Clinical Pharmacy in Clinical Pharmacy in HaematologyHaematology

DRUGS USED IN DRUGS USED IN DISORDERS OF DISORDERS OF

COAGULATIONCOAGULATION AND AND HEMOPOIESIS HEMOPOIESIS

Spectrum of haematological Spectrum of haematological diseases diseases

Deficiency anaemias Deficiency anaemias Disorders of haemoglobin structure Disorders of haemoglobin structure Haemolytic structure Haemolytic structure Aplastic anaemia Aplastic anaemia Haematological malignancies: leukaemias and Haematological malignancies: leukaemias and

lymphomas lymphomas (all aspects of management, including bone marrow (all aspects of management, including bone marrow transplantation) transplantation) Congenital and acquired bleeding disorders Congenital and acquired bleeding disorders Thromboembolic disorders and anticoagulation Thromboembolic disorders and anticoagulation Transfusion medicine Transfusion medicine Haematological problems associated with Haematological problems associated with

perinatal care; perinatal care; intensive care; renal medicine, organ intensive care; renal medicine, organ

transplantation, transplantation, orthopaedic and vascular surgery (in adults). orthopaedic and vascular surgery (in adults).

Thrombus formation at the Thrombus formation at the site of the damaged site of the damaged

vascular wallvascular wall

A model of blood A model of blood coagulationcoagulation

ANTICOAGULANT ANTICOAGULANT DRUGS DRUGS

The ideal anticoagulant drug would The ideal anticoagulant drug would prevent pathologic thrombosis and limit prevent pathologic thrombosis and limit reperfusion injury, yet allow a normal reperfusion injury, yet allow a normal response to vascular injury and limit response to vascular injury and limit bleeding. Theoretically this could be bleeding. Theoretically this could be accomplished by preservation of the TF-VIIa accomplished by preservation of the TF-VIIa initiation phase of the clotting mechanism initiation phase of the clotting mechanism with attenuation of the secondary intrinsic with attenuation of the secondary intrinsic pathway propagation phase of clot pathway propagation phase of clot development. At this time such a drug does development. At this time such a drug does not exist; all anticoagulants and fibrinolytic not exist; all anticoagulants and fibrinolytic drugs have an increased bleeding risk as drugs have an increased bleeding risk as their principle toxicity their principle toxicity

INDIRECT THROMBIN INDIRECT THROMBIN INHIBITORSINHIBITORS

The indirect thrombin inhibitors are so-The indirect thrombin inhibitors are so-named because their antithrombotic effect is named because their antithrombotic effect is exerted by their interaction with a separate exerted by their interaction with a separate protein, antithrombin. protein, antithrombin. Unfractionated Unfractionated heparin (UFH), low-molecular-weight heparin (UFH), low-molecular-weight heparin (LMWH)heparin (LMWH), and the synthetic , and the synthetic pentasaccharide pentasaccharide fondaparinuxfondaparinux bind to bind to antithrombin and enhance its inactivation of antithrombin and enhance its inactivation of factor Xa. Unfractionated heparin and to a factor Xa. Unfractionated heparin and to a lesser extent LMWH also enhance lesser extent LMWH also enhance antithrombin's inactivation of thrombin.antithrombin's inactivation of thrombin.

HeparinHeparinHeparin is a heterogeneous mixture of sulfated Heparin is a heterogeneous mixture of sulfated mucopolysaccharides. It binds to endothelial cell mucopolysaccharides. It binds to endothelial cell surfaces and a variety of plasma proteins. Its surfaces and a variety of plasma proteins. Its biologic activity is dependent upon the endogenous biologic activity is dependent upon the endogenous anticoagulant antithrombin. Antithrombin inhibits anticoagulant antithrombin. Antithrombin inhibits clotting factor proteases, especially thrombin (IIa), clotting factor proteases, especially thrombin (IIa), IXa, and Xa, by forming equimolar stable complexes IXa, and Xa, by forming equimolar stable complexes with them. In the absence of heparin, these reactions with them. In the absence of heparin, these reactions are slow; in the presence of heparin, they are are slow; in the presence of heparin, they are accelerated 1000-fold. Only about a third of the accelerated 1000-fold. Only about a third of the molecules in commercial heparin preparations have molecules in commercial heparin preparations have an accelerating effect because the remainder lack an accelerating effect because the remainder lack the unique pentasaccharide sequence needed for the unique pentasaccharide sequence needed for high-affinity binding to antithrombin. The active high-affinity binding to antithrombin. The active heparin molecules bind tightly to antithrombin and heparin molecules bind tightly to antithrombin and cause a conformational change in this inhibitor. The cause a conformational change in this inhibitor. The conformational change of antithrombin exposes its conformational change of antithrombin exposes its active site for more rapid interaction with the active site for more rapid interaction with the proteases (the activated clotting factors). Heparin proteases (the activated clotting factors). Heparin functions as a cofactor for the antithrombin-protease functions as a cofactor for the antithrombin-protease reaction without being consumed. Once the reaction without being consumed. Once the antithrombin-protease complex is formed, heparin is antithrombin-protease complex is formed, heparin is released intact for renewed binding to more released intact for renewed binding to more antithrombin. antithrombin.

