1. PREPARED BY :- NAGESH PANDIT
ROLL NO :- 1155
DEPTT OF PEDIATRICS
Drug-induced bleeding
disorders
2. Physiological deficiencies
The 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.
3. 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.
4. DRUGS ASSOCIATED WITH
BLEEDING DISORDER :-
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 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.
7. 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%.
8. 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.
9. 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 – dependent
inactivation of thrombin, FXa
Accelerates AT-III –
dependent inactivation of
FXa and thrombin
Risk of
bleeding
Low Low
10. Warfarin and vitamin K
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 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 anticoagulant
action, e.g. clofibrate, anabolic steroids, erythromycin.
12. 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
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 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.
15. WARFARIN
Indication Long-term oral anticoagulation
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 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.
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 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).
20. 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.
21. THROMBOLYTIC THERAPY
Indication Recent onset 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 – 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.
23. Aspirin and non-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 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.
