Transcript drugs used in disorders of coagulation and hemopoiesis

Clinical Pharmacy in
Haematology
DRUGS USED IN
DISORDERS OF
COAGULATION AND
HEMOPOIESIS
Spectrum of haematological diseases
Deficiency anaemias
 Disorders of haemoglobin structure
 Haemolytic structure
 Aplastic anaemia
 Haematological malignancies: leukaemias and lymphomas
(all aspects of management, including bone marrow
transplantation)
 Congenital and acquired bleeding disorders
 Thromboembolic disorders and anticoagulation
 Transfusion medicine
 Haematological problems associated with perinatal care;
intensive care; renal medicine, organ transplantation,
orthopaedic and vascular surgery (in adults).

Thrombus formation at the site of
the damaged vascular wall
A model of blood coagulation
ANTICOAGULANT DRUGS
The ideal anticoagulant drug would prevent
pathologic thrombosis and limit reperfusion injury,
yet allow a normal response to vascular injury and
limit bleeding. Theoretically this could be
accomplished by preservation of the TF-VIIa
initiation phase of the clotting mechanism with
attenuation of the secondary intrinsic pathway
propagation phase of clot development. At this
time such a drug does not exist; all anticoagulants
and fibrinolytic drugs have an increased bleeding
risk as their principle toxicity
INDIRECT THROMBIN
INHIBITORS
The indirect thrombin inhibitors are so-named because
their antithrombotic effect is exerted by their
interaction with a separate protein, antithrombin.
Unfractionated heparin (UFH), low-molecularweight heparin (LMWH), and the synthetic
pentasaccharide fondaparinux bind to antithrombin
and enhance its inactivation of factor Xa.
Unfractionated heparin and to a lesser extent LMWH
also enhance antithrombin's inactivation of thrombin.
Heparin
Heparin is a heterogeneous mixture of sulfated
mucopolysaccharides. It binds to endothelial cell surfaces and
a variety of plasma proteins. Its biologic activity is dependent
upon the endogenous anticoagulant antithrombin.
Antithrombin inhibits clotting factor proteases, especially
thrombin (IIa), IXa, and Xa, by forming equimolar stable
complexes with them. In the absence of heparin, these
reactions are slow; in the presence of heparin, they are
accelerated 1000-fold. Only about a third of the molecules in
commercial heparin preparations have an accelerating effect
because the remainder lack the unique pentasaccharide
sequence needed for high-affinity binding to antithrombin.
The active heparin molecules bind tightly to antithrombin and
cause a conformational change in this inhibitor. The
conformational change of antithrombin exposes its active site
for more rapid interaction with the proteases (the activated
clotting factors). Heparin functions as a cofactor for the
antithrombin-protease reaction without being consumed. Once
the antithrombin-protease complex is formed, heparin is
released intact for renewed binding to more antithrombin.
The antithrombin binding region of commercial
unfractionated heparin consists of repeating sulfated
disaccharide units composed of D-glucosamine-L-iduronic
acid and D-glucosamine-D-glucuronic acid. Highmolecular-weight fractions of heparin with high affinity for
antithrombin markedly inhibit blood coagulation by
inhibiting all three factors, especially thrombin and factor
Xa. Unfractionated heparin has a molecular weight range
of 5000-30,000. In contrast, the shorter-chain lowmolecular-weight (LMW) fractions of heparin inhibit
activated factor X but have less effect on thrombin than the
HMW species. Nevertheless, numerous studies have
demonstrated that LMW heparins such as enoxaparin,
dalteparin, and tinzaparin are effective in several
thromboembolic conditions. In fact, these LMW
heparins¾in comparison with UFH¾have equal efficacy,
increased bioavailability from the subcutaneous site of
injection, and less frequent dosing requirements (once or
twice daily is sufficient).
Monitoring of Heparin Effect
Toxicity
A.
BLEEDING
The major adverse effect of heparin is bleeding. This risk
can be decreased by scrupulous patient selection, careful
control of dosage, and close monitoring. Elderly women
and patients with renal failure are more prone to
hemorrhage. Heparin is of animal origin and should be
used cautiously in patients with allergy. Increased loss of
hair and reversible alopecia have been reported. Longterm heparin therapy is associated with osteoporosis and
spontaneous fractures. Heparin accelerates the clearing
of postprandial lipemia by causing the release of
lipoprotein lipase from tissues, and long-term use is
associated with mineralocorticoid deficiency.
Monitoring of Heparin Effect
Toxicity
B. HEPARIN-INDUCED
THROMBOCYTOPENIA
Heparin-induced thrombocytopenia (HIT) is a systemic
hypercoagulable state that occurs in 1-4% of
individuals treated with UFH for a minimum of 7 days.
Surgical patients are at greatest risk. The reported
incidence of HIT is lower in pediatric populations
outside the critical care setting and is relatively rare in
pregnant women. The risk of HIT may be higher in
individuals treated with UFH of bovine origin
compared with porcine heparin and is lower in those
treated exclusively with LMWH.
HEPARIN Contraindications
Heparin is contraindicated in patients with HIT,
hypersensitivity to the drug, active bleeding, hemophilia,
significant thrombocytopenia, purpura, severe
hypertension, intracranial hemorrhage, infective
endocarditis, active tuberculosis, ulcerative lesions of the
gastrointestinal tract, threatened abortion, visceral
carcinoma, or advanced hepatic or renal disease. Heparin
should be avoided in patients who have recently had
surgery of the brain, spinal cord, or eye, and in patients
who are undergoing lumbar puncture or regional anesthetic
block. Despite the apparent lack of placental transfer,
heparin should be used in pregnant women only when
clearly indicated.

