3. INTRODUCTION:
Hematotoxicology is the study of adverse effects of
drugs, nontherapeutic chemicals and other agents
in our environment on blood and blood-forming
tissues (Bloom, 1997).
This subspecialty draws on the discipline of
hematology and the principles of toxicology
4. ORAL ANTICOAGULANTS
Mode of Action
■ All oral anticoagulants act by inhibiting vitamin K
(which is a cofactor in the post-ribosomal synthesis
of clotting factors II, VII, IX, and X), by interfering
with the activity of vitamin K 2,3-epoxide reductase
and vitamin K quinone reductase.
5. The therapeutic window for oral
anticoagulants is relatively narrow.
And there is considerable interindividual
variation in the response to a given dose.
A number of factors, including: concurrent
medications and genetics factors
6. For these reasons, therapy with these
drugs must be routinely monitored to
maximize both safety and efficacy.
This is routinely performed with the PT,
with results expressed in terms of the
international normalized ratio (INR)
8. Inhibition of CYP2C9.
Induction of CYP2C9
Interference with absorption of warfarin
from the gastrointestinal tract
Displacement of warfarin from albumin
in plasma, which temporarily increases
the bioavailability of warfarin
9. TOXICOKINETICS
Following oral administration, warfarin is
bioavailable to the extent of 100%, peaking in the
plasma in about 1 hour, with a volume of
distribution of 0.126 L/kg and protein binding of 98
to 99%.
Elimination half-life is about 40 hours.
Duration of action may extend up to 5 days.
10. Oral anticoagulants have been associated
with the development of warfarin-induced
skin necrosis that is due to the
development of extensive microvascular
thrombosis in the affected skin.
This uncommon toxic effect is thought to
be related to a rapid drop in protein C
following administration of the drug,
resulting in impaired protein C function
12. administration of warfarin during pregnancy,
particularly the first 12 weeks of pregnancy,
is associated with congenital anomalies in
25–30% of exposed infants Many of the
anomalies are related to abnormal bone
formation
Vitamin K is necessary for the synthesis of
proteins other than the coagulation-related
factors, including osteocalcin, a major
component of bone
13. TOXIC (CLINICAL) FEATURES:
The primary effect of warfarin overdose is
prolongation of prothrombin time, and
subsequent risk of haemorrhage.
The onset of prolonged PT. usually appears within
24 hours of ingestion, and peaks between 36 to 72
hours.
14. CLINICAL MANIFESTATIONS:
Begin a few days or weeks after ingestion, and include:
epistaxis,
gingival bleeding
pallor
haematuria
melaena.
Other symptoms include back pain, bleeding lips,
mucous membrane haemorrhage, abdominal pain and
vomiting, .
Later, paralysis due to cerebral haemorrhage, and finally
haemorrhagic shock and death may occur.
17. 1. INVESTIGATIONS:
a. The international normalised ratio (INR) or
prothrombin time (PT) are the best values to
monitor.
The onset of INR elevation or PT prolongation is
between 12 and 24 hours post-ingestion.
Any increase in INR or prolongation of
prothrombin time when compared to normal
controls, indicates toxicity.
18. b. Determination of blood clotting factors II, VII,
IX, and X may be helpful in guiding therapy in
symptomatic patients.
Since clotting factors may be abnormal with a
normal INR or PT, they are a more sensitive
measure of toxicity and may be more useful in
guiding vitamin K1 therapy.
c. Monitor haemoglobin and haematocrit if bleeding
occurs. Monitor urine and stool for occult blood.
19. 2. STABILISATION:
a. Admit to intensive care facility and monitor
clotting parameters.
Watch out for signs of bleeding.
Administer whole blood or plasma if bleeding is
severe
Premature discharge of such patients at 3 to 4
weeks post ingestion prior to full normalisation of
factor levels has resulted in fatalities.
20. b. Frequent outpatient monitoring should be done on
patients discharged on oral vitamin K1 to ensure
compliance and adequacy of treatment.
Factor assays should be normal prior to
discontinuation of vitamin K1.
21. 3. DECONTAMINATION:
a. Emesis and gastric lavage are contraindicated
due to the potential risk of inducing bleeding.
b. Activated charcoal can be administered.
Patients on chronic anticoagulation therapy should
receive activated charcoal after an acute overdose.
22. ANTIDOTE:
Vitamin K1 (phytomenadione, phytonadione,
phylloquinone).
a. Mode of action: Since oral anticoagulants are
vitamin K antagonists, administration of vitamin
K1 sets right the anomaly.
Vitamins K2 (menaquinones), K3 (menadione),
and K4 (menadiol sodium diphosphate) are not
recommended, since they can induce haemolysis,
hyperbilirubinaemia, and kernicterus in neonates,
and haemolysis in G6PD deficient patients
23. b. Indications: Prophylactic treatment for a
suspected large ingestion of warfarin is not
recommended.
PT or INR should be checked 24 hours after
ingestion.
