toxicology

1. (Heparin and Low-Molecular-Weight Heparins)

2. Anticoagulants:
1. Heparin and Low-Molecular-Weight Heparins:
 dalteparin
 enoxaparin
 Nadroparin
 parnaparin
 reviparin
 tedelparin
 tinzaparin.

3. Heparins and Low Molecular Weight:
Heparins:
Heparin was discovered by McLean, a medical student,
in 1916, and isolated by Howell (who owned the
laboratory in which McLean worked), in 1922.
 Low Molecular Weight Heparins (LMWH):
are fragments of heparin with anticoagulant activity, and
are isolated from standard heparin by gel filtration
chromatography or differential precipitation with
ethanol.

4. Uses:
 Heparin is used in the prophylaxis and treatment of
deep vein thrombosis, embolism, and post-surgical
arterial embolism.

5. Toxicokinetics

6. Heparin and LMW heparins administered parenterally
(usually subcutaneously or intravenously).
Onset of action is immediate (IV), or delayed by 1 to 2
hours (SC).
Half-life of heparin varies from 1 to 5 hours, and it is
cleared and degraded mainly by the reticuloendothelial
system

7. It is cleaved by heparinase into oligosaccharides in the
liver and spleen.
Low molecular weight (LMW) heparins have longer half
lives than heparin.
They are metabolized more slowly than normal heparin

8. Mode of Action:
Heparin inhibits thrombosis by accelerating the
binding of the protease inhibitor antithrombin III to
thrombin and other serine proteases involved in
coagulation.

9. Adverse Effects:
 1. The adverse effect of heparin is haemorrhage.
Common sites of bleeding may include the GI tract,
skin, urinary tract, and the pulmonary and
cardiovascular systems.

10. Heparin-induced thrombocytopenia (HIT) represents
another mechanism of immune-mediated platelet
destruction.
This disorder is due to the development of antibodies
that react with a multimolecular complex formed by the
interaction between heparin and a protein, usually
platelet factor 4 (PF 4)

11. This results in platelet activation and aggregation.
During the process of platelet activation, platelet
microparticles that promote thrombin generation are
released.
Consequently, HIT is associated with both
thrombocytopenia and an increased risk of arterial and
venous thrombosis

12. 2. HITTS may manifest as thrombotic
phenomena:
deep venous thrombosis
pulmonary emboli
 myocardial infarction
 cerebral thrombosis
Adrenal infarction
 renal artery embolism
 skin necrosis
aortic and limb arterial thrombosis,

13. HITTS may manifest as haemorrhagic phenomena:
 cerebral haemorrhage
 GI bleeding
 adrenal haemorrhage
 epistaxis
 Haematuria
 Intramuscular Haematoma
 HITTS carries a 30% death rate.
 Mild thrombocytopenia may be noted in up to 30% of patients
on heparin therapy and is generally transient.
 Clinically significant thrombocytopenia occurs in less than 10%
of patients on heparin therapy, and this too is generally transient.

14. Factors associated with an increased risk
of bleeding with heparin include:
Aspirin use
 underlying morbid condition
 alcohol consumption
renal failure
female sex.

15. Heparin use during pregnancy may be associated with
increased susceptibility to premature delivery, foetal
loss, neonatal death, and maternal death.
 Skin necrosis has been reported following heparin and
low molecular-weight heparin (LMWH) therapy.

16. Skin necrosis at the sites of subcutaneous heparin
injections have been ascribed to the complications of
heparin-induced thrombocytopenia.
 The onset of skin reactions warrants prompt
discontinuation of heparin and close monitoring for
thrombocytopenia and platelet-aggregating antibodies.

17. Hyperkalaemia and secondary hypoaldosteronism
have been reported following either unfractionated
heparin therapy or low-molecular-weight heparin
therapy, especially in patients with diabetes mellitus or
renal insufficiency.
 Long term administration of heparin is associated with
an increased risk of clinically significant
osteoporosis
 The mechanism underlying the development of
osteoporosis in these patients is not known.