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
WARFARIN & THE COUMARIN
ANTICOAGULANTS
The clinical use of the coumarin anticoagulants
began with the discovery of an anticoagulant
substance formed in spoiled sweet clover silage
which caused hemorrhagic disease in cattle.
Warfarin is one of the most commonly
prescribed drugs, used by approximately 1.5
million individuals, and several studies have
indicated that the drug is significantly underused
in clinical situations where it has proven benefit
Warfarin is generally administered as the sodium
salt and has 100% bioavailability.
Coumarin anticoagulants
Administration & Dosage
Treatment with warfarin should be initiated with
standard doses of 5-10 mg rather than the large loading
doses formerly used. The initial adjustment of the
prothrombin time takes about 1 week, which usually
results in a maintenance dose of 5-7 mg/d. The
prothrombin time (PT) should be increased to a level
representing a reduction of prothrombin activity to
25% of normal and maintained there for long-term
therapy. When the activity is less than 20%, the warfarin
dosage should be reduced or omitted until the activity
rises above 20%.
Schematic representation of the
fibrinolytic system
FIBRINOLYTIC DRUGS
Fibrinolytic drugs rapidly lyse thrombi
by catalyzing the formation of the serine
protease plasmin from its precursor
zymogen, plasminogen. These drugs
create a generalized lytic state when
administered intravenously. Thus, both
protective hemostatic thrombi and target
thromboemboli are broken down. The
Box: Thrombolytic Drugs for Acute
Myocardial Infarction, describes the use of
these drugs in one major application
Fibrinolytic drugs
Streptokinase
Anistreplase
alteplase
Reteplase
Tenecteplase
ANTIPLATELET AGENTS
several targets for platelet inhibitory drugs have
been identified:

Inhibition of prostaglandin synthesis
ASPIRIN

Inhibition of ADP-induced platelet aggregation
CLOPIDOGREL & TICLOPIDINE

BLOCKADE OF PLATELET GLYCOPROTEIN
IIB/IIIA RECEPTORS (Abciximab, Eptifibatide,
Tirofiban )
ADDITIONAL ANTIPLATELET-DIRECTED DRUGS
(Dipyridamole, Cilostazol )

ASPIRIN

Aspirin inhibits the synthesis of thromboxane A2 by
irreversible acetylation of the enzyme cyclooxygenase.