The antithrombin binding region of commercial The antithrombin binding region of commercial unfractionated heparin consists of repeating unfractionated heparin consists of repeating sulfated disaccharide units composed of D-sulfated disaccharide units composed of D-glucosamine-L-iduronic acid and D-glucosamine-D-glucosamine-L-iduronic acid and D-glucosamine-D-glucuronic acid. High-molecular-weight fractions of glucuronic acid. High-molecular-weight fractions of heparin with high affinity for antithrombin heparin with high affinity for antithrombin markedly inhibit blood coagulation by inhibiting all markedly inhibit blood coagulation by inhibiting all three factors, especially thrombin and factor Xa. three factors, especially thrombin and factor Xa. Unfractionated heparin has a molecular weight Unfractionated heparin has a molecular weight range of 5000-30,000. In contrast, the shorter-chain range of 5000-30,000. In contrast, the shorter-chain low-molecular-weight (LMW) fractions of heparin low-molecular-weight (LMW) fractions of heparin inhibit activated factor X but have less effect on inhibit activated factor X but have less effect on thrombin than the HMW species. Nevertheless, thrombin than the HMW species. Nevertheless, numerous studies have demonstrated that LMW numerous studies have demonstrated that LMW heparins such as enoxaparin, dalteparin, and heparins such as enoxaparin, dalteparin, and tinzaparin are effective in several thromboembolic tinzaparin are effective in several thromboembolic conditions. In fact, these LMW heparins¾in conditions. In fact, these LMW heparins¾in comparison with UFH¾have equal efficacy, comparison with UFH¾have equal efficacy, increased bioavailability from the subcutaneous site increased bioavailability from the subcutaneous site of injection, and less frequent dosing requirements of injection, and less frequent dosing requirements (once or twice daily is sufficient). (once or twice daily is sufficient).

Monitoring of Heparin Monitoring of Heparin Effect Effect

Toxicity Toxicity A.A. BLEEDINGBLEEDING

The major adverse effect of heparin is The major adverse effect of heparin is bleeding. This risk can be decreased by bleeding. This risk can be decreased by scrupulous patient selection, careful control of scrupulous patient selection, careful control of dosage, and close monitoring. Elderly women dosage, and close monitoring. Elderly women and patients with renal failure are more prone and patients with renal failure are more prone to hemorrhage. Heparin is of animal origin to hemorrhage. Heparin is of animal origin and should be used cautiously in patients with and should be used cautiously in patients with allergy. Increased loss of hair and reversible allergy. Increased loss of hair and reversible alopecia have been reported. Long-term alopecia have been reported. Long-term heparin therapy is associated with heparin therapy is associated with osteoporosis and spontaneous fractures. osteoporosis and spontaneous fractures. Heparin accelerates the clearing of Heparin accelerates the clearing of postprandial lipemia by causing the release of postprandial lipemia by causing the release of lipoprotein lipase from tissues, and long-term lipoprotein lipase from tissues, and long-term use is associated with mineralocorticoid use is associated with mineralocorticoid deficiency.deficiency.

Monitoring of Heparin Monitoring of Heparin EffectEffect

Toxicity Toxicity B. HEPARIN-INDUCEDB. HEPARIN-INDUCED TTHROMBOCYTOPENIAHROMBOCYTOPENIAHeparin-induced thrombocytopenia (HIT) is a Heparin-induced thrombocytopenia (HIT) is a systemic hypercoagulable state that occurs in systemic hypercoagulable state that occurs in 1-4% of individuals treated with UFH for a 1-4% of individuals treated with UFH for a minimum of 7 days. Surgical patients are at minimum of 7 days. Surgical patients are at greatest risk. The reported incidence of HIT greatest risk. The reported incidence of HIT is lower in pediatric populations outside the is lower in pediatric populations outside the critical care setting and is relatively rare in critical care setting and is relatively rare in pregnant women. The risk of HIT may be pregnant women. The risk of HIT may be higher in individuals treated with UFH of higher in individuals treated with UFH of bovine origin compared with porcine heparin bovine origin compared with porcine heparin and is lower in those treated exclusively with and is lower in those treated exclusively with LMWH. LMWH.

