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Drugs Acting on the Blood or Blood-forming Organs



Anemia can be treated pharmacologically by providing components needed for RBC production, including hemoglobin synthesis, and by stimulating bone marrow formation of RBC.

Vitamin B12 is essential for DNA synthesis. Deficiency causes inhibited nuclear maturation and division. RBC maturation arrest in the bone marrow leads to megaloblastic or pernicious anemia. Vitamin B12, a porphyrin-like compound consisting of a ring structure that contains a centrally located cobalt, is derived from the diet and microbial synthesis in the GI tract. However, except for ruminants, microbial production occurs in the large intestine, from which vitamin B12 is not readily absorbed. Dietary deficiency of B12 is rare; deficiency usually results from poor absorption from the GI tract.

Vitamin B12 absorption is complex and depends on gastric acid, pepsin, and intrinsic factor secreted from gastric parietal cells or pancreatic duct cells. Intrinsic factor binds to and protects vitamin B12 from digestion. In this form, B12 binds to highly specific receptor sites in the brush border of the ileum, where it enters enterocytes by pinocytosis. Interference with its absorption in the ileum results in continuous depletion, although many months of defective absorption are necessary before deficiency develops. Vitamin B12 is bound in the plasma to transcobalamin. It is stored in large quantities in the liver and slowly released as needed. It is excreted into the bile but undergoes enterohepatic cycling.

Vitamin B12 (dogs: 100–200 μg, PO, SC, sid; cats: 50–100 μg, PO, SC, sid) is available in oral and parenteral preparations of cyanocobalamin. There are no significant toxicities associated with therapy. Indications for therapy are limited to cases of vitamin B12 malabsorption, such as ileectomy, gastrectomy, or deficiency malabsorption syndromes (eg, exocrine pancreatic insufficiency). Chronic administration of H2-receptor blockers (cimetidine, ranitidine, famotidine) can also lead to vitamin B12 deficiency because an acid environment is necessary for its absorption.

Folic acid is needed for DNA and RNA synthesis. Anemia associated with folic acid deficiency is characterized as megaloblastic. Sources of folic acid in the diet include yeast, liver, kidney, and green vegetables, although it can also be formed by microbes. Folic acid is stored in the liver but not as avidly as vitamin B12. Because folic acid is destroyed by catabolic processes every day, serum levels decrease rapidly in the presence of deficient diets. Absorption of folic acid is not as sensitive as that of vitamin B12, although jejunal pathology can result in folate deficiency.

Folic acid (dogs: 5 mg, PO, sid; cats: 2.5 mg, PO, sid) is available in both oral and parenteral formulations. Significant toxicity is not associated with therapy. Indications for therapy include inadequate intake due to administration of selected drugs (eg, methotrexate, potentiated sulfa drugs, some anticonvulsants [eg, primidone and phenytoin]), liver disease, malabsorption, or other chronic debilitating diseases.

Iron is necessary for hemoglobin formation. It is available in the diet either as a heme form, which is a small percentage of the total but readily absorbed, or a nonheme form. Absorption of the nonheme form is profoundly affected by diet. Iron is absorbed from the proximal jejunum, where it immediately combines in the enterocyte to the globulin transferrin. It is transported in the plasma in this form, but the binding is loose and iron can be easily transferred to tissues. Iron enters cells via specific receptors that interact with transferrin. In the cell, iron combines with the protein apoferritin to become ferritin, the soluble form of iron storage. Smaller quantities are also stored as the insoluble hemosiderin; the amount of this storage form increases when the total amount of iron in the body is much more than apoferritin can accommodate. There is no mechanism for the excretion of iron other than via the GI tract. GI elimination occurs by exfoliation of enterocytes containing iron, biliary elimination, and elimination of dietary iron that has not been absorbed.

Indications for iron therapy are limited to treatment or prevention of iron deficiency (eg, blood loss, pregnancy). Iron is available in both oral and parenteral preparations. Oral preparations should be ferrous salts, such as sulfate (dogs: 100–300 mg, sid; cats: 50–100 mg, sid), gluconate, and fumarate. Therapy can be continued for several months to replenish body iron stores. Response to iron therapy can be assessed by monitoring circulating hemoglobin concentrations. Side effects are dose-related. Parenteral preparations are indicated for initial treatment of iron deficiency or if oral preparations cannot be tolerated or are not feasible (ie, neonatal pigs). Iron dextrans can be given as a single IM injection (100 mg) at 2–4 days of age in newborn piglets. Toxicity may be seen and is manifest as pale skin, bloody diarrhea, and shock (see Iron Toxicity in Newborn Pigs). When efficacy of parenteral preparations is compared, dextran complexes and hydrogenated dextrans are more efficient than dextrins. Hemoglobin formation requires pyridoxine and the trace elements copper and cobalt (necessary for B12 synthesis by ruminal microflora). “Shotgun” preparations contain a combination of hematinic agents; the efficacy of such products is questionable. As with any hematinic preparation, provision of these compounds will be ineffective if the nutritional status of the animal is poor.