The FDA has approved the use of 325 mg/d for primary
prophylaxis of myocardial infarction but urges caution in this
use of aspirin by the general population except when
prescribed as an adjunct to risk factor management by
smoking cessation and lowering of blood cholesterol and
blood pressure. Meta-analysis of many published trials of
aspirin and other antiplatelet agents confirms the value of this
intervention in the secondary prevention of vascular events
among patients with a history of vascular events.
FIBRINOLYTIC INHIBITORS:
AMINOCAPROIC ACID
Clinical uses of
aminocaproic acid are
as adjunctive therapy
in hemophilia, as
therapy for bleeding
from fibrinolytic
therapy, and as
prophylaxis for
rebleeding from
intracranial
aneurysms.
FIBRINOLYTIC INHIBITORS:
AMINOCAPROIC ACID
 Aminocaproic acid (EACA), which is chemically similar to
the amino acid lysine, is a synthetic inhibitor of
fibrinolysis. It competitively inhibits plasminogen
activation. It is rapidly absorbed orally and is cleared
from the body by the kidney. The usual oral dosage of
EACA is 6 g four times a day. When the drug is
administered intravenously, a 5 g loading dose should be
infused over 30 minutes to avoid hypotension.
Tranexamic acid is an analog of aminocaproic acid and
has the same properties. It is administered orally with a
15 mg/kg loading dose followed by 30 mg/kg every 6
hours, but the drug is not currently available in the USA.
Hematopoiesis

Hematopoiesis, the production from
undifferentiated stem cells of circulating
erythrocytes, platelets, and leukocytes, is a
remarkable process that produces over 200 billion
new blood cells per day in the normal person and
even greater numbers of cells in people with
conditions that cause loss or destruction of blood
cells. The hematopoietic machinery resides
primarily in the bone marrow in adults and
requires a constant supply of three essential
nutrients¾iron, vitamin B12, and folic acid¾as
well as the presence of hematopoietic growth
factors, proteins that regulate the proliferation
and differentiation of hematopoietic cells.
Inadequate supplies of either the essential
nutrients or the growth factors result in deficiency
of functional blood cells.
Absorption, transport, and storage
of iron

The average diet contains
10-15 mg of elemental iron
daily. A normal individual
absorbs 5-10% of this iron,
or about 0.5-1 mg daily.
Iron is normally absorbed in
the duodenum and proximal
jejunum, although the more
distal small intestine can
absorb iron if necessary.
Iron absorption increases in
response to low iron stores
or increased iron
requirements. Total iron
absorption increases to 1-2
mg/d in normal
menstruating women and
may be as high as 3-4
mg/d in pregnant women.
The only clinical indication for the use of
iron preparations is the treatment or
prevention of iron deficiency anemia

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1. Oral iron therapy- a wide variety of oral
iron preparations are available. Because
ferrous iron is most efficiently absorbed, only
ferrous salts should be used. Ferrous sulfate,
ferrous gluconate, and ferrous fumarate are all
effective and inexpensive and are
recommended for the treatment of most
patients.
2. Parenteral iron therapy- parenteral
therapy should be reserved for patients with
documented iron deficiency who are unable to
tolerate or absorb oral iron and for patients
with extensive chronic blood loss who cannot
be maintained with oral iron alone.
Enzymatic reactions that use vitamin B12, folates
Vitamin B12 serves as a cofactor for several essential biochemical reactions in
humans. Deficiency of vitamin B12 leads to anemia, gastrointestinal
symptoms, and neurologic abnormalities.
 The most characteristic clinical manifestation of vitamin
B12 deficiency is megaloblastic anemia. The typical
clinical findings in megaloblastic anemia are macrocytic
anemia, often with associated mild or moderate
leukopenia or thrombocytopenia (or both), and a
characteristic hypercellular bone marrow with an
accumulation of megaloblastic erythroid and other
precursor cells. The neurologic syndrome associated
with vitamin B12 deficiency usually begins with
paresthesias and weakness in peripheral nerves and
progresses to spasticity, ataxia, and other central
nervous system dysfunctions.
Hematopoietic growth factors
The hematopoietic growth factors are glycoprotein
hormones that regulate the proliferation and
differentiation of hematopoietic progenitor cells in
the bone marrow. The first growth factors to be
identified were called colony-stimulating factors
because they could stimulate the growth of
colonies of various bone marrow progenitor cells
in vitro. Many of these growth factors have been
purified and cloned, and their effects on
hematopoiesis have been extensively studied.
Erythropoietin (epoetin alfa), granulocyte
colony-stimulating factor (G-CSF),
granulocyte-macrophage colony-stimulating
factor (GM-CSF), and interleukin-11 (IL-11),
thrombopoietin