Heparin
Benedict R. Lucchesi, M.D., Ph.D.
Department of Pharmacology
University of Michigan Medical School
Heparin
Chemistry
–Low molecular weight
fractions of heparin have a
high affinity for
ACTIVATED FACTOR X
(Xa), but have less of an
effect on thrombin.
Antithrombin-Binding Structure of Heparin
I
II
OSO-3
COO-
O
O
OH
IV
*OSO
O
COOOH
CH2OSO3
O
O
O
III
O
OH
NH R’’
D-Glucosamine D-Glucuronic
Unit
Acid
R’= H or -SO3R’’= COCH3 or -SO3-
3
O
V
H2CO R’
O
O
OH
O
HNSO3OSO3HNSO3D-Glucosamine L-Iduronic
D-Glucosamine
Acid
* Antithrombin binding region
Groups essential for high
affinity binding of antithrombin
ATIII
Thrombin
Lysine
Sites
5
13 or more saccharide units
Heparin
ATIII
Factor Xa
Lysine
Sites
5
<13
Low Molecular Weight Heparin
Inhibition of thrombin and Factor Xa by the Heparin/AT III complex
through a unique pentasaccharide unit. Binding to thrombin requires a
minimum of 13 saccharide units. Low molecular weight heparin acts to
inhibit Factor Xa and requires that the latter only bind to AT III.
Anticoagulant Therapy
Heparin
–Actions of Heparin
»Inactive by itself as an anticoagulant
»Requires the presence of a plasma cofactor-
ANTITHROMBIN III (AT III)
»Heparin potentiates the action of AT III
»Heparin-AT III-complex neutralizes the actions of:
Factors II, IX, X, XI, XII and XIII
»Binds to lysine sites on AT III, leads to
conformational change at the arginine reactive center
INTRINSIC PATHWAY
EXTRINSIC PATHWAY
IXa
VIIa / Tissue Factor
TFPI
VIIIa
aPC
= sites of
Heparin/ATIII
Inhibition
FACTOR Xa
Prothrombin
aPC
Protein S
Platelet
Aggregation
Va
Thrombin
PC / Thrombomodulin
aPC
Inactivation Va & VIIIa
Fibrinogen
XIIIa
Fibrin
Actions of Heparin
1. Low concentrations of heparin increase the
activity of AT III considerably, especially
against Factor Xa and THROMBIN - these are
the most sensitive components of the
coagulation cascade
2. Rationale for the clinical use of “mini-dose”
heparin
3. Inhibition of THROMBIN requires that both the
AT III complex and the ENZYME bind to
heparin
4. Inhibition of FACTOR Xa requires that heparin
only bind to AT III
Actions of Heparin (continued)
5. Binds strongly to AT III - leads to
conformational change of AT III
6. Active site of AT III is exposed
7. The active AT III inhibits the
proteases involved in coagulation Factors II, IX, X, XI, XII and XIII
8. Heparin is NOT consumed, but is
released from the AT III complex and
is available to react to AT III.
Heparin Pharmacokinetics
• Heparin binds to saturable sites on
the endothelial cells
• It is internalized and depolymerized
• It displaces platelet factor 4 from the
endothelial cells - a protein that
neutralizes heparin
Heparin-Anticoagulant action is modified by:
Fibrin -
–Clot bound fibrin binds thrombin and protects it
from inactivation by heparin-AT III.
Platelets –Bind factor Xa and protect it from heparin-AT
III complex inhibition and by secreting platelet
factor 4
»Not the case with HIRUDIN (AT III independent).
»Subendothelial thrombin is protected from heparinAT III as well.
Heparin-Contraindications
–Patients who are hypersensitive
–Presence of active bleeding or hemophilia
–Thrombocytopenia
–Purpura
–Severe hypertension
–Intracranial hemorrhage
–Bacterial endocarditis
–Active tuberculosis
–Ulcerative lesions of GI tract
Heparin-Contraindications
–Threatened abortion
–Visceral carcinoma
–During or after surgery on the brain,
spinal cord or eye
–Patients undergoing lumbar puncture
or regional anesthesia block
–History of heparin-induced
thrombocytopenia
Heparin-Adverse Effects
Side Effects
Dose Related
Major Bleeding
Yes
Thrombocytopenia
Yes
with thrombosis
Yes
Osteoporosis
Yes
Anaphylaxis
No
Skin necrosis
?
Local urticaria
?
Hypoaldosteronism
?