HEPARIN HEPARIN Contraindications Contraindications Heparin is contraindicated in patients Heparin is contraindicated in patients

with HIT, hypersensitivity to the drug, active with HIT, hypersensitivity to the drug, active bleeding, hemophilia, significant bleeding, hemophilia, significant thrombocytopenia, purpura, severe thrombocytopenia, purpura, severe hypertension, intracranial hemorrhage, hypertension, intracranial hemorrhage, infective endocarditis, active tuberculosis, infective endocarditis, active tuberculosis, ulcerative lesions of the gastrointestinal tract, ulcerative lesions of the gastrointestinal tract, threatened abortion, visceral carcinoma, or threatened abortion, visceral carcinoma, or advanced hepatic or renal disease. Heparin advanced hepatic or renal disease. Heparin should be avoided in patients who have should be avoided in patients who have recently had surgery of the brain, spinal cord, recently had surgery of the brain, spinal cord, or eye, and in patients who are undergoing or eye, and in patients who are undergoing lumbar puncture or regional anesthetic block. lumbar puncture or regional anesthetic block. Despite the apparent lack of placental Despite the apparent lack of placental transfer, heparin should be used in pregnant transfer, heparin should be used in pregnant women only when clearly indicated.women only when clearly indicated.

WARFARIN & THE COUMARIN WARFARIN & THE COUMARIN ANTICOAGULANTSANTICOAGULANTS

The clinical use of the coumarin The clinical use of the coumarin anticoagulants began with the discovery of anticoagulants began with the discovery of an anticoagulant substance formed in an anticoagulant substance formed in spoiled sweet clover silage which caused spoiled sweet clover silage which caused hemorrhagic disease in cattle. hemorrhagic disease in cattle.

Warfarin is one of the most commonly Warfarin is one of the most commonly prescribed drugs, used by approximately prescribed drugs, used by approximately 1.5 million individuals, and several studies 1.5 million individuals, and several studies have indicated that the drug is significantly have indicated that the drug is significantly underused in clinical situations where it underused in clinical situations where it has proven benefit has proven benefit

Warfarin is generally administered as the Warfarin is generally administered as the sodium salt and has 100% bioavailability. sodium salt and has 100% bioavailability.

Coumarin anticoagulants

Administration & Dosage Administration & Dosage

Treatment with warfarin should be initiated Treatment with warfarin should be initiated with standard doses of 5-10 mg rather than with standard doses of 5-10 mg rather than the large loading doses formerly used. The the large loading doses formerly used. The initial adjustment of the prothrombin time initial adjustment of the prothrombin time takes about 1 week, which usually results in a takes about 1 week, which usually results in a maintenance dose of 5-7 mg/d. The maintenance dose of 5-7 mg/d. The prothrombin time (PT)prothrombin time (PT) should be increased should be increased to a level representing a reduction of to a level representing a reduction of prothrombin activity to 25% of normal and prothrombin activity to 25% of normal and maintained there for long-term therapy. When maintained there for long-term therapy. When the activity is less than 20%, the warfarin the activity is less than 20%, the warfarin dosage should be reduced or omitted until the dosage should be reduced or omitted until the activity rises above 20%. activity rises above 20%.

Schematic representation Schematic representation of the fibrinolytic systemof the fibrinolytic system

FIBRINOLYTIC DRUGSFIBRINOLYTIC DRUGS

FFibrinolytic drugs rapidly lyse thrombi ibrinolytic drugs rapidly lyse thrombi by catalyzing the formation of the serine by catalyzing the formation of the serine protease protease plasminplasmin from its precursor from its precursor zymogen, plasminogen. These drugs zymogen, plasminogen. These drugs create a generalized lytic state when create a generalized lytic state when administered intravenously. Thus, both administered intravenously. Thus, both protective hemostatic thrombi and target protective hemostatic thrombi and target thromboemboli are broken down. The Box: thromboemboli are broken down. The Box: Thrombolytic Drugs for Acute Myocardial Thrombolytic Drugs for Acute Myocardial Infarction, describes the use of these Infarction, describes the use of these drugs in one major application drugs in one major application

FFibrinolytic drugsibrinolytic drugs

StreptokinaseStreptokinase

AnistreplaseAnistreplase

alteplasealteplase

ReteplaseReteplase

TenecteplaseTenecteplase

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

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 factorsThe 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