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Drug induced bleeding disorders
1) The document discusses various drugs that can cause bleeding disorders, including heparin, warfarin, thrombolytic agents, and anti-platelet drugs. It provides details on the mechanisms of action and risks of bleeding for each class of drugs. 2) Physiological deficiencies in coagulation factors in neonates can result in bleeding disorders. The pattern of bleeding seen in neonates is different from adults. 3) Minor bleeding from drugs like warfarin may be treated with stopping the drug, while severe bleeding requires vitamin K and clotting factor concentrates. Reversing heparin requires protamine sulfate.
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Overview of bleeding disorders, causes by drugs, and physiological deficiencies in newborns.
Details on Heparin's mechanism, indications, contraindications, and management of bleeding.
Warfarin mechanism, drug interactions, risks, and treatment protocols for bleeding control.
Mechanisms and types of thrombolytic drugs, their clinical applications, and risks of bleeding.
Administration guidelines for thrombolytic therapy, anti-platelet drugs, and associated bleeding risks.
Closure of the presentation.
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Drug induced bleeding disorders
- 1. PREPARED BY :-NAGESH PANDIT ROLL NO :- 1155 DEPTT OF PEDIATRICS Drug-induced bleeding disorders
- 2. Physiological deficiencies Thecoagulation system of the newborn infant is complex and reflects hepatic immaturity. Most of the clotting factors are present in reduced concentration in the newborn infant apart from factors V, VIII and fibrinogen. These physiological deficiencies in clotting factors result in prolongation of the prothrombin time (PT) and activated partial thromboplastin time (APTT) and as a consequence of this, reference ranges reflecting both gestational and neonatal age must be used to assess coagulation in the neonate. The platelet count is normal in the neonate although there may be a qualitative platelet abnormality. Fibrinolysis in the neonate is similar to that of adults. The pattern of bleeding seen in neonates – umbilical bleeding, cephalohematomas, bleeding after circumcisionoozing after venepuncture and bleeding into the skin – is different from that seen in adults.
- 3. Introduction:- Drugs area common cause of an acquired bleeding disorder. In many cases the drug may be obvious, e.g. an anticoagulant, but in other cases it may be less clear, as with the inhibitory effect on vitamin K metabolism observed with some cephalosporin.
- 4. DRUGS ASSOCIATED WITH BLEEDINGDISORDER :- HEPARIN WARFARIN AND VIT K ANTAGONIST THROMBOLYTIC AGENTS ANTI – PLATELETS DRUGS
- 5. HEPARIN Unfractionated heparin(UFH), the low molecular weight heparins (LMWHs) and fondaparinux (a synthetic pentasaccharide) are anticoagulants that potentiate the action of antithrombin by increasing its inhibitory activity. The inhibitory activity of UFH is directed against both thrombin (IIa) and factor Xa whereas that of the LMWH is primarily against factor Xa. Fondaparinux has exclusively anti-Xa activity. Bleeding in patients receiving heparin is usually secondary to excessive anticoagulation. Heparin is metabolized by the liver and excreted by the kidneys and LMWHs may accumulate in patients with impaired renal function. The average half-life of heparin administered IV is approximately 60 min in adults and can be as short as 30 min in the newborn.
- 6. Heparin doesnot cross the placenta. The half-life of heparin is dose-dependent; the higher the dose, the longer the circulating half-life. In thrombotic disease, the half-life may be shorter than normal in patients with significant thromboembolism (pulmonary embolism) and longer than normal in patients with cirrhosis and uremia.
- 7. Anticoagulation withheparin is contraindicated in the following circumstances: a recent central nervous system hemorrhage; bleeding from inaccessible sites; malignant hypertension; bacterial endocarditis; recent surgery of the eye, brain, or spinal cord; and current administration of regional or lumbar block anesthesia. A pre-existing coagulation defect or bleeding abnormality is a relative contraindication. Despite these precautions, the frequency of bleeding in patients given heparin anticoagulation is 0.2-1.0%.
