P1: PSB Printer: Yet To Come
9780521704632c23 CUFX213A/Peck 9780521618168 December 29, 2007 14:58
23 Drugs affecting coagulation
Thrombocytopenia – A non-immune based thrombocytopenia (type I) occurs
within four days of anticoagulant doses of heparin. This rarely has clini-
cal significance and the platelet count recovers without stopping heparin.
This contrasts with the more severe (type II) immune-mediated thrombocy-
topenia, which occurs within 4 to 14 days of starting intravenous or subcutaneous
heparin (fractionated and unfractionated). Heparin complexes with platelet fac-
tor 4, which is bound by IgG causing platelet aggregation and thrombosis. Half of
these patients develop serious thrombosis after the platelet count starts to fall and
mortality is high, mainly from pulmonary embolus. In addition 20% get arterial
thrombosis leading to stroke and limb ischaemia.
Cardiovascular – hypotension may follow rapid intravenous administration of a
large dose.
Miscellaneous – osteoporosis, due to complexing of mineral substance from bone,
and alopecia have been reported. Heparin (including LMWH) can cause hyper-
kalaemia, which may be due to inhibition of aldosterone secretion. Patients with
diabetes mellitus and chronic renal failure are particularly susceptible and the risk
increases with the duration of therapy.Kinetics
As the potency of commercial preparations varies, unfractionated heparin is pre-
sented as units.ml−^1 rather than mg.ml−^1 .Itisineffective orally and may only be
given subcutaneously or intravenously. It has a low lipid solubility and does not
cross the BBB or placenta. Owing to its negative charge it is highly bound in plasma
to anti-thrombin III, albumin, proteases and fibrinogen. It is metabolized by hep-
atic heparinase and the products are excreted in the urine. During hypothermia (e.g.
cardiopulmonary bypass) clearance is reduced. Its effects are reversed by protamine.Low-molecular-weight heparins (LMWHs)
Enoxaparin, dalteparin, tinzaparin
These drugs are derived from the depolymerization of heparin by either chemical or
enzymatic degradation. Their molecular weights vary from 2000 to 8000 Da.Uses
LMWHs have proven benefit over unfractionated heparin in reducing the incidence
of fatal PE after major orthopaedic surgery.
Advantages include:
Single daily dose, due to a longer half-life
Reduced affinity for von Willebrand factor
Less effect on platelets
Reduced risk of heparin induced thrombocytopenia
Reduced need for monitoring