Disorders of the Hematologic System

KEY TERMS AND DEFINITIONS

LEARNING OBJECTIVES

After completing this chapter, you should be able to

1. List the different types of anemia.

2. Describe the presentation and laboratory abnormalities associated with the different types of anemia.

3. State the therapies used to treat each type of anemia.

4. List medications that can cause neutropenia and thrombocytopenia, and state drugs that are useful for neutropenia.

5. Explain the factors that cause clot formation and list the most common sites of clot formation.

6. Describe acute and chronic treatment of clots.

7. Explain the therapeutic effects, most common side effects, and adverse reactions of anticoagulant medications.

8. State brand and generic names of anticoagulant medications, along with routes of administration, dosage forms, and available doses.

Red blood cells (RBCs), or erythrocytes, circulate through the blood and function to carry oxygen to tissues. The lifespan of RBCs is about 120 days, at which time they are removed from the system by macrophages. To ensure the RBC mass stays constant, erythropoiesis takes place with the help of erythropoietin. Anemia occurs when there is not sufficient RBC mass and is determined by several different measurements. These laboratory values or calculations include hemoglobin, hematocrit, the number of RBCs, indices of RBC size and color, and other factors depending on the type of anemia (see Table 26-1).

Anemia can be classified based on the cause (excessive blood loss, destruction of blood cells, hemolysis, or ineffective production of RBCs) or based on the RBC size: microcytic (small), normocytic (normal), or macrocytic (large). Within each type, there are specific causes of the anemia; that is, anemia is a component of an underlying disease or problem. Anemic patients may present with varying clinical effects. In general, patients may experience fatigue, pallor (paleness to the skin), dizziness, faintness, difficulty breathing, rapid heart rate, headache, and lack of concentration. Other manifestations may occur, specific to the type of anemia, and will be described with each type of anemia.

Microcytic Anemia

The classic origin of microcytic anemia is iron deficiency. Deficiency of iron may result from a number of different causes, including lack of sufficient iron in the diet, inadequate absorption of iron, and blood loss. Absorption may be altered due to surgery or the absence of acid in the stomach, which could occur in patients taking medications like proton pump inhibitors. Gastrointestinal (GI) bleeding is a main cause of blood loss, although menstruation, other types of hemorrhaging, and blood donation may also be contributors.

Regardless of the cause, hemoglobin is below normal in iron deficiency anemia, and other laboratory values help describe this type of anemia. Mean corpuscular volume (MCV) is the measure of the average volume of RBCs and relates to RBC size. MCV is low in iron deficiency anemia. Serum iron, ferritin, iron saturation, and total iron binding capacity (TIBC) are also used to evaluate the anemia. Serum iron is low, as is ferritin, which is considered the storage form of iron. TIBC is the capacity of iron to be bound by transferrin, a transport protein of iron. TIBC is high in patients with iron deficiency anemia because with the lack of iron, there is plenty of availability for iron to be bound to transferrin.

Patients with low iron levels, as defined by typical laboratory assessment, present with classic symptomatology of tiredness, weakness, and pallor. Tongue soreness, thin/brittle nails, and koilonychia (concave surface to nails) may also be present. Patients may also experience cravings for dirt, clay, or ice chips; this phenomenon of craving substances not fit to eat is referred to as pica.

Therapy to correct the objective and subjective signs of this anemia involves treatment of an underlying cause and the use of exogenous (produced by a manufacturer other than the body) iron. If, for example, a GI bleed or other type of hemorrhage is the contributing factor, it should be treated appropriately. Replenishing iron may be accomplished through the use of oral iron products. Ferrous sulfate is most often used and is inexpensive, though other salt forms, such as ferrous gluconate and ferrous fumarate, are available (see Medication Table 26-1; Medication Tables are located at the end of the chapter). Approximately 200 mg of elemental iron per day is needed to treat iron deficiency.

Iron is best absorbed when taken on an empty stomach and in an acidic environment. Many patients, however, are not able to tolerate this administration technique due to nausea and GI irritation and, therefore, the dose is titrated (gradually increased to the desired dose) or is taken with a light meal or snack. Other adverse effects of oral iron include constipation, dark stools, heartburn, and abdominal cramping. To ensure iron absorption, milk and antacids should not be ingested at the same time iron is taken. Vitamin C (ascorbic acid) may increase the absorption if taken with iron in the form of vitamin C supplements or orange juice. There are iron-containing products that also contain vitamin C and other vitamins in the dosage form (see Medication Table 26-2).