- 8. In individualswho are actively bleeding, unfractionated heparin can be effectively neutralized by protamine sulphate, a strongly basic drug that binds to the heparin. A dose of 1 mg of protamine sulphate will neutralize approximately 100 units of heparin. In overdose, protamine sulphate can function as an anticoagulant and no more than 50 mg of protamine sulphate should be administered at any one time. Protamine sulphate neutralizes only 60% of the anti-Xa activity of the low molecular weight heparins and is, therefore, less effective in correcting the bleeding problems associated with their use. Protamine sulphate does not bind to fondaparinux and is, therefore, of no value in the management of patients on fondaparinux who are bleeding. Protamine itself is an anticoagulant; thus, if too much is given, clotting time may be prolonged. Although excess protamine has an anticoagulant effect, it rarely (if ever) is a cause of clinical bleeding. Once heparin is neutralized, the patient is returned to the original “ prothrombotic ” state.
- 9. UNFRACTIONATED HEPARIN LMWHEPARIN (ENOXAPARIN) Indication Thrombus of indeterminate age Thrombus of indeterminate age Dose 75 U/kg/bolus, 20-28 * U/kg/hr by continuous infusion IV 1.0-1.5 * mg/kg q12hr SC Adjustment ↑ dose by 5-10% q6hr until adequate level or PTT is achieved ↑ or ↓ by 10-20% Course 5-14 days 5 days-6 mo Monitors/goal PTT 2 1/2times control; thrombin time infinity; heparin level 0.3-0.7 U/mL LMW heparin level 4 hr after 4th dose = 0.5-1.0 U/mL Mechanism Accelerates AT-III – dependent inactivation of thrombin, FXa Accelerates AT-III – dependent inactivation of FXa and thrombin Risk of bleeding Low Low
- 10. Warfarin and vitaminK antagonists Warfarin is a 4-hydroxycoumarin derivative that exerts its action by blocking the regeneration of vitamin K from its epoxide. The major complication of all vitamin K antagonists is bleeding and this risk increases as the intensity of treatment, i.e. the INR, increases.
- 11. The anticoagulant actionof warfarin is potentiated by many drugs and these include: • Drugs that displace warfarin from its plasma protein binding sites, e.g. statins • Drugs that inhibit the metabolic clearance of warfarin, e.g. cimetidine, omeprazole, amiodarone, allopurinol • Drugs that interfere with vitamin K metabolism, e.g. cephalosporins, high dose salicylates • Drugs that independently increase the anticoagulant action, e.g. clofibrate, anabolic steroids, erythromycin.
- 12. Minor bleedingepisodes in patients receiving oral anticoagulants may be treated with local measures and withdrawal of the drug. In cases of severe or life- threatening hemorrhage, rapid reversal of anticoagulation is required and this is most effectively achieved by the use of a combination of vitamin K and clotting factor concentrates (containing factors II, VII, IX and X) and less effectively by vitamin K and fresh frozen plasma
- 13. Prothrombin time(PT) is the clotting test used to assess warfarin anticoagulation. Current recommendations are based on the International Normalized Ratio (INR), which permits comparison of PT using a wide variety of reagents or instruments. The INR for standard treatment of thrombosis is 2.0- 3.0.
- 14. Contraindications tocoumarin anticoagulants are essentially the same as those for heparin therapy. The oral anticoagulants are teratogenic, cross the placenta, and should not be givenduring pregnancy, particularly during the 1st trimester. Although breast milk contains warfarin, the quantity is insignifi cant and the drug can be used to treat the lactating mother without a significant effect on the infant.