Epoetin alfa is the synthetic form of the human glycoprotein erythropoietin (ERP). Epoetin alfa is indicated in the treatment of anemia associated with chronic renal failure in dogs and cats. The initial dosage is 100 U/kg, SC, 3 times/wk for 4 mo, while monitoring PCV, followed by a maintenance dosage of 75–100 U/kg, SC, 2–3 times/wk. The most significant adverse effects in dogs and cats are the development of antibodies to ERP, resistance to treatment, and worsening of anemia. Other potential adverse effects include iron deficiency, hypertension, fever, local cellulitis, arthralgia, mucocutaneous ulcers, polycythemia, and CNS disturbances (seizures).

Anabolic steroids are compounds structurally related to testosterone that have similar protein-anabolic activity but minimal androgenic effects, such as masculinization. As part of their anabolic activity, these compounds increase the circulating RBC mass and possibly granulocytic mass. Clinical indications for use of anabolic steroids include chronic, nonregenerative anemias. Response to therapy is variable, and the time to clinical improvement is long, frequently ≥3 mo. The proposed mechanisms of action include increased ERP production via ERP-stimulating factor, differentiation of stem cells into ERP-stimulating factor-sensitive cells (eg, hemocytoblasts), and direct stimulation of erythroid-progenitor cells. The effect of anabolic steroids requires adequate ERP levels and sufficient cells in the bone marrow. Thus, the effectiveness of anabolic steroids in treating anemia may be limited, depending on the cause.

Anabolic steroids can be divided into 2 categories depending on the presence or absence of an alkyl group at the 17-carbon position. They are available as oral and parenteral preparations, including oil-based products intended for slow release. The absorption and disposition of anabolic steroids depend on the type of preparation and the animal species. Most are eliminated after hepatic metabolism. The alkylated products are more effectively absorbed when given PO and are more effective stimulants of bone marrow. Alkylated anabolic steroids include oxymetholone (dogs and cats: 1–5 mg/kg, PO, every 18–24 hr). Nonalkylated anabolic steroids include nandrolone decanoate (dogs: 1–1.5 mg/kg, IM/wk; cats: 1 mg/kg, IM/wk; horse: 1 mg/kg, IM, once every 4 wk). Boldenone undecylenate is approved for horses at 1.1 mg/kg, IM, every 3 wk. Side effects of anabolic steroids include sodium and water retention, virilization, and hepatotoxicity. The alkylated products are more hepatotoxic than the non-alkylated products, particularly in cats. Cholestatic liver damage develops early and can be significant but frequently is reversible.


Lyophilized concentrates of one or more clotting factors are available as topical or local hemostatics. Most act to provide an artificial factor or structural matrix that facilitates control of capillary bleeding. An intact hemostatic mechanism is necessary. These absorbable products are indicated for capillary oozing from small, superficial vessels. Concentrated factors include thromboplastin, thrombin (available as a powder, solution, or sponge), collagen, and fibrinogen. Artificial matrices include fibrin foam, absorbable gelatin sponge, and oxidized cellulose.

Astringents act locally by precipitating proteins. These agents do not penetrate tissues and, thus, are restricted to surface cells. They can be damaging to surrounding tissues. Examples include ferric sulfate, silver nitrate, and tannic acid.

Epinephrine and norepinephrine are hemostatics by virtue of their vasoconstrictive effects. They may be included in topical medications to decrease blood flow to the tissues, or applied intranasally in tampons to decrease epistaxis.

Systemic hemostatics include fresh blood or blood components administered to animals that have a coagulation factor deficiency. Examples include fresh plasma, fresh frozen plasma, cryoprecipitate, and platelet-rich plasma.

Vitamin K is a hemostatic only in instances of vitamin K deficiency. It is necessary for hepatic synthesis of coagulation factors II, VII, IX, and X. The principal indication is treatment of rodenticide toxicity, moldy sweet clover poisoning (dicumarol), and sulfaquinoxaline toxicity.

