PREPARED BY :- NAGESH PANDITROLL NO :- 1155DEPTT OF PEDIATRICS

Drug-induced bleeding disorders

Physiological deficienciesThe coagulation 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.

Introduction:-Drugs are a 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.

DRUGS ASSOCIATED WITH BLEEDING DISORDER :-HEPARINWARFARIN AND VIT K ANTAGONISTTHROMBOLYTIC AGENTSANTI – PLATELETS DRUGS

HEPARINUnfractionated heparin (UFH), the low molecular weightheparins (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.

Heparin does not 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.

Anticoagulation with heparin 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%.

In individuals who 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.

UNFRACTIONATED HEPARIN

LMW HEPARIN (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 – dependentinactivation of thrombin, FXa

Accelerates AT-III – dependent inactivation of FXa and thrombin

Risk of bleeding

Low Low

Warfarin and vitamin K antagonistsWarfarin 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.

The anticoagulant action of 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

anticoagulantaction, e.g. clofibrate, anabolic steroids,

erythromycin.

Minor bleeding episodes 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

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.

Contraindications to coumarin 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.

WARFARIN

Indication Long-term oral anticoagulation

Dose 0.1-0.2 mg/kg/day PO

Adjustment ↑ dose q 2 days by 20-30% untilappropriate, stable INR

Course Weeks to months

Monitors/goal INR 2.0-3.0Mechanism Impairs vitamin K – dependent

carboxylation of FII, FVII, FIX, FX,proteins C and S

Risk of bleeding Low

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.

The currently available 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.

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.

Thrombolytic therapy cannot 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).

For patients receiving 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.

THROMBOLYTIC THERAPY

Indication Recent onset of life- orlimb-threatening thrombus

Dose rTPA 0.1-0.2 mg/kg/hr IV

Adjustment Increase dose for lack of clinicaleffect

Course 6-12 hr

Monitors/goal “ Lytic state ” : FDP or D-dimer(TPA)

Mechanism Activation of plasminogen toplasmin

Risk of bleeding

Medium to high

Anti – platelet dugs :-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.

Aspirin and non-steroidal anti-inflammatory drugs.

Dipyridamole.Ticlopidine and clopidogrel.drugs selectively bind to and block theplatelet 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.

Aspirin is the 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.

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