The Blood Detective: Tackling Medication-Induced Hematological Disorders

Blood serves as a vital means of life. Studying blood and its disorders is a necessary part of the work of pharmacists focused on improving patient health. To manage and prevent blood disorders, pharmacists take on the role of “blood detectives” by focusing on the pharmacodynamics, pharmacokinetics, and adverse effects (AEs) of medications.¹ Without pharmacists working in hematology, an increase in mortality rates would occur because of contraindications or deadly AEs from blood disorder medications.

Image credit: Felipe Caparrós | stock.adobe.com

Although hematologists assist patients in identifying disorders and known treatments, the field has limitations and challenges, ranging from diagnosing the cause of illness to identifying medications causing disorders. There can be numerous causes of a single disorder, so additional testing may be required to determine the appropriate treatment. For example, factors such as inadequate nutrients, other illnesses, or pregnancy can cause anemia, which is a blood disorder caused by a lack of hemoglobin.

Medication for blood disorders can cause AEs that affect other regions of the body and react with other drugs. Although challenges may arise from the patient’s current condition, in rare cases, blood disorders can be an AE caused by certain medications.

Medication-Induced Hematological Disorders

Medication-induced hematological disorders (MIHDs) are rare drug reactions caused by medications and can be fatal.² The mechanism of action of certain medications can cause an immune response or affect blood synthesis in the bone marrow, leading to various types of hematological disorders that affect different components of blood.² Medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), antineoplastic drugs, and anticonvulsants can cause MIHDs such as drug-induced anemia, thrombocytopenia, and neutropenia.³

Prevalence and Significance in Clinical Practice

MIHDs highlight the importance of a pharmacist’s role in understanding drug interactions and preventing AEs. Pharmacists can take varying approaches to treat, prevent, and identify the disorders. For instance, pharmacists can create a treatment plan to prevent MIHDs and alter the initial prescription.

Common Culprits: Drugs That Cause Hematological Disorders

Certain medications have been shown to induce myriad hematological disorders, including aplastic anemia and hemolytic anemia. Some of these medications include hydroxychloroquine, sulfamethoxazole with trimethoprim, cephalosporins, phenytoin, and heparin, among others. Although hematological disorders are not as commonly induced by medications compared with liver or pulmonary disorders, they still require precautions and monitoring because of associated high morbidity and mortality rates.

During clinical trials that are testing pharmaceuticals, certain drug reactions are not regularly caught during the preclinical or clinical phase. They are instead observed during the postmarketing surveillance phase. Commonly seen MIHDs include aplastic anemia, agranulocytosis, megaloblastic anemia, thrombocytopenia, and hemolytic anemia.

Aplastic Anemia

Aplastic anemia is a condition in which the blood cells are significantly reduced due to the impaired function of the bone marrow.² Researchers believe that certain medications induce aplastic anemia by triggering the immune system to attack cells in the bone marrow, directly attacking the DNA of the bone marrow cells by idiosyncratic means.²

Some of the drugs shown to induce aplastic anemia include salicylates (eg, aspirin), antimalarial medications (eg, hydroxychloroquine), diuretics (eg, hydrochlorothiazide, furosemide), antibiotics (eg, sulfamethoxazole, trimethoprim [Bactrim; Able Laboratories Inc], amoxicillin), anticonvulsants (eg, phenytoin), and other medications that contain a benzene ring in their chemistry.²

Agranulocytosis

Agranulocytosis is an acute condition in which a patient’s absolute neutrophil count is less than 100 neutrophils/μL.⁴ Agranulocytosis has 2 main etiologies, hereditary and acquired.⁴ Genetic mutations and medications are the main examples of the hereditary and acquired etiologies of agranulocytosis, respectively.