Vitamin K1 (phytonadione) is a plant form of vitamin K that is safer and more effective with more rapid restoration of coagulation factors than other analogs such as vitamin K3 (menadione). The preferred routes for administering phytonadione are SC and PO, although it can be given by slow IV (anaphylactic reactions have been reported) or IM injections. After IM administration, bleeding may occur at the injection site. The dosage regimen selected depends on the nature of the anticoagulant toxicity. Vitamin K1 must be given as long as the anticoagulant is present in the body at toxic levels; this duration varies depending on the roden-ticide. Second-generation coumarin derivatives or indane-diones are potent and have long half-lives. Several weeks of vitamin K1 therapy may be necessary after ingestion of these long-acting rodenticides. Coagulation status should be monitored during therapy. The lag period after administration of phytonadione and synthesis of new clotting factors is 6–12 hr.

Desmopressin is a synthetic analog of vasopressin and is used to treat diabetes insipidus. In animals with von Willebrand's disease, desmopressin transiently elevates von Willebrand's factor and shortens bleeding time. It may be useful in dogs with von Willebrand's disease (0.4 μg/kg, SC; 1 μg/kg, IV, diluted in 20 mL of saline and given over 10 min), permitting surgical procedures or controlling capillary bleeding.


Anticoagulants interfere either directly or indirectly with the clotting cascade.

Heparin is a heterogeneous mixture of sulfated (anionic) mucopolysaccharides named because of its initial discovery in high concentrations in the liver. It is prepared from porcine intestinal mucosa and bovine lung. It acts indirectly to facilitate endogenous anticoagulants, specifically antithrombin III and heparin cofactor II. These molecules form stable complexes with (and thus inactivate) clotting factors, especially thrombin. Heparin is released in its active form after inactivation of the clotting factor and thus can interact with other molecules. The effect is greater with low concentrations of heparin. Heparin is also antithrombotic due to binding to endothelial cell walls, thus impairing platelet aggregation and adhesion.

Clinical indications for heparin therapy include the prevention or treatment of venous or pulmonary embolism and embolization associated with atrial fibrillation. It is also used as an anticoagulant for diagnostic use and blood transfusions. Heparin is used in conjunction with blood and/or plasma to treat disseminated intravascular coagulopathy (DIC) and other hypercoagulable conditions. It has also been used to clear hyperlipidemia.

Heparin is available as a sodium or calcium salt. Absorption and distribution of heparin are limited by the large size and polarity of the molecule. Oral absorption is poor; hence, it is a parenteral anticoagulant. Although anticoagulant activity is first order, half-life of the drug is dose-dependent, steady-state concentrations are difficult to achieve, and pharmacokinetics vary among individuals. Heparin is metabolized by heparinase in the liver and by reticuloendothelial cells. Metabolites of heparinase activity are excreted in the urine. The half-life is prolonged in renal or hepatic failure.

Heparin can be given IV (either intermittently or as a constant infusion) or SC. Deep SC or intrafat injection prolongs persistence of therapeutic concentrations. Large hematomas can develop after deep IM injection. High-dose heparin therapy (dogs: 150–250 U/kg, SC, tid; cats: 250–375 U/kg, SC, bid) has been recommended for established thromboembolism. Lower dosages (dogs and cats: 75 U/kg, SC, tid; horses: 25–100 U/kg, SC, tid) are indicated in the management of DIC. Blood coagulation times (eg, activated partial thromboplastin time) should be monitored during therapy. Side effects and toxicities of heparin are limited to potential hemorrhage and, because heparin is a foreign protein, possible allergic reactions. Heparin is contraindicated in bleeding animals and in DIC unless replacement blood or plasma therapy is also given.

Low-molecular-weight heparins (LMWH, eg, dalteparin and enoxaparin) are alternatives to “unfractionated heparin” and are used extensively in humans as anticoagulants for various thromboembolic conditions. LMWH differ from heparin in that the molecular weights are approximately one-tenth that of heparin, dosing can be sid-bid in humans, there is no need to monitor activated partial thromboplastin time, the risk of bleeding and thrombocytopenia is smaller, and the effect on thrombin is less than that of heparin. LMWH target antifactor Xa activity. Limited efficacy, safety, and dosing data are available to guide use in veterinary medicine. However, a suggested dosage regimen for dalteparin in dogs and cats is 100–200 IU/kg, SC, sid-bid, and a suggested dosage regimen for enoxaparin in dogs and cats is 1–2 mg/kg, SC, bid, while monitoring prothrombin time. Individual responses to LMWH appear to be quite variable in cats.