- 15. WARFARIN Indication Long-term oralanticoagulation Dose 0.1-0.2 mg/kg/day PO Adjustment ↑ dose q 2 days by 20-30% until appropriate, stable INR Course Weeks to months Monitors/goal INR 2.0-3.0 Mechanism Impairs vitamin K – dependent carboxylation of FII, FVII, FIX, FX, proteins C and S Risk of bleeding Low
- 16. Thrombolytic agents :- Thrombolytic drugs act by stimulating endogenous fibrinolysis. T-PA or U-PA convert plasminogen to plasmin, a potent proteolytic enzyme which breaks down both cross-linked and non-cross-linked fibrin.
- 17. The currentlyavailable thrombolytic agents include: • Recombinant human tissue plasminogen activator (rt- PA) • Urokinase (U-PA) • Reteplase – a recombinant non-glycosylated form of human t-PA that contains only 357 of the 527 amino acids of the original protein • Tenecteplase – a recombinant fibrin-specific form of t- PA but engineered at three sites to confer a higher fibrin specificity than native t-PA and a greater resistance to inactivation by endogenous plasminogen activator type I (PAI-1) – the major inhibitor of t-PA • Staphylokinase • Streptokinase and its anisolyated derivative APSAC.
- 18. T-PA, urokinase,reteplase and tenecteplase produce their pharmacological actions by converting plasminogen to plasmin at the site of fibrin deposition. In contrast staphylokinase and streptokinase bind to free plasminogen in the plasma leading to systemic hyperfibrinolysis. Bleeding occurs in 3–40% of patients receiving thrombolytic therapy and this risk is greatly increased in patients who are also receiving anti-platelet drugs or other anticoagulants. Thrombolytic therapy predisposes to bleeding by depleting the plasma concentration of procoagulant proteins and by the generation of anticoagulant fibrin(ogen) degradation products.
- 19. Thrombolytic therapycannot distinguish between a pathological thrombus occluding a critical vessel, e.g. Coronary artery, and a physiological thrombus that is preventingbleeding from a critical site, e.g. in the cerebral circulation. Platelet function in patients receiving thrombolytic therapy is also impaired because of inhibition of platelet aggregation by high levels of FDPs and also by impaired platelet adhesion by plasmin-induced proteolysis of glycoprotein Ib (GpIb) and von Willebrand factor (vWF).
- 20. For patientsreceiving thrombolytic therapy and who develop minor bleeding episodes the thrombolytic agent, together with any anticoagulant or anti-platelet agent, must be discontinued. For life-threatening bleeding episodes, a fibrinolytic inhibitor should be given e.g. tranexamic acid. Fresh frozen plasma and/or cryoprecipitate or a fibrinogen concentrate should be given to restore depleted clotting factors.
- 21. THROMBOLYTIC THERAPY Indication Recentonset of life- or limb-threatening thrombus Dose rTPA 0.1-0.2 mg/kg/hr IV Adjustment Increase dose for lack of clinical effect Course 6-12 hr Monitors/goal “ Lytic state ” : FDP or D-dimer(TPA) Mechanism Activation of plasminogen to plasmin Risk of bleeding Medium to high
- 22. Anti – plateletdugs :- A wide variety of drugs are in common use that have potent anti-platelet actions and such drugs are often used in combination, for example aspirin and clopidogrel. The risk of hemorrhage is significantly increased when anti-platelet drugs are used in combination with other anticoagulants, for example warfarin and aspirin.
- 23. Aspirin andnon-steroidal anti-inflammatory drugs. Dipyridamole. Ticlopidine and clopidogrel. drugs selectively bind to and block the platelet GpIIb/IIIa complex like abciximab. Platelet function abnormalities can be induced by certain antibiotics, particularly the β-lactam antibiotics like penicillin G, ticarcillin and carbenicillin. Some cephalosporins also appear to interfere with vitamin K metabolism resulting in an additional and additive increased risk of bleeding.
- 24. Aspirin isthe only commonly used antiplatelet agent, and the usual dose is 80 mg/day (1 baby aspirin daily). There is no need to monitor aspirin therapy.
- 25.