosis

Acute myocardial infarction

Fibrinolytic Inhibitors

Inhibit plasminogen activation and include: Aminocaproic acid Tranexamic acid

Clinical uses: Adjunctive therapy in hemophilia Therapy for bleeding from fibrinolytic drugs

Adverse effect is intravascular thrombosis Should not be used in DIC or bleeding of the kidney

and ureters (potential for excessive clotting)

Fibrinolytic Inhibitors Cont,d

Aprotinin inhibits fibrinolysis by free plasmin It also inhibits the plasmin-streptokinase

complex in patients who have received it Approved for use in patients undergoing

coronary artery bypass grafting

Plasma Fractions

Spontaneous bleeding occurs when factor activity is less than 5–10% of normal

Factor VIII deficiency (classic hemophilia) & factor IX deficiency (Christmas disease) are the most common heritable coagulation defects

Cryoprecipitate is used to treat fibrinogen defects in DIC & liver disease

Desmopressin acetate increases the factor VIII activity and is used for minor surgery (tooth extraction)

SummaryIn English

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