Vitamin K antagonists (oral anticoagulants) differ from heparin primarily in their duration of activity and magnitude of effect. Their primary importance has been because of their toxic rather than therapeutic effects. Therapeutic indications include oral longterm treatment and prevention of recurrence of thrombotic conditions (eg, aortic or pulmonary thromboembolism and venous thrombosis) in cats, dogs, and horses.

There are several groups of vitamin K antagonists. They interfere with the hepatic synthesis of vitamin-K-dependent clotting factors by blocking the reduction of vitamin K epoxide after clotting factor synthesis, thus effectively reducing the concentration of vitamin K. Their anticoagulant activity (and therefore therapeutic or toxic effect) is delayed for 8–12 hr after administration or accidental ingestion because of the persistence of factors synthesized before administration. Factor VII has the shortest half-life and is the first factor to become deficient.

The vitamin K antagonists are rapidly and completely absorbed after administration PO. Levels peak in 1 hr. They are almost totally protein bound in the plasma, and their volume of distribution is limited to the plasma volume. They are metabolized by the liver to primary metabolites and then conjugated to glucuronides. They undergo an enterohepatic cycle. A variety of factors can increase the activity of these drugs, including hypoproteinemia, antimicrobial therapy, hepatic disease, hypermetabolic states, pregnancy, and the nephrotic syndrome. The potential for drug interactions is significant. Because they are highly protein bound, they can be displaced by other drugs that are protein bound (eg, acetylsalicylic acid and phenylbutazone), and their anticoagulant effects can be increased to the point of toxicity. Drug interactions also are seen with other antihemostatics.

Warfarin sodium is the most commonly used therapeutic preparation. The dosage is 0.1–0.2 mg/kg, PO, sid, for dogs and cats, and 0.067–0.167 mg/kg, PO, sid, for horses. Toxicity, manifest as hemorrhage, is a major concern with vitamin K antagonists. Coagulation times (particularly prothrombin time), CBC, and clinical evidence of bleeding (eg, occult blood in feces and urine) must be monitored carefully during warfarin therapy.

Fibrinolytic agents increase the activity of plasmin (fibrinolysin), the endogenous compound that is responsible for dissolving clots. The inactive precursor of plasmin is plasminogen, which exists in 2 forms: plasma soluble form and fibrin (clot) bound form. Streptokinase and streptodornase are synthesized by streptococci and activate both forms of plasminogen. They are used locally as a powder, infusion, or irrigation in the treatment of selected chronic wounds (eg, burns, ulcers, chronic eczemas, ear hematomas, otitis externa, osteomyelitis, chronic sinusitis, or other chronic lesions) that have not responded to other therapy. Tissue-type plasminogen activator (tPA) preferentially activates the fibrin-bound form of plasminogen. Unlike parenterally administered streptokinase, tPA does not induce a systemic proteolytic state. Selective clot lysis occurs without increasing circulating plasmin; thus, tPA has a lower risk of bleeding than does parenteral streptokinase. While tPA has been used to treat aortic thromboembolism in cats (0.25–1.0 mg/kg/hr, IV, for a total dosage of 1–10 mg/kg), both the risk of death due to reperfusion (and release of toxic metabolites) and the expense of this genetically engineered product may limit its use.

Antithrombotic drugs affect platelet activity, which is normally controlled by substances (such as prostaglandins) generated both outside and within the platelet. Platelet activity can be modulated by interacting with these substances. NSAID inhibit the formation of cyclooxygenase, the enzyme responsible for the synthesis of prostaglandin products from arachidonic acid that has been released into cells and platelets. The formation of all prostaglandins is inhibited, including that of thromboxane, a potent platelet aggregator and vasoconstrictor. In addition to its inhibitory effects on cyclooxygenase, aspirin irreversibly acetylates thromboxane synthetase, the specific enzyme responsible for the synthesis of thromboxane. Aspirin is a potent inhibitor of platelet activity; new platelets must be generated before the effects of aspirin on platelet activity disappear. At higher dosages, aspirin inhibits prostacylin, a prostaglandin product that counteracts the thrombogenic effects of thromboxane. Thus, the drug must be used cautiously for antiplatelet effects. The antiplatelet dosage for dogs is 5–10 mg/kg, PO, every 24–48 hr, and for cats 80 mg, PO, every 48–72 hr.

Last full review/revision March 2012 by Mark J. Novotny, DVM, MS, PhD, DACVCP

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