Drugs used in coagulation disorders By S.Bohlooli, Ph.D.

Mechanism of blood coagulation    Thrombogenesis Blood coagulation Regulation of coagulation and fibrinolysis   Fibrin inhibition:  1 -antiprotease,  2 macroglobulin,  2 -antiplasmin, antithrombin Fibrinolysis: plasmin

Thrombogenesis

Blood coagulation

A model of blood coagulation

Fibrinolysis

Basic pharmacology of the anticoagulant drugs    Indirect thrombin inhibitors Direct thrombin inhibitors Warfarin and the Coumarin anticoagulants

Indirect thrombin inhibitors    Unfractioned heparin Low molecular-weight heparin:  Enoxoparin, daltaparin, tinzaprin foundaparinux

Differences between fondaparinux, LMWH and HMWH heparin

The antithrombin-binding structure of heparin

Toxicity     Bleeding Thrombocytopenia Caution in patient with allergy Contraindicated in:        Hypersensitive Actively bleeding Hemophilia Thrombocytopenia Sever Hypertension Intracranial hemorrhage Advanced renal or hepatic disease

Direct thrombin inhibitors     Hirudin, lepirudin Bivalirudin Agatroban Melagatran  Ximelagatran: oral prodrug

Warfarin and the Coumarin anticoagulants

Warfarin :Mechanism of action    Block the  -carboxylation of several glutamate residue in prothrombine and factors VII, IX, and X As well as the endogenous antigoagulant proteins C and S There is 8- to 12-hour delay in the action of warfarin

Warfarin :Mechanism of action

Warfarin: Toxicity      bleeding Readily crosses the placenta   Hemorrhagic disorders Abnormal bone formation Cutaneous necrosis Frank infarction of breast, fatty tissues intestine, and extremities Venous thrombosis

Basic pharmacology of the Fibrinolytic drugs

Contraindications to Thrombolytic Therapy 1.

2.

3.

4.

5.

6.

7.

Surgery within 10 days, including organ biopsy, puncture of noncompressible vessels, serious trauma, cardiopulmonary resuscitation Serious gastrointestinal bleeding within 3 months History of hypertension (diastolic pressure >110 mm Hg) Active bleeding or hemorrhagic disorder Previous cerebrovascular accident or active intracranial process Aortic dissection Acute pericarditis

Basic pharmacology of Antiplatelet agents     Clyclooxygenase inhibitors: Aspirin ADP receptor antagonists: Clopidogrel, ticlopidine Blockers of GP IIB/IIIA receptors: abciximab, eptifibatide, tirofiban Phosphodiesterase inhibitors: dipyridamole, cilostazol

Structure of ticlopidine and clopidogrel

Toxicity:Ticlopidine    nausea, vomiting, and diarrhea severe neutropenia: 2.4% patients Fatal agranulocytosis with thrombopenia

Clinical pharmacology of drugs used to prevent clotting   Venous thrombosis  Risk factors:  Inherited disorders   Acquired diseases Anithrombotic management   Prevention Treatment of established disease Arterial thrombosis  Antiplatelet drugs

Drugs used in bleeding disorders     Vitamin K Plasma fractions Fibrinolytic inhibitors: aminocaproic acid Serine protease inhibitors: aprotinin

Vitamin K

Vitamin K  to promote the biosynthesis of the  -carboxy glutamate (Gla) forms of:  factors II (prothrombin), VII, IX, and X    anticoagulant proteins C and S, protein Z (a cofactor to the inhibitor of Xa) the bone Gla protein osteocalcin, matrix Gla protein, growth arrest-specific protein 6 (Gas6) four transmembrane monospans of unknown function

Vitamin K Deficiency     increased tendency to bleed Ecchymoses, epistaxis, hematuria, gastrointestinal bleeding, and postoperative hemorrhage fetal warfarin syndrome: vitamin K dependent protein in bone deficits in bone mineral density and fractures

Toxicity   Phylloquinone and the menaquinones are nontoxic menadione and its derivatives:  hemolytic anemia and kernicterus in neonates, especially in premature infants