Medications For Coagulation and Platles

MEDICATIONS FOR COAGULATION AND PLATLES Coagulation inhibitors • Tissue factor pathway inhibitor o Quenches factor VIIa-TF complex • Antithrombin III o Binds to factor IIa to form an inactive thrombin-antithrombin complex o Also incapacitates Xa, IXa, XIa, XIIa o Potentiated by heparin • Protein C o Cleaves cofactor Factor VIIIa and Va o Needs to be activated • Protein S o Enhances the activity of protein C o Does not require prior activation • Thrombomodulin o Activated by thrombin o Binds to thrombin to alter its conformation o Activates protein C Fibrinolysis • • • • • Activated at the time of coagulation Tissue plasminogen activator (tPA) and urokinase tPA activates plasminogen and form plasmin Plasmin cleaves fibrin Inhibitors of fibrinolysis o Thrombin-activated fibrinolysis inhibitor removes the binding site of plasminogen and tPA o Plasminogen activator inhibitor o Plasmin inhibitor (2-antiplasmin) Approach to investigation of haemostasis • • • Bleeding history o Acquired/congenital o Family history, family tree o Detail of site, frequency, character ▪ Coagulation factor → soft tissue/muscle, joint ▪ Platelet → mucosal bleeding First line test attempts to mimic in vivo process, but sometimes misleading o Prothrombin time (PT) → measures extrinsic coagulation system ▪ Depends on factors VII, X, V,II and fibrinogen ▪ Citrated platelet poor plasma, add tissue factor, phospholipid and calcium, then measure time to clot formation o Activated Partial Thromboplastin Time (APTT) → measures intrinsic coagulation system ▪ Dependent on factor XII, XI, IX, VIII, II, V, X and fibrinogen ▪ Citrated anticoagulant platelet poor plasma ▪ Add Ca, contact factor activator (micronised silica), then measure time to clot formation o Platelet count Specific assays Caveats • Prolongation of clotting times does not necessarily correspond to bleeding risk o Factor XII deficiency leads to gross prolongation of the APTT, but is not associated with any bleeding tendency • Deficiency in one or more coagulation factors • Specific or non-specific inhibitors • Normal screening tests do not necessarily imply normal haemostasis Disseminated intravascular coagulation • Excessive and widespread activation of coagulation leading to consumption of clotting factors and inhibitors with loss of normal regulatory mechanisms. • Laboratory results: o Prolonged PT, APTT o Prolonged thrombin time TT o Reduced fibrinogen level o Elevated D-Dimer (D-Dimer is a fibrin degradation product) Clinical problems of haemostasis • Haemophilia o Factor VIII (Haemophilia A) deficiency o Factor IX deficiency (Haemophilia B, Christmas disease) o X linked recessive o Soft tissue bleeding (muscles) and haemarthrosis o Prolonged APTT • von Willibrand’s disease o Quantitative and qualitative abnormality of vWF o Autosomal dominant o Mucosal bleeding o Von Willebrand factor (VWF) is a large multimeric Acts as a bridging molecule at sites of vascular injury for normal platelet adhesion ▪ Under high shear conditions, it promotes platelet aggregation ▪ Acts as a carrier for factor VIII in the circulation, maintaining the normal level of factor VIII by increasing the half-life of factor VIII fivefold o Most common of the inherited bleeding disorders (1% of population) o VWF synthesized by endothelial cells and megakaryocytes Lupus anticoagulant o Acquired inhibitor of phospholipid coagulation activation o Associated with both venous and arterial thrombotic risk o APTT is prolonged ▪ • Anticoagulation • • • A clincial therapy that inhibits the normal coagulation or haemostatic process Prevent the development of a pathological thrombus (venous, arterial) and subsequent embolization e.g. peri-operative deep venous thrombosis, atrial fibrillation Stop the progression of an established thrombus and decrease the risk of embolization e.g. DVT, PE Warfarin • Haemorrhagic component of sweet clover • Competitive antagonist of vitamin K • Vitamin K gamma carboxylates FII, VII, IX, X, Protein C and S • Warfarin results in a decrease in the functional factors II, VII, IX and X, resulting in an anticoagulant effect • Orally available • Maximal effects occurs 2-4 days • Highly protein bound • • • • • Hepatic metabolism Drug interactions (numerous): o Antibiotics potentiate warfarin (increase effect) o Anticonvulsants inhibit warfarin Toxic effects: bleeding, teratogenic (cause birth defects) Monitoring: o Thromboplastin is assigned a value ISI for calibration to reference thromboplastin o PT patient/ PT normal ISI= INR (International normalized ratio) o Venous thromboembolism 2.0-3.0 o Atrial fibrillation 2.0-3.0 o Mechanical heart valves 3.0-4.5 Reversal: o Oral or intravenous vitamin K o Prothrombin complex (FII,IX,X) o Fresh frozen plasma Heparin • Heterogenous polymer of repeating disaccharide units • MW (molecular weight) = 3 000 to 30 000 • Only active parentally • Low molecular weight heparin: o Chemical or enzymatic derivative of unfractionated heparin with a mean MW of ~5000 o Fondaparinux = synthetic pentasaccharide o Mechanism: ▪ Potentiates antithrombin~1000 times (Binds to factor IIa to form an inactive thrombin-antithrombin complex and also incapacitates Xa, IXa, XIa, XIIa ) ▪ inhibit Xa and Thrombin ▪ LMWHs have higher anti-Xa/anti-IIa ratios, which are typically between 2.0 and 4.0 ▪ Any pentasaccharide sequence irrespective of chain length, inhibits Xa o Advantages: ▪ More predictable anticoagulant response ▪ Longer half life o Side effects: ▪ Bleeding (reversible with protamine) ▪ Heparin induced thrombocytopenia (platelet deficiency that causes bleeding into tissues, bruising, slow blood clotting after injury) ▪ Osteoporosis o Monitoring: ▪ Activated Partial Thromboplastin Time ▪ 1.5-2.5 times normal range ▪ AntiXa level for LMWH or Fondaparinux Antiplatelet therapy • Prevent thrombosis in arteries of the heart, cardiac chambers (A fib), brain, limb and venous system • • • • Aspirin (Acetylsalicylic acid) Thienopyridines (Clopidrogel) Phosphodiesterase inhibitors (Dipyridamole) Glycoprotein IIb/IIIa antagonist (abciximab and tirofiban) Fibrinolytic drugs • Used in the treatment of acute myocardial infarction • Recombinant tPA- Alteplase • Streptokinase Tenecteplase • Acute myocardial infarction • Recombinant tissue type plasminogen activator (tPA) • Clinical criteria: o Must be administrated within 12 hours of onset of attack o Patients with chest pain suggestive of acute myocardial ischemia who present up to 12 (and possibly up to 24) hours after symptom onset are candidates for reperfusion therapy with either fibrinolytic therapy or primary percutaneous coronary intervention (PCI) if the following electrocardiographic evidence is present: new ST-elevation at the J point in two anatomically contiguous leads Patients with typical and persistent symptoms in the presence of a new or presumably new left bundle branch block. o All patients who cannot receive primary PCI in a timely manner should be considered for fibrinolytic therapy. All available fibrinolytic agents, compared with placebo, reduce mortality in acute ST elevation MI. • Effects of thrombolysis: o Prolonged APTT o Prolonged TT (thrombin time) o Reduced plasma fibrinogen o Elevated D-Dimer