Although there is not a clear mechanism by which medications can induce agranulocytosis, it has been postulated that the bone marrow and neutrophils are directly compromised through apoptosis, leading to the subsequent activation of inflammasomes.⁴ Medications that can induce agranulocytosis include analgesics and anti-inflammatory drugs (eg, naproxen); antithyroid medications (eg, propylthiouracil); antiarrhythmics (eg, procainamide); antihypertensives (eg, enalapril, nifedipine); antidepressants (eg, amitriptyline); antimalarials (eg, chloroquine); anticonvulsants (eg, phenytoin); antibiotics such as cephalosporins; and other medications, including ranitidine.⁴

Megaloblastic Anemia

Megaloblastic anemia is a condition characterized by the presence of megaloblasts, which are large red blood cell precursors. With their presence, DNA synthesis is impaired, leading to an inhibition of nuclear division.⁵

The main etiologies of megaloblastic anemia are folate and vitamin B12 deficiencies, as these vitamins are vital for DNA synthesis.⁵ Other etiologies of megaloblastic anemia include copper deficiency and medications.⁵

Medications induce megaloblastic anemia mainly by changing megaloblastic shapes in bone marrow as well as disrupting the absorption of folic acid and vitamin B12.⁵ Drugs shown to induce megaloblastic changes in bone marrow include allopurinol, azathioprine, hydroxyurea, and methotrexate. Drugs shown to disrupt the absorption of vitamin B12 and folate include metformin, aminoglycosides, phenytoin, and oral contraceptives.⁵

Thrombocytopenia

Thrombocytopenia is a condition in which the platelet count is too low, leading to difficulty in stopping bleeds. The normal platelet count in an adult usually ranges from 150,000 to 450,000 platelets/μL.^6,7

Thrombocytopenia can be acquired or inherited.⁶ The most common etiology for acquired thrombocytopenia is medication.^7,8 It is shown that drug-dependent antibodies bind to the fragment antigen-binding regions of platelets tightly but reversibly only in the presence of medications that cause thrombocytopenia.^7,8 Medications shown to induce thrombocytopenia include heparin, abciximab, quinidine, ranitidine, and carbamazepine.^7,8 It has been shown that drug-induced thrombocytopenia resolves in approximately 14 days after the offending agent is removed.8

Hemolytic Anemia

Hemolytic anemia is a condition in which the red blood cell undergoes destruction prematurely. This condition typically occurs through phagocytosis and sequestration due to the deformability of red blood cells. The etiologies of hemolytic anemia are numerous and include autoimmune, envenomation, enzymopathy, infections, and medications.⁹

Drug-induced hemolytic anemia is considered a rare occurrence. Common drugs listed as culprits include β-lactamase inhibitors, penicillins, ceftriaxone, methyldopa, and NSAIDs. Drug-induced hemolytic anemia progresses gradually and is often resolved once the offending agent is removed. These medications induce hemolytic anemia by splenic destruction, which increases oxidative stress and decreases energy in the process.⁹

Detection and Diagnosis: The Pharmacist’s Role

Pharmacists can identify signs and symptoms of MIHDs through patient history, physical examinations, and communication with the patient’s health care providers. MIHDs can occur by direct drug or metabolite toxicity or an immune reaction. Additionally, pharmacists can recognize drugs that cause MIHDs and provide education on signs and symptoms to report.⁹

Reviewing patient history and medication profiles is important in identifying and preventing drug-induced hematological reactions. Collecting a thorough medical history can help identify preexisting factors that may increase the risk of such a reaction. A comprehensive assessment of medication profiles is essential to recognize drug interactions, avoid contraindications, and identify cumulative effects of medications on the hematologic system over time.

Pharmacists can also utilize laboratory tests and collaborate with health care teams on the diagnosis. A complete blood count (CBC) test measures red blood cells, white blood cells, platelets, hemoglobin, hematocrit, and mean corpuscular volume (MCV). However, the CBC is not definitive, so other laboratory results must be taken into account for diagnoses. CBC results in the following areas may indicate a hematologic disorder²:

• Red blood cell count, hemoglobin, hematocrit: Low levels may indicate anemia, although other laboratory values need to be taken into consideration.
• Red blood cell count: High values may indicate erythrocytosis or thalassemia.
• Hemoglobin or hematocrit: High values may indicate cancer or heart disease.
• White blood cell count: A low level is known as leukopenia. A high level may indicate an infection or inflammation, or it may indicate an immune system disorder or bone marrow disease.
• Platelet count: A low count is known as thrombocytopenia, and a high count is known as thrombocytosis.
• MCV: High MCV means the red blood cells are too large, which could indicate liver disease or a vitamin deficiency.

In a peripheral blood smear examination, common clinical indications of MIHDs include unexplained anemia, leucopenia, or thrombocytopenia; unexplained leukocytosis, lymphocytosis, or monocytosis; or unexplained jaundice or hemolysis.^2,10-12

Managing MIHDs

The key strategy to address MIHDs is to discontinue the causative agent and manage the patient’s symptoms. The sooner the causative agent is discontinued, the better the chances are of survival and reversal.