18. Drug Interactions:
Potentiation of oral anticoagulants, methotrexate, and
oral hypoglycaemics.
Salicylates and dipyridamole enhance activity of
heparin.
 Bleeding tendency enhanced with NSAIDs and aspirin.
Incompatible with aminoglycoside antibiotics.

19. Toxic (Clinical) Features:
1. Overdose of heparin results in rapid prolongation of
coagulation time and active bleeding.
2. Hypotension and respiratory distress develop.
3. Chronic heparin therapy is associated with
hyperkalaemia due to aldosterone suppression.
4. Abrupt withdrawal of heparin can put the patient at
increased risk for transient ischaemic attack or cerebral
stroke.

20. Treatment

21. 1. Admit patient to intensive care and monitor blood
clotting parameters.
2. Evaluate airway, breathing, and circulatory status.
3. Undertake complete blood count, platelet count,
coagulation profile (bleeding time, clotting time), and
activated partial thromboplastin time.

23. There is a large interpatient variability in
anticoagulant response to heparin as evaluated
by the aPTT.
Similar doses of heparin may lead to 12-fold
variations in aPTT. The baseline aPTT accounts for
most of the variability and should be determined prior
to initiating therapy.

24. Other coagulation test such as PT may be used for
monitoring heparin effects.
5. Urinalysis should be obtained for detection of
haematuria. Examine sputum and stool for the presence
of blood.

25. Because of the short duration of action of aqueous heparin
after therapeutic doses, treatment of extremely prolonged
clotting time or minor bleeding during therapy is usually
managed simply by decreasing or stopping the heparin
dose or frequency of injections.

26. In the event of significant hemorrhage, a heparin
antagonist should be used to reverse the effects of
heparin on coagulation
Replace blood loss with whole blood or plasma.
Exchange transfusion has been successful in neonates.
Antidote: Protamine sulfate is used in severe
overdose involving heparin or LMW heparins

27. Protamine is a low molecular- weight protein, and
forms ionic bonds with heparin rendering it devoid of
anticoagulant activity.
 Protamine reacts with heparin to form a stable salt,
resulting in neutralisation of heparin’s anticoagulant
activity (within 30 to 60 seconds)
Each milligram of protamine (given IV) inactivates 100
U of heparin.
a. Dose: 2 mg/kg (maximum 50 mg), slow IV over 10
minutes.

28. There is a significant risk of anaphylaxis which is
enhanced in patients with a history of allergy to fish.
Diabetic patients receiving protamine-containing
insulin (NPH) are also at increased risk.

30. a. Withdraw heparin.
• However, current opinion is that LMWHs are not recommended
to be used as alternative anticoagulant therapy in patients with
HITTS.
b. Substitute with LMW heparins.
• because in some patients, a thrombus may grow or embolise
before warfarin becomes effective.
c. Warfarin as sole therapy may be risky,

31. d. Dextran therapy.
• When re-exposure to heparin is essential and plateletaggregating antibodies are still
present, aspirin, dipyridamole, have been used with variable success to prevent
recurrence of thrombocytopenia and thrombosis.
e. Administer antiplatelet drugs (aspirin,
dipyridamole).
f. Incidence of venous thrombosis can be
minimised with IV streptokinase.

32. g. Heparin-associated thrombocytopenia has been
treated successfully with IV immunoglobulin (0.4
gm/kg), followed by platelet transfusion.
h. Lepirudin (rDNA) is indicated specifically for
anticoagulation in patients with heparin-induced
thrombocytopenia and associated thromboembolic disease,
in order to prevent further thromboembolic complications.

33. Reference:
Modern Medical Toxicology 4th Edition
Jaypee Brothers Medical Publishers (P) Ltd
Completely Updated, revised and profusely
illustrated