Another consideration for the optimal absorption of iron is the understanding that iron is mainly absorbed in the duodenum. Enteric-coated products are formulated with a barrier to control the location of absorption and are thought to reduce GI upset. Iron products that are enteric coated, however, may reach the small intestine, where absorption is not the most favorable, and these products are not the best option. Similarly, sustained-release iron formulations do not allow for duodenal absorption. Oral iron therapy usually continues for a 3- to 6-month period, though it is usually individualized to patient need and response.

Patients who are not able to tolerate oral iron, have absorption problems, or are losing iron rapidly, may require intravenous (IV) iron for correction of their deficits. A few IV iron products are available: iron dextran (INFeD), iron sucrose (Venofer), sodium ferric gluconate (Ferrlecit), ferumoxytol (Feraheme), ferric derisomaltose (Monoferric), and ferric carboxymaltose (Injectafer) (see Medication Table 26-3). Iron dextran may be administered in daily doses or as a total dose infusion over several hours based on the hemoglobin level and deficit. The calculation used for iron dextran dosing is based on the hemoglobin deficit and the patient’s ideal body weight.

Besides allergic reactions, iron dextran may also cause pain at the IV site, fever, and muscle or joint pain. Iron sucrose, sodium ferric gluconate, ferumoxytol, and ferric carboxymaltose have less potential to cause allergic reactions and do not require a test dose, but they cannot be administered as a single total dose infusion. Instead, these IV iron forms are administered in smaller, repeated doses. For example, ferumoxytol is administered to patients with iron deficiency in chronic kidney disease as a single 510-mg dose followed by a second 510-mg dose 3–8 days later; similarly, ferric carboxymaltose is administered as two 750-mg doses one week apart. Iron sucrose may be administered in several daily doses or an alternative schedule with a maximum amount of 1,000 mg in a 14-day period. Ferric derisomaltose is the newest approved product; the dose is dependent on the patient’s weight and is administered over at least 20 minutes. It does also require observation after infusion for potential hypersensitivity reaction.

Macrocytic Anemia

Macrocytic anemia falls at the other end of the spectrum of RBC size and results from deficiency of vitamin B₁₂ and/or folic acid; it is also referred to as megaloblastic (large cell) anemia. In macrocytic anemia, vitamin B₁₂ and folic acid levels are below normal on laboratory data, and MCV is above normal. Causes of vitamin B₁₂ deficiency may be dietary deficiency or deficiency of intrinsic factor, which is secreted by the parietal cells in the stomach and is essential for the absorption of vitamin B₁₂. Lack of vitamin B₁₂ due to deficiency of intrinsic factor is referred to as pernicious anemia and is determined by the Schilling test, which uses intramuscular and radio-labeled vitamin B₁₂ to evaluate the renal elimination of B₁₂. Radio-labeled vitamin B₁₂ has been tagged with a radioactive substance to be more readily identified and measured for testing purposes. If less than 5% of the administered vitamin B₁₂ is detected in the urine, pernicious anemia is diagnosed. Due to shortages of the radio-labeled product, this test may be difficult to perform. Causes of folic acid deficiency include a deficient diet, impaired absorption such as after gastric bypass surgery, alcoholism, pregnancy, or medication. Examples of drugs involved in folic acid deficiency are phenytoin (Dilantin), trimethoprim (Primsol), methotrexate (Rheumatrex), carbamazepine (Tegretol), or sulfasalazine (Azulfidine).

Presentation of macrocytic anemia involves weakness and pallor. Other signs may include a sore, beefy, red tongue and central nervous system symptoms, including paresthesias (abnormal burning or tingling sensations) and numbness. Replacing vitamin B₁₂ and folic acid is the treatment for macrocytic anemia. Vitamin B₁₂ (cyanocobalamin) is administered intramuscularly as a daily injection for 7 days, then once a week for 4 weeks, and then monthly as a maintenance dose. A similar response may be seen with the use of oral cobalamin products, although high doses are required to ensure adequate absorption, as is patient adherence with daily dosing. Folic acid may be taken orally as a 1-mg dose once daily for approximately 2–3 weeks. Macrocytic anemia should not be treated using folic acid alone without vitamin B₁₂ because although the MCV and anemia would normalize, the neurological symptoms would not be addressed or improved.