Frequency
5%
5 - 15%
0.4%
Rare
Rare
Rare
Rare
Rare
Heparin-Induced
Thrombocytopenia
vs
Heparin-Induced Thrombocytopenia
and
Thrombosis
Heparin-Adverse Effects
(continued)
Heparin-Induced Thrombocytopenia TWO FORMS:
–Mild reduction in platelet count, 2-15 days
after initiation of full-dose heparin therapy
–Platelet count usually remains above
100,000/µl. Bleeding risk is minimal
Heparin-Adverse Effects (continued)
Heparin-Induced Thrombocytopenia-and
Thrombosis
–Severe reduction in platelet count, 7-14 days
after initiation of therapy with full-dose or lowdose heparin
–May be associated with thrombotic
complications, including arterial thrombosis with
platelet-fibrin clots that may cause MI or stroke
–Presence of antiplatelet IgG in patients with
severe form ?
–May be less common with heparin from pork.
Heparin - Laboratory Monitoring
aPTT / TCT
–Therapy is routinely monitored by means of the
aPTT (at UofM it is the TCT)
–A clotting time of 1.5 to 2.0 times the normal
mean aPTT value (50 - 70 seconds) is therapeutic
–Initially the aPTT should be measured and the
infusion rate adjusted every 4 hours.
–Once a steady state is achieved, daily monitoring
is sufficient.
Resistance to Heparin
• Some patients may not show a
prolongation of the aPTT unless very
high doses of heparin are used
• Presence of an increased concentration of
FACTOR VIII will give rise to a very
short control aPTT - they may not be
truly resistant to heparin
Heparin-Resistance to Heparin
(continued)
• Accelerated clearance of heparin may exist - as
in the case of massive pulmonary embolism
• Inherited AT III deficiency have 40 - 60 % of the
normal plasma concentration of AT III. They
respond normally to heparin
• Acquired AT III deficiency as with hepatic
cirrhosis, nephrotic syndrome or disseminated
intravascular coagulation; large doses of heparin
may not prolong the aPTT
Heparin - Managing OverAnticoagulation
• Anticoagulant effect of heparin disappears
within hours after discontinuation of the drug.
• Mild bleeding due to heparin can be
controlled without administration of an
antagonist.
• Antagonists are used if bleeding is lifethreatening.
Heparin - Managing of OverAnticoagulation
Management depends on:
–Degree of over-anticoagulation
–Presence or absence of bleeding
–A specific, immediate heparin antagonist
–Protamine Sulfate
–Use 25 - 50 mg intravenously
–Side-effects largely allergic in nature
Heparin: Managing
Overanticoagulation (cont’d)
• Protamine binds to the acidic (negatively charged)
heparin molecule - neutralizes heparin.
• Protamine also interacts with platelets, fibrinogen, and
other plasma proteins.
• Use smallest dose, give by slow IV infusion - do not
exceed 50 mg over 10 min. - Causes, flushing,
bradycardia, dyspnea, hypotension, anaphylaxis.
• Use 1 mg of protamine for every 100 units of heparin
remaining in the patient.
• Protamine sulfate is a low molecular weight, basic
(positively charged) protein.
Heparin - Clinical Uses
–Effective for the prevention and treatment of:
• venous thrombosis and pulmonary embolism
• mural thrombosis after acute MI
• managing unstable angina
• prevention of coronary artery rethrombosis
• used to prevent blood clotting in extracorporeal
•
•
circulation - e.g. surgery, hemodialysis
treat selected cases of disseminated intravas-cular
coagulation (DIC)
treat fetal growth retardation in pregnant women
Heparin - Recommendations for
Clinical Use
Pregnancy - heparin is the anticoagulant of choice
–does not cross the placenta
–no untoward effects in the fetus or newborn
–given in therapeutic doses - 15,000 U sc q 12 hrs
to women with prosthetic heart valves or venous
thromboembolism
–doses in excess of 20,000 U per 24 hrs for more
than 5 months is questionable -due to risk of
OSTEOPOROSIS
Low Molecular-Weight Heparins
Enoxaparin (Lovenox™)
Dalteparin (Fragmin™)
–contain a lower proportion of the critical
pentasaccharide sequence than the parent
compound.
–they increase the action of ATIII on factor Xa,
but not its action on thrombin.
Low Molecular-Weight Heparins
• The LMWHs are not inactivated by platelet
factor 4, therefore activity extends to factor Xa
bound to platelet membranes.
• In clinical doses, no affect on platelet reactivity,
PT or aPTT.
• Currently approved for prevention of deep vein
thrombosis:
• After hip or knee surgery or abdominal surgery.
• Unstable angina (NQWMI).
Low Molecular Weight Heparins
• Do not require routine monitoring of INR, PT,
or aPTT.
• One fixed dose administered subcutaneously.
– 30 mg every 12 hours.
• Must not be administered IM and is not
intended for IV administration.
• Use with caution in patients with a history of
heparin-induced thrombocytopenia.
• Reversed by protamine, 1 mg for each mg of
LMWH.