If results are normal, PT and INR should be
repeated at 48 hours after ingestion.
If PT or INR is elevated, then Vitamin K1 may be
given.
c. Dose:(reference)
24. 5. SUPPORTIVE MEASURES:
a. Administer fresh frozen plasma and/or
prothrombin complex concentrate and packed
red blood cells as needed for significant active
bleeding.
The usual dose of fresh frozen plasma given
to correct coagulation factor deficiency is 15
ml/kg, but the recommended dose required to
reverse over anticoagulation due to warfarin has
not been established.
27. HIRUDIN:
Hirudin is a polypeptide, present in leeches (Hirudo
medicinalis) and is a highly selective thrombin
inhibitor.
It is a naturally occurring 65-amino acid polypeptide
that is produced from the saliva of the medicinal
leech.
28. The most common complication observed with
selective thrombin inhibitor therapy is haemorrhage.
Although the incidence of major bleeding is less
when compared with other anticoagulants.
Bleeding from puncture wound sites, anaemia,
haematomas, haematuria, gastrointestinal and
rectal bleeding, epistaxis, intracranial bleeding and
haemothorax have been reported.
29. Other non-haemorrhagic effects seen in clinical
trials include :
Hypotension
cardiac arrest
dyspnoea, fever
nausea, vomiting, diarrhoea
cardiac arrhythmias, and
abnormal hepatic and renal function.
Some of these complications are likely related to
underlying disease processes.
Acute allergic reactions and formation of antihirudin
antibodies have also been reported.
30. Overdose results in significant
haemorrhage which responds well
to prothrombin complex
concentrate.
31. Treatment involves symptomatic and supportive
measures.
If bleeding is suspected:
monitor patient’s haematocrit, haemoglobin,
activated partial thromboplastin time, INR, platelet
count and fibrinogen.
Monitor vital signs, ECG, renal and hepatic function
in symptomatic patients.
No specific antidotes are available for the
direct thrombin inhibitors.
32. If excessive anticoagulation occurs, discontinue the
drug or decrease the infusion dosage.
If necessary, blood loss and reversal of bleeding
tendency can be managed with
packed red blood cells
and cryoprecipitate or fresh frozen plasma.
33. THROMBOLYTICS:
Thrombolytic agents are plasminogen activators
which cleave the Arg-Val bond of plasminogen
resulting in the formation of plasmin
Common examples include :
Alteplase, anistreplase, reteplase, streptokinase,
tenectoplase, urokinase, and tissue plasminogen
activator
34. Concurrent administration of thrombolytic agents
with oral anticoagulants is contraindicated when the
prothrombin time is greater than 15 seconds.
Concurrent use of thrombolytic agent with drugs
known to significantly affect platelet integrity (e.g.
aspirin, indomethacin, dipyridamole,
phenylbutazone) should also be avoided
35. Treatment of toxic effects arising from the
use of these agents involves the
following measures:
If bleeding is suspected, monitor patient’s haematocrit,
haemoglobin, partial thromboplastin time, prothrombin
time/INR, platelet count, and fibrinogen. Monitor vital signs,
renal and hepatic functions in symptomatic patients.
Discontinue the drug.
Replace volume as required.
If bleeding continues, administer transfusion
products. Cryoprecipitate (10 U) can be given.
36. If patient continues to bleed, 2 to 6 U of
fresh-frozen plasma may be necessary.
If the bleeding is persistent in spite of the
above measures, 10 U of platelets and
antifibrinolytic drugs (e-aminocaproic acid or
tranexamic acid) must be given.
The use of aminocaproic acid as an antidote
for streptokinase has not been documented,
but it may be considered in an emergency
situation.
37. ANTIPLATELET DRUGS:
Common examples include aspirin( chapter 29),
dipyridamole, and ticlopidine.
Ticlopidine is a thienopyridine which inhibits
platelet function by inducing a thrombasthenia-like
state. It is used for prevention of thrombosis in
cerebral vascular and coronary artery disease that
can lead to myocardial infarction,
38. The oral bioavailability of ticlopidine is 80 to 90 per
cent, with peak concentrations occurring at
approximately 2 hours. It is reported to reversibly
(98%) bind to plasma proteins, mainly
to serum albumin and lipoproteins, and is extensively
metabolised by the liver
39. Adverse effects include bleeding, nausea, vomiting,
abdominal pain, diarrhoea, cholestatic jaundice,
elevated liver enzyme levels, agranulocytosis,
anaemia, and thrombocytopenia. Neutropenia has
also been reported. Aplastic anaemia has occurred.
Skin rashes are a common side effect with this
agent
40. Ticlopidine has been rarely implicated in overdoses.
Treatment is symptomatic and supportive.
Granulocyte colony-stimulating factor (G-CSF) has
been used to treat severe neutropenia/leukopenia
associated with ticlopidine therapy.
The mortality from ticlopidine induced thrombotic
thrombocytopenic purpura may be reduced by
plasma exchange or plasmapheresis