Normocytic Anemia

Anemia may also be classified as normocytic, in which the RBCs are of normal size and the MCV is within normal values. Patients with long-standing disease states often also experience anemia that is normocytic in nature. Examples of chronic diseases associated with anemia are congestive heart failure, malignancy (cancer), systemic lupus, rheumatoid arthritis, endocarditis (inflammation of the inner layer of the heart), osteomyelitis (infection and inflammation of the bone or bone marrow), and chronic lung infections. This anemia is also referred to as anemia of inflammation. In addition to low hemoglobin and a normal MCV, laboratory data may show a low TIBC, decreased iron, and a normal to high ferritin level. Correction of this anemia is to treat the underlying chronic disease state.

Chronic kidney disease is another example of disease that can lead to normocytic/normochromic anemia. In this situation, erythropoietin is not effectively produced by the kidney, and RBCs have an abbreviated lifespan; however, other causes for the anemia should be evaluated and ruled out to ensure appropriate therapy. Erythropoietin-stimulating agents (ESAs) may be utilized for patients with chronic kidney disease, dialysis dependent or not, to maintain hemoglobin in the range of 10–12 g/dL. The available ESAs, epoetin alfa (Procrit, Epogen), epoetin alfa-epbx (Retacrit, a biosimilar agent), and darbepoetin alfa (Aranesp), are administered either subcutaneously or intravenously. Dosing of epoetin alfa is 50–100 units per kilogram of body weight (units/kg) 3 times a week, while the usual darbepoetin alfa dosing is 0.45 microgram per kilogram of body weight (mcg/kg) once weekly or 0.75 mcg/kg every other week for patients not on dialysis. Sufficient iron is needed to ensure an appropriate response to the ESAs and may be supplemented orally or intravenously.

ESAs may also be considered for anemia resulting from cancer therapy. Some chemotherapeutic agents are myelosuppressive, meaning they tend to cause a reduction of blood cells, including RBCs, white blood cells, and platelets formed in the bone marrow. ESAs may be part of the cancer therapy to treat anemia and low hemoglobin for patients receiving myelosuppressive therapy. They are not recommended when the anticipated outcome of the therapy is cure as some studies have shown risk of progression of the cancer and shortened survival with the use of ESAs in certain types of cancer. The main goal of this therapy, therefore, is to improve quality of life and to reduce the need for blood transfusions in patients with a significantly low hemoglobin level or symptoms from the anemia.² There are guidelines, however, for ESA initiation, dose adjustments, and duration of therapy in this indication. The dose is adjusted based on response and hemoglobin levels. High blood pressure and thromboembolic events are side effects that have been related to ESA usage. In fact, uncontrolled high blood pressure is a contraindication for epoetin alfa and darbepoetin alfa (see Medication Table 26-4).

Hemolytic Anemia

Classified based on its cause, hemolytic anemia occurs when RBCs are destroyed prematurely. Hemolytic anemia may be caused by a variety of factors, including an autoimmune process; infections such as malaria; drugs or chemicals such as sulfonamides, nitrates, nitrofurantoin, salicylates, lead, or copper; and radiation. Specific laboratory work that reveals hemolytic anemia includes an elevated reticulocyte count, a low level of haptoglobin (the protein that binds to free hemoglobin), elevated lactate dehydrogenase (LDH), and bilirubin. For autoimmune hemolytic anemia, further testing involves a Coombs’ test, which helps determine if patients have warm or cold antibodies on RBCs. Splenomegaly (enlarged spleen), hepatomegaly (enlarged liver), weakness, and lymphadenopathy (enlarged lymph nodes) may be present with warm hemolytic anemia and involves immune globulin (IgG) antibodies. Treatment strategies may include corticosteroids, folic acid, removal of the spleen, blood transfusions, and IV IgG. Cold autoimmune hemolytic anemia involves IgM antibodies and may be associated with malignancy. Transfusions with warm blood and avoiding cold exposure are therapies for this type of anemia.

Drug-Induced Neutropenia

Neutropenia is a condition involving a white blood cell (WBC) count below normal and is defined as having an absolute neutrophil count (ANC) below 1,500/μL. The ANC is calculated by multiplying the WBC count by the percent of mature (segmented) neutrophils and immature WBCs (bands) from the differential report on the complete blood count laboratory data. Causes of neutropenia include infection, congenital factors, primary immune neutropenia, and drug-related causes. Drug-induced neutropenia may further be divided into chemotherapy-involved and nonchemotherapy-involved drugs.

As discussed previously, cytotoxic or myelosuppressive chemotherapeutic agents have the ability to reduce blood counts, including WBCs. Examples of these agents include methotrexate, cyclophosphamide (Cytoxan), and doxorubicin (Adriamycin, Doxil), among several others or combinations of drugs. Patients receiving these medications are at risk for developing febrile neutropenia (reduced WBC count with fever), severe infections, and morbidity and fatality related to the infections. Granulocyte colony-stimulating factors (G-CSFs) are available to prevent or treat chemotherapy-induced neutropenia to reduce the related infections and potential time spent in the hospital (see Medication Table 26-5). Some chemotherapy regimens put patients at high risk for neutropenia, and certain patient factors, such as older age and comorbidities (coexisting medical conditions), also increase the risk of developing neutropenia. Filgrastim (Neupogen) is a G-CSF used to prevent and treat neutropenia. It is dosed as a 5 mcg/kg daily subcutaneous (SUBQ) injection. Pegfilgrastim (Neulasta) is a G-CSF with a longer action than filgrastim; therefore, this drug is used only for prevention of the neutropenia at a dose of 6 mg subcutaneously. Both medications should be administered starting 24–72 hours after the chemotherapy is given, and the pegfilgrastim should not be administered within 2 weeks of the next cycle of chemotherapy. Both drugs also have biosimilar agents approved for use. The most common side effect of filgrastim and pegfilgrastim is bone pain. Other less common adverse effects include rupture of the spleen and allergic reactions with manifestations of rash, wheezing, and low blood pressure.

In addition to cancer chemotherapy, other medications may also cause neutropenia, or agranulocytosis, though less commonly. The drugs either produce an immune-mediated process in which the drug or drug metabolite binds to the neutrophil membrane and forms antibodies or has a direct toxic effect on the cells. A list of drugs from varying classes of medications with probability of causing neutropenia has been formulated based on case reports and population studies. Some of the more common offenders include clozapine (Clozaril), antithyroid drugs, sulfasalazine, and ticlopidine. The low WBC count may be delayed 3–6 months after the drug treatment begins but could occur within days to weeks if the cause is immune-mediated. Patients may be asymptomatic or may present with a sore throat or fever. Treatment involves discontinuing the suspected drug although identifying the specific drug may be difficult, especially if patients are taking multiple medications. The neutropenia usually resolves within 1–3 weeks of stopping the drug. Treatment may also include treating the infection or using a G-CSF though high-grade evidence for their use is not available. Table 26-2 lists some medications that have been implicated as causes of neutropenia.

Drug-Induced Thrombocytopenia

Medications may also cause a reduction in the platelet count, or thrombocytopenia, caused by drug-dependent antibodies that allow destruction of platelets. Several medications have caused thrombocytopenia. The drugs with the most frequent reports of reduction of platelets include heparin, abciximab (ReoPro), quinine, quinidine, sulfonamides, vancomycin, gold salts, beta-lactam antibiotics, and valproic acid (Depakote, Depakene) products.

Heparin is the most common drug that is implicated as a cause of thrombocytopenia. Low molecular weight heparin (LMWH) products also may cause thrombocytopenia, but the incidence is lower compared to heparin. There are two types of heparin-induced thrombocytopenia: heparin-induced thrombocytopenia type I (HIT-I) (sometimes referred to as heparin-associated thrombocytopenia [HAT]) and heparin-induced thrombocytopenia type II (HIT-II). HIT-I involves a direct effect on platelets and a lesser reduction of platelets, while HIT-II involves an immune-mediated effect with antibodies directed against heparin complexes and a significant reduction of platelets. A test for heparin antibodies may be used to determine if a patient has HIT-II, although it is not very sensitive, giving false negative results. The serotonin release assay is also a test used to verify HIT-II and carries high sensitivity and specificity, which are statistical measures of how good a test is at identifying true positives and negatives over false positives and negatives. In HIT-II, the platelet count begins to fall within 5–10 days of the heparin initiation, and the formation of clots is a risk. Consequently, it may sometimes be referred to as HITT for heparin-induced thrombocytopenia and thrombosis.

Treatment of drug-induced thrombocytopenia includes stopping the causative drug. Because of the risk of thrombosis in HIT-II, other types of anticoagulants should be utilized. These drugs include the direct thrombin inhibitor argatroban, the factor Xa inhibitor fondaparinux (Arixtra), and the direct oral anticoagulant drugs (DOACs). Details of these drugs are described later in the chapter. Once the platelet count has recovered to greater than 150,000/μL and the patient has been on a stable dose of a direct thrombin inhibitor, warfarin may be initiated as oral therapy as an option if the DOACs and fondaparinux are not used and continued.

Coagulation Disorders

Deep Vein Thrombosis and Pulmonary Embolism

A DVT presents with a wide range of symptoms, from no symptoms at all to redness, pain, and swelling in the area of the clot. Many patients have DVTs with no long-lasting effects while others may have serious consequences. The two most serious complications are post-thrombotic syndrome, extensive serious tissue damage resulting from prolonged lack of blood flow to the area, and death secondary to pulmonary embolism (PE). Untreated DVT can be associated with fatal PE.

CASE?

Mr. Parton was given heparin in the hospital and then started on rivaroxaban (Xarelto). He was told he must take rivaroxaban for the next 3 months. Why was it important for him to receive immediate treatment for his DVT?

A pulmonary embolus is formed when a DVT (usually from the leg) breaks off, travels through the veins, and ultimately becomes lodged in the lungs. Symptoms of a pulmonary embolus include sudden-onset shortness of breath, chest pain, or sudden death.

Treatment of Deep Vein Thrombosis and Pulmonary Embolism

If left untreated, a blood clot would eventually be dissolved by the body (if the patient survived); however, treatment must be provided for clots to prevent them from getting bigger, breaking off, or forming new clots. The treatment of all clots is divided into one of two categories: drugs that break up clots (thrombolytics) and drugs that prevent clot growth (embolization) or formation (anticoagulants). Antiplatelet medications also prevent clot formation. Thrombolytics are used only in severe cases of DVT and PE and are discussed in detail along with antiplatelet agents in Chapter 17 so this chapter focuses primarily on anticoagulant medications.

Patients who develop a clot will receive anticoagulant medications for as little as 3 months and some will require therapy for the rest of their lives. The circumstances in which the clot is formed and whether this is a first episode or a recurrence are the primary determining factors for duration of therapy.

Anticoagulants

Patients often refer to anticoagulants as “blood thinners.” This can be misleading because they do not in fact thin the blood; instead, they change the ability of the blood to form clots. This makes the blood flow more freely when the skin is cut, making the blood appear thinner. All anticoagulant medications stop the clotting cascade at some point in the pathway. Anticoagulants affect all blood in the body, not just the blood in the area of the clot. For this reason, bleeding (inside and outside of the body) and bruising are the most common risks associated with any anticoagulant. Bleeding is most commonly seen from the mucous membranes (nose and mouth); from the GI tract, manifesting as bright red or very dark tarry stools; and from the genitourinary tract, manifesting in red- or pink-tinged urine. Bruising can occur anywhere on the body.

It should be noted that all anticoagulant medications have different doses depending on the reason for administration. If the patient already has a clot, a high dose of anticoagulant (known as the treatment dose) is prescribed and if the patient is at high risk for a clot, but does not have one yet, a lower dose (called the prophylaxis dose) is used to prevent a clot from forming. Anticoagulant medications are divided into classes based on the area of the clotting cascade each type affects. These are listed in Medication Table 26-6. Figure 26-1 shows the clotting cascade that was discussed in Chapter 25 showing the step that each medication inhibits.

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The clotting cascade shows the factors that each medication inhibits.

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Heparin

Heparin (also called unfractionated heparin or UFH) is a protein normally produced in the body. The heparin that is used in therapy is usually derived from porcine (pig) sources but is chemically similar to human heparin. Physiologically, heparin controls the coagulation cascade by accelerating the activity of antithrombin, a blood factor that “ties up” several different clotting factors (mainly IIa and Xa) and preventing them from contributing to the formation of a thrombus (see Figure 26-1).

ALERT!

Regular vials of heparin sodium have been confused with vials of heparin sodium lock flush, resulting in severe over- or under-dosing of the patient. The concentration of heparin sodium vials ranges from 1,000 units/mL up to 40,000 units/mL and heparin lock flush vials range from 10 units/mL to 100 units/mL. The ISMP (Institute for Safe Medication Practices) considers heparin a high-risk medication because of the potential for fatal dosing errors. Double check all doses before dispensing.

UFH has a wide variety of indications, including the prevention and treatment of DVT/PE, heart attack, stroke, and the prevention of clot formation during surgery, dialysis, and blood transfusions, just to name a few. Also, very low doses of heparin are used to ensure that a clot does not form in an IV line—this is called a heparin lock flush or Hep-Lock.

Heparin may be administered by continuous IV infusion, intermittent IV injection, or intermittent SUBQ injection. The dose and route of administration depend on the reason for giving heparin. The healthcare team can confirm heparin is working by measuring one of two lab tests; the activated partial thromboplastin time (aPTT) or the anti-Xa assay (the X represents the Roman numeral 10 and the a stands for active—this may also be called the heparin assay). Both of these blood tests show an increase when heparin is in the body. If the number is too high, there is too much heparin and the patient is at risk for bleeding; if it is too low, there is not enough heparin and the patient is not receiving the desired effect. Most commonly, IV infusions are dosed using an institution-specific dosing protocol. This is a sheet with dosing instructions for the nurse based on the patient’s weight, aPTT or anti-Xa test results, and reason for taking heparin. It usually includes a bolus dose (used to kick-start the inhibition of the clotting cascade), an initial infusion rate based on the patient’s weight, and directions for dose adjustment based on aPTT/anti-Xa results. Intermittent IV and SUBQ dosing is based on weight, and the aPTT/anti-Xa is not always tested when these methods are used. IV infusions are most commonly used to provide a treatment dose and intermittent dosing is most commonly used for prophylaxis dosing.

CASE?

Which was most likely used on Mr. Parton in the hospital: IV continuous infusion, IV intermittent, or SUBQ heparin?

If too much heparin is given to the patient, the aPTT/anti-Xa will rise too high and the patient will be at risk for bleeding. If this occurs, a drug called protamine can be administered to reverse the effects of heparin. Heparin is safe to be used in adults, infants and children, and pregnant or lactating women.

PRACTICE POINT

Protamine sulfate is a drug that is approved by the U.S. Food and Drug Administration (FDA) only for the reversal of heparin overdose. It is available as a 10-mg/mL solution for slow IV injection (over 10 minutes). Each milligram of protamine neutralizes approximately 100 heparin units, so the usual dose of 50 mg should neutralize a 5,000-unit dose of heparin.

Low Molecular Weight Heparin

Low molecular weight heparins (LMWHs) are derived from natural heparin and have a very similar action. They are primarily indicated for the prevention and treatment of DVT, PE, and the treatment of heart attacks. Two LMWHs are available in the United States: enoxaparin (Lovenox) and dalteparin (Fragmin). There are several important differences between unfractionated heparin and LMWHs. First, LMWHs stay active in the body longer so doses are given less often. Second, blood tests are not often used in the dosing of these medications. Doses of LMWHs are determined by the patient’s body weight and may require adjustment in patients with poor kidney function. Also, LWMHs are dosed subcutaneously only, are not administered intravenously, and are safe to use in adults and pregnant women.

PRACTICE POINT

LMWHs are supplied in prefilled syringes and may be used by the patient at home. Counseling by a pharmacist will be needed to ensure that the patient knows how to use a prefilled syringe and to self-inject properly.

ALERT!

LMWHs can be reversed with the administration of protamine, although this is currently an unlabeled use, and the reversal is less complete than occurs with protamine reversal of heparin.

Vitamin K Antagonist

Warfarin (still commonly known as Coumadin, although this is no longer an available brand name) is a widely used oral anticoagulant available generically in the United States. It acts by antagonizing the action of vitamin K, a nutrient essential to the formation of clotting factors II (prothrombin), VII, IX, and X, reducing the effectiveness of these factors in the body. Because of its mechanism, it may be a few days before the body responds to the drug (while current levels of clotting factors are eventually depleted), and it also takes time for its effects to end (while new clotting factors are being synthesized). Warfarin is a drug that has what is called a “narrow therapeutic window.” This means that the dosing must be adjusted precisely at all times. Too little and the patient is at risk for having clots; too much and the patient is at risk for bleeding. Because of this, patients must remember to take each dose at the same time every day. Frequent blood testing is required to make sure the dose is appropriate for the patient and to adjust it if necessary. The test, called the international normalized ratio (INR), may also be abbreviated PT/INR (for prothrombin time/INR). The INR evaluates how long it takes the sample blood to clot compared to “normal” blood (blood that is not under the influence of anticoagulant medications). Normal blood has an INR of approximately 1 (there are no units of measure associated with an INR). When warfarin is administered the INR increases, thus indicating that it takes longer for the blood to form a clot. A specific INR goal range will be determined for each patient based on the reason they are taking the warfarin. For example, a patient who is taking warfarin to treat a DVT will most commonly have an INR goal of between 2 and 3. Patients will typically have an INR drawn at least once per month while on warfarin and may have it drawn as frequently as every few days. Doses are adjusted based on the INR results: too low and more warfarin is given; too high and less is given. Patients frequently may come into the pharmacy with new prescriptions for warfarin as their provider attempts to find the right dose for that patient. It may take days to weeks to get the INR in the correct range.

PRACTICE POINT

The management of warfarin therapy can be complex. It is common for a patient to be managed through an anticoagulation clinic in addition to the oversight of the primary physician. Anticoagulation clinics may be run by pharmacists, nurses, or other healthcare professionals. The purpose of these clinics is to make sure that anticoagulation is being managed properly. INR levels are drawn in these clinics, and the practitioner will decide what action to take regarding the warfarin dose. Technicians may be employed in these settings to assist in the INR measurements and administrative tasks associated with the clinic.

ALERT!

It is common for patients beginning warfarin therapy to remain on LMWH or another anticoagulant until the INR reaches the correct range and even for a few days after to guarantee the full effect of the dose is seen. This may appear as a “duplicate therapy” warning in some patient profile software, and it will be up to the pharmacist to follow up or dismiss it.

Warfarin interacts with many other drugs so careful review of the profile by the pharmacist is required for any patient using warfarin. INR levels may change when patients change their eating habits (far more or less) of foods containing medium to high levels of vitamin K (such as green leafy vegetables). Patients need pharmacist counseling regarding these issues.

PRACTICE POINT

A medication guide must be provided to patients whenever warfarin is dispensed.

For patient safety, warfarin tablets are color coded. Tablet size ranges from 1–10 mg, and each strength is always the same color regardless of the manufacturer. For example, warfarin 1 mg (all manufacturers) and Jantoven 1 mg tablets are always pink. This helps the patient identify when a pill is the wrong strength, and it helps providers determine what strength the patient is on at home when the patient does not remember the dose.

When the INR is too high (indicating a relative overdose of warfarin), the practitioner may decide to let it come down on its own or, in order to prevent or stop a bleeding episode, that more intervention is necessary. If bleeding is severe the patient may need a blood product called fresh frozen plasma to stop it. In less severe cases of bleeding or when warfarin must be reversed to prevent a bleeding episode, vitamin K (phytonadione, Mephyton) may be used. Vitamin K may be administered orally, IV, or subcutaneously.

PRACTICE POINT

Severe allergic reactions have been associated with IV administration of vitamin K. For safety, all IV doses of vitamin K should be in an IV bag, not sent to the nursing unit in a vial to be given IV push. Dispensing in this way dilutes the dose and allows administration to be stopped before the entire dose is given if a reaction is noticed, minimizing the consequences.

The heparins and warfarin reduce the ability of the blood to coagulate (form clots) by interfering with a number of different processes in the coagulation cascade. Recent advances in anticoagulation therapy have produced more focused treatments that act on fewer and more specific processes in the cascade, which may lead to fewer side effects and more precise control.

Factor Xa Inhibitors

The use of oral factor Xa (FXa) inhibitors has been increasing steadily in the United States over the last 10 years (X is the Roman numeral 10, and a is for active). FXa inhibitors available in the United States include Fondaparinux (Arixtra) for SUBQ injection, as well as rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa) oral tablets. Fondaparinux is similar to LMWH in indications and administration (SUBQ only). The oral FXa inhibitors have a variety of indications, including atrial fibrillation and treatment and prevention of DVT and PE. The factor Xa inhibitors are synthetic molecules, manufactured rather than derived from human or animal sources. Fondaparinux dose is decided based on patient weight and reason for using the drug. Doses are reduced or the drug is stopped in patients with low kidney function. Oral FXa inhibitors are dosed once or twice daily, require no monitoring tests and have relatively few drug-drug or drug-food interactions. Caution is used in patients with low kidney or hepatic function. In the event of an overdose or bleeding event, FXa inhibitors can be difficult to reverse. Andexanet alpha (Andexxa) is indicated for the reversal of apixaban and rivaroxaban and may be used off-label to reverse edoxaban. This intravenous medication is expensive, typically >$10,000 per dose, and frequently has use restricted to very specific situations.

PRACTICE POINT

The oral forms of FXa inhibitors and direct thrombin inhibitors include rivaroxaban, apixaban, edoxaban, and dabigatran. These medications are known collectively as direct oral anticoagulants, or DOACs.

PRACTICE POINT

The need to switch between different anticoagulant medications is common, especially going from injectable to oral. Careful timing is required to ensure that the effect of the first anticoagulant wears off just as the new anticoagulant starts working. This requires in-depth understanding of the pharmacokinetic properties of the medications. This is commonly referred to as an anticoagulant transition.

Direct Thrombin Inhibitors

Three direct thrombin inhibitors are available in the U.S. market, including Argatroban (no alternate name), bivalirudin (Angiomax), and dabigatran (Pradaxa). Bivalirudin is available for IV administration and is used short term during certain cardiac procedures. Argatroban is a continuous IV infusion and is used to provide anticoagulation to a patient who has had HIT-II (as mentioned earlier in the chapter). It requires constant monitoring and careful dose adjustment. No reversal agent is available for argatroban. These agents are not commonly used for anticoagulation unless other options are contraindicated or otherwise not available for use.