It is also important to consider prophylactic antibiotics to reduce the risk of secondary infections. Glucocorticoids have been shown to help conditions such as autoimmune hemolytic anemia. Corticosteroids are also recommended by experts in severe cases of heparin-induced thrombocytopenia (HIT), although this approach has been controversial due to limited availability of supporting data.³

It is also advisable to avoid the use of certain medications in the context of patient-specific factors. For example, patients with known G6PD deficiencies should not be given medications that can cause hemolysis. To prevent HIT, direct oral anticoagulants are now preferred over heparin for ease of administration and a stronger safety and efficacy profile.³

Vitamin supplementation may also be useful in some cases. For instance, vitamin B12 supplementation can help manage drug-induced megaloblastic anemia.³

Laboratory tests, such as CBC, should be routinely monitored by looking at appropriate parameters. Changes in routes of administration should also be considered depending on the patient’s status. The necessary parameters to ensure resolution should be followed as advised, and anticoagulation should be continued for at least 2 to 3 weeks to minimize the risk of thrombosis.³

Although an adverse drug reaction such as a drug-induced hematological disorder is unpredictable, appropriate steps can be taken to minimize the chances of one occurring.² Chand et al recommend utilizing the expertise of a clinical pharmacist to educate and counsel the patient, obtain a detailed medication history to reduce polypharmacy, and address the disorder as soon as possible.²

Prevention and Education

Strategies to help prevent MIHDs are as follows³:

• Conduct detailed medical history: Pharmacists should conduct a detailed review of a patient’s medical history, including current medications, hematological conditions, and previous reactions to medications.
• Individualized medication plan: Patients’ medication regimens should be tailored to their age, sex, and existing hematological conditions.
• Routine monitoring: Blood tests should be conducted routinely in patients taking medications that cause hematological disorders.
• Patient education: Pharmacists should educate patients on AEs associated with their medications and the importance of reporting all adverse drug reactions.

Pharmacists should provide patients with detailed information on medications prescribed by their primary care provider as follows^2,12:

• Medication management: Pharmacists should communicate with patients about the medication’s purpose, dosage, and strength; how to take it; and signs of potential AEs, as well as when to follow up.
• Lifestyle management: Pharmacists should educate patients on the importance of adopting lifestyle changes that can positively affect their condition, such as exercising and eating foods that are rich in iron for patients with anemia, and vitamin B12 for patients with megaloblastic anemia. Patients should also be advised against smoking and a sedentary lifestyle because these are risk factors for hematological disorders.

Conclusion

Pharmacists can assess a patient’s history to identify any etiologies and risk factors that can increase their chances of a hematologic blood disorder.^2,12 Additionally, if any concerns arise that result in changing a drug regimen, pharmacists play an important role in documenting these occurrences to provide better communication with other health care providers on the patient’s care team.¹²

References

1. The evolving role of the hematology/oncology pharmacist. American Society of Hematology. December 2017. Accessed January 15, 2024. https://ashpublications.org/ashclinicalnews/news/3500/The-Evolving-Role-of-the-Hematology-Oncology
2. Chand S, Dikkatwar MS, Pant RD, et al. Drug induced hematological disorders: an undiscussed stigma. IntechOpen. October 25, 2023. Accessed January 15, 2024. https://www.intechopen.com/online-first/85540
3. DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey L, eds. Chapter e125: Drug-Induced Hematologic Disorders. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach. 12th ed. McGraw Hill; 2023. Accessed January 15, 2024. https://accesspharmacy.mhmedical.com/book.aspx?bookID=3097
4. Sedhai YR, Lamichhane A, Gupta V. Agranulocytosis. In: StatPearls. StatPearls Publishing; 2023. Accessed January 15, 2024. https://www.ncbi.nlm.nih.gov/books/NBK559275/
5. Hariz A, Bhattacharya PT. Megaloblastic anemia. In: StatPearls. StatPearls Publishing; 2023. Accessed January 15, 2024. https://www.ncbi.nlm.nih.gov/books/NBK537254/
6. Thrombocytopenia. National Heart Lung and Blood Institute. Updated March 24