Hematinics
Anemia develops as a result of three main mechanisms: hemorrhage, hemolysis, and decreased erythrocyte production. Some causes of anemia can be treated pharmacologically by directly addressing the mechanisms of decreased erythrocyte production. For example, insufficient production of erythropoietic stimuli can be treated with erythropoiesis-stimulating agents such as epoetin alfa or darbepoetin. Similarly, deficiency of vitamins or minerals required for erythrocyte and hemoglobin synthesis can be reversed with their supplementation.
Hematinics are nutrients required for hematopoiesis. For specific drugs used to treat anemia that is due to decreased erythrocyte production, see the table Erythropoiesis-Stimulating Agents and Hematinics for Treatment of Anemia.
Erythropoiesis-Stimulating Agents and Hematinics for Treatment of Anemia
Product | Role in RBC Synthesis | Indications for Supplementation | Dosing | Disadvantages/Adverse Effects |
|---|---|---|---|---|
Erythropoiesis-Stimulating Agents | ||||
Epoetin alfa (recombinant human erythropoietin) | Mimics endogenous erythropoietin, stimulating bone marrow precursors | Anemia associated with chronic kidney disease (decreased erythropoietin production) | Dogs and cats: Initial dose 100 U/kg, SC, 3 times/wk, until low end of target PCV range is reached; then frequency decreased to q 7 d | Autoantibody development leading to treatment resistance and worsening anemia (pure red cell aplasia) is the most serious adverse effect Concurrent iron supplementation is recommended to decrease the risk of iron deficiency |
Darbepoetin alfa | Synthetic form of erythropoietin, with same action and 3-fold longer half-life | Anemia associated with chronic kidney disease (decreased erythropoietin production) Its use has now superseded that of epoetin, because of decreased frequency of dosing required and evidence suggesting decreased frequency of pure red cell aplasia | Dogs: Initial dose 0.45–1.5 mcg/kg, SC, q 7 d until low end of target PCV range is reached Cats: Initial dose 0.7–1.8 mcg/kg, SC, q 7 d until low end of target PCV range is reached When target PCV is reached, dosing interval is extended as tolerated (eg, to every 2–3 wk) | Same effects as for epoetin Less common adverse effects of both epoetin and darbepoetin include injection site reactions, vomiting, diarrhea, polycythemia, hypertension, and seizures |
Hematinics | ||||
Vitamin B12 (cobalamin, cyanocobalamin) | Essential for DNA synthesis and RBC maturation in the bone marrow Deficiency results in macrocytic anemia (also called megaloblastic anemia) | Malabsorption from the GI tract due to disease or drugs, such as chronic enteropathy (eg, inflammatory bowel disease), ileectomy, gastrectomy, exocrine pancreatic insufficiency Chronic administration of antacids (H2-receptor antagonists or proton-pump inhibitors) | Parenteral: 20–50 mcg/kg, SC, q 7 d for 4–6 wk; then monthly Oral: 50 mcg/kg, PO, q 24 h for at least 12 wk | No major toxicity |
Folic acid (folate, vitamin B9) | Essential for DNA and RNA synthesis Deficiency results in macrocytic anemia | Dietary deficiency Malabsorption (duodenum and proximal jejunum) Liver disease (decreased storage) Interfering drugs (eg. methotrexate, potentiated sulfonamides) Chronic blood loss | Varied dosing reported Dogs: 5 mg, PO, q 24 h for 1 mo Cats: 2.5 mg/cat, PO, q 24 h for 1 mo Injectable (both dogs and cats): 1–5 mg, SC, q 7 d for 1 mo | No major toxicity |
Iron | Necessary for hemoglobin formation Deficiency results in microcytic, hypochromic anemia | Dietary deficiency Iron depletion (eg, chronic blood loss) | Parenteral preparations are indicated for initial treatment or if oral preparations cannot be tolerated or are not feasible (eg, in neonatal pigs) Iron dextrans (dogs 10–20 mg/kg, IM [maximum 300 mg/dog]; cats 10 mg/kg, IM) once, or continue monthly in absence of oral supplementation Ferrous sulfate (dogs: 100–300 mg/d; cats: 50–100 mg/d), although other ferrous salts can be used Treatment for several months is often indicated | Adverse effects are dose-related GI upset can be decreased by administration with food At toxic doses, iron can cause potentially life-threatening GI, cardiovascular, and hepatic dysfunction Pain on IM injection |
Hemostatics
Hemostatic agents, also known as antihemorrhagic agents, are substances that promote hemostasis or cessation of hemorrhage.
Hemostatics can be applied topically or administered systemically (see the table Topical and Systemic Hemostatic Agents). Topical hemostatics are applied most commonly for bleeding associated with invasive procedures or with minor, clean wounds.
Topical and Systemic Hemostatic Agents
Product Type | Examples | Mechanisms of Action | Specific Indications and Doses | Disadvantages |
|---|---|---|---|---|
Topical | ||||
Astringents | Ferric sulfate Silver nitrate Tannic acid | Local precipitation of proteins | Bleeding nail beds | Can damage surrounding tissues Exothermic reaction resulting in discomfort |
Catecholamines | Epinephrine Norepinephrine | Local vasoconstriction | Epistaxis Dental bleeding Applied with cotton-tipped applicator or soaked tampon inserted into nasal passages | Can be difficult to apply Efficacious only for small-vessel bleeding |
Mechanical hemostatic agents | Porcine gelatin Oxidized regenerated cellulose Microfibrillar collagen | Mechanical barrier to bleeding; matrix for clot formation Some products also bactericidal | Hepatobiliary surgery Laparoscopic splenic biopsy | — |
Mechanical hemostatic agents for bone | Bone wax Alkylene oxide copolymer | As for other mechanical hemostatic agents; designed specifically for bleeding bone surfaces | Spinal surgery Maxillectomy Mandibulectomy Sternotomy | — |
Active hemostatic agents, including sealants | Fibrin sealants Topical thrombin Thrombin + gelatin | Active stimulation of hemostasis; active coagulation factors Include clotting factors with or without structural matrix | Broad applications | — |
Systemic | ||||
Antidiuretic hormone analog | Desmopressin (1-deamino-8-ᴅ-arginine vasopressin) | Stimulates release of von Willebrand factor from vascular endothelial cells and platelets | Type I von Willebrand disease Hemophilia 1 mcg/kg, IV or SC, 30 min before surgery, then q 90 min during surgery | Hypersensitivity reactions reported Affects free water balance |
Vitamin K | Vitamin K1(phytonadione) | Necessary for hepatic synthesis of procoagulant factors II, VII, IX, and X | Anticoagulant rodenticide toxicosis Moldy sweet clover (dicumarol) toxicosis (cattle) Sulfaquinoxaline toxicosis (pigs, poultry) Synthetic dysfunction in hepatic failure Dietary deficiency For dicumarol or first-generation anticoagulant rodenticide toxicosis, liver failure, or dietary deficiency: 0.25–5 mg/kg, SC or PO, q 24 h for 2 wk For second-generation anticoagulant rodenticide toxicosis: 2.5–5 mg/kg, SC or PO, q 24 h for 4 wk | Anaphylactic reactions reported with some formulations when administered IV With IM injection, risk of hemorrhage associated with underlying disease Possible requirement of accompanying plasma-product treatment because new clotting factor synthesis has been reported to take 6–12 h |
Plasma products | Fresh frozen plasma (FFP) Refrigerated plasma (RP) Frozen plasma (FP) Cryoprecipitate Cryo-poor plasma Platelet-rich plasma (PRP) Platelet concentrate (PC) | Replacement of lost or deficient coagulation factors or (in the case of PRP, PC) platelets | Clinical bleeding associated with congenital or acquired coagulopathy Platelet products indicated for active bleeding associated with thrombocytopenia or thrombocytopathia For FFP, RP, or FP: 6–20 mL/kg, IV, to effect For cryoprecipitate, cryo-poor plasma, PRP, or PC: 1 U/10 kg, IV slowly over 4 h, to effect | Risk of transfusion reactions, including allergic reaction, febrile nonhemolytic reactions, transfusion-related acute lung injury Reduce rate if patient predisposed to cardiac overload |
Antifibrinolytics | ||||
Epsilon-aminocaproic acid | Lysine analogue, blocking the lysine-binding site of plasminogen, thereby preventing plasmin activation | 50 mg/kg, IV or PO, q 6–8 h, to effect For Greyhounds: loading dose 15–40 mg/kg, IV; then 500–1,000 mg, PO, q 8 h for 5 d | Mostly GI effects (nausea, vomiting, abdominal pain, diarrhea) | |
Tranexamic acid | As for epsilon-aminocaproic acid | 10–15 mg/kg diluted, IV slowly, q 8 h; or 10 mg/kg bolus, then 10 mg/kg/h CRI for 3 h Topical use also reported | GI effects (nausea, vomiting), thrombotic events, and neurotoxicosis (humans) | |
For minor procedures such as toenail clipping, a topical hemostatic agent may be all that is needed to augment hemostasis and control bleeding. However, for surgical bleeding from a vascular organ, topical agents tend to be used in addition to other surgical hemostatic techniques, such as vessel ligation.
Most topical hemostatics are not specifically approved for veterinary use, and their application is supported predominantly by anecdotal reports rather than veterinary literature. In general, the smallest amount of hemostatic required to achieve hemostasis should be used.
Thromboprophylactics
Treatment with thromboprophylactic agents (see the table Drugs Used for Thromboprophylaxis) is indicated in documented thrombosis or in diseases associated with a high risk of thrombosis, such as immune-mediated hemolytic anemia (IMHA) in dogs; cardiomyopathy in cats; protein-losing nephropathy (PLN), particularly in dogs; and heartworm disease.
Antithrombotic Drugs
Antithrombotic Drug Choices | Mechanisms of Action | Dosing Recommendations | Drug Monitoring |
|---|---|---|---|
Antiplatelet drugs | |||
Aspirin | Inhibits conversion of platelet-derived arachidonic acid to thromboxane A2, and hence thromboxane A2–induced platelet activation and aggregation Generally less efficacious than clopidogrel | Ideal dose to maximize benefit and minimize adverse effects is not known Dogs: 0.5–10 mg/kg, PO, q 24 h, long-term Cats: 81 mg/cat, PO, q 72 h, long-term | Not required, but hematocrit and renal function should be periodically monitored |
Clopidogrel | Adenosine phosphate (P2Y12) receptor antagonist | Dog: 1.1–3 mg/kg, PO, q 24 h, long-term Cats: 18.75 mg/cat, PO, q 24 h, long-term | Not required, but platelet aggregometry is useful in research settings |
Anticoagulants | |||
Rivaroxaban | Direct inhibitor of factor Xa | Dogs: 1–2 mg/kg, PO, q 24 h, long-term Cats: 0.5–1.0 mg/kg, PO, q 24 h, long-term | Not required, but rivaroxaban's specific anti-Xa activity is useful in research settings |
Dalteparin | Low-molecular-weight heparin, which binds to and potentiates the endogenous anticoagulant antithrombin, enhancing its inhibition of factor Xa Minimal factor IIa inhibition (unlike unfractionated heparin) | Dogs: 100–175 U/kg, SC, q 8 h, as needed for antithrombotic effect Cats: 75 U/kg, SC, q 6 h, as needed for antithrombotic effect | Not required, but titration to target anti-Xa activity has been investigated |
Enoxaparin | Low-molecular-weight heparin with mechanism as for dalteparin | Dogs: 0.8 mg/kg, SC, q 6 h, as needed for antithrombotic effect Cats: 0.75–1.0 mg/kg, SC, q 6 h, as needed for antithrombotic effect | Not required, but can consider titration to target anti-Xa activity |
Unfractionated heparin | Binds to and potentiates the endogenous anticoagulant antithrombin and enhances its inhibition of several coagulation factors, particularly factors Xa and IIa (thrombin) | Dogs: 100 U/kg, IV bolus, then CRI at 480–900 U/kg/d; or 150–300 U/kg, SC, q 6 h, as needed for antithrombotic effect Cats: Only SC route has been investigated; initial dose 250 U/kg, SC, q 6 h, as needed for antithrombotic effect Optimal dose likely varies from case to case | Close monitoring of either activated clotting time, activated partial thromboplastin time, or anti-Xa activity is necessary, because of narrow therapeutic index, to maximize antithrombotic effect and minimize hemorrhagic complications |
Thrombolytics | |||
Tissue plasminogen activator (alteplase) | Binds to fibrin within thrombus, initiating fibrinolysis and converting plasminogen to plasmin | Dogs: Using a 250 mcg/mL injection, 25 mcg/dog, intracamerally in anterior chamber of affected eye, once (total volume must not exceed 0.1 mL) | Monitor for response to treatment and for adverse effects (eg, hyperkalemia); recommended only for hospitalized patients with intensive monitoring and 24-h observation |
A variety of thromboprophylactic drugs are available for veterinary patients, including antiplatelet drugs and anticoagulants (anti–clotting factor drugs).
Antiplatelet drugs are first-line treatment for disease associated with arterial thrombosis (eg, cardiomyopathy in cats, PLN in dogs). Aspirin and, increasingly, clopidogrel are the most commonly used antiplatelet medications in veterinary medicine.
Anticoagulants are first-line treatment for diseases associated with venous thrombosis (eg, IMHA in dogs).
A combination of antiplatelet drugs and anticoagulants may be indicated in diseases associated with a high risk of thrombosis (eg. IMHA), where the potential benefits are thought to outweigh the risks (of bleeding) in the individual patient.
Direct orally administered anticoagulants, particularly rivaroxaban, as well as injectable anticoagulants (low-molecular-weight heparin and unfractionated heparins) are the most commonly used anticoagulants in veterinary medicine. In dogs, tissue plasminogen activator (alteplase) is used to dissolve intraocular fibrinous clots and in the pleural cavity for treatment of fibrinous pleuropneumonia.
Historically, warfarin (a vitamin K antagonist) was used as an anticoagulant in veterinary medicine. Because of marked interindividual variation in its efficacy, however, coupled with a narrow therapeutic index and the broad availability of safer alternatives, the use of warfarin is no longer recommended.