The newest direct thrombin inhibitor, dabigatran (Pradaxa), is available orally. Similar to the oral FXa inhibitors, dabigatran requires little or no monitoring and has very few drug-drug and drug-food interactions that impact how it works. GI side effects such as nausea, vomiting, and GI bleeding have been the primary side effects associated with dabigatran and can result in patients discontinuing therapy. Because of the potential for loss of potency upon exposure to moisture, dabigatran capsules should be stored and dispensed only in the original manufacturer’s bottle or blister packaging. A bleeding episode or overdose associated with dabigatran can be treated with intravenous idarucizumab (Praxbind). This is a monoclonal antibody that binds to dabigatran and its metabolites, rendering it ineffective.

PRACTICE POINT

Pharmacies should not repackage dabigatran in standard vials, and patients should not remove the capsules from their packaging to place them in pill boxes or organizers. Once the original manufacturer’s bottle is opened, its contents of dabigatran capsules are stable for up to 4 months assuming tight reclosure and proper storage.⁵ The FDA requires a medication guide with each dabigatran prescription.

SUMMARY

Anemia is characterized by a reduction in red blood cells (RBCs) or hemoglobin, thereby reducing the oxygen-carrying capacity of the blood. Different laboratory values are utilized to describe anemia, and clinical symptoms can result from it. Anemia may be classified in different ways based on the specific cause or on the cell structure. The main type of microcytic anemia is iron deficiency anemia, which is treated through the administration of oral or intravenous (IV) iron. Macrocytic anemia involves vitamin B₁₂ or folic acid deficiency, and their replacement is the appropriate therapy for correction. Anemia of chronic disease is a type of normocytic anemia. Treatment of the underlying disorder will improve the anemia and for kidney disease, erythropoietin-stimulating agents (ESAs) may be used due to the impaired release of erythropoietin from the kidneys. ESAs may also be used, within certain guidelines, to improve quality of life and reduce the need for blood transfusion support in patients receiving myelosuppressive chemotherapy. Other types of anemia include hemolytic anemia, sickle cell anemia, thalassemia, and sideroblastic anemia.

Neutropenia may be caused by chemotherapeutic medications and nonchemotherapeutic medications through direct toxic effects, as well as through antibody formation and immune-mediated processes. Due to the risk of febrile neutropenia, interruptions in chemotherapy regimens, and hospitalizations, the G-CSFs, filgrastim and pegfilgrastim, are used for the treatment and prevention of chemotherapy-induced neutropenia. The most common nonchemotherapy drugs implicated in neutropenia are clozapine, methimazole (Tapazole), sulfasalazine, and trimethoprim/sulfamethoxazole (Bactrim). The suspected drug should be stopped, and G-CSFs may be considered.

Drug-induced thrombocytopenia may involve a number of different medications, with the most common one being heparin. There are two types of heparin-induced thrombocytopenia: HIT-I and HIT-II. HIT-II is an immune-mediated process that puts patients at risk of developing thromboses. Direct thrombin inhibitors, the factor Xa inhibitor fondaparinux, or newer oral agents may be used to prevent thrombosis once the heparin is discontinued. Other medications thought to cause thrombocytopenia should also be discontinued, and the platelet count should soon recover.

Blood clots are formed by a number of internal and external factors coming together to inappropriately activate the clotting cascade. Blood clots can manifest in several ways, including heart attacks, strokes, deep vein thrombosis (DVT), and pulmonary embolism (PE). These clots can have serious consequences, including severe tissue damage and even death. Treating clots usually involves giving an anticoagulant to prevent the clot from getting any bigger or breaking off while the body dissolves it over a period of weeks to months. Available anticoagulants include heparin, low molecular weight heparin (LMWH), direct thrombin inhibitors, factor Xa inhibitors, and warfarin. The most common side effect of all anticoagulants is bruising and bleeding. Some anticoagulants have antidotes or reversal agents and others do not. Active prevention in high-risk patients is very important, and this includes drug therapy and nondrug therapy.

REVIEW QUESTIONS

1. What is anemia and what clinical effects could be experienced in patients with anemia?

2. How is anemia classified?

3. List five risk factors for clot development.

4. Which oral anticoagulant medication has special storage requirements to keep in the original bottle?

5. How are anticoagulants different from thrombolytics?

MEDICATION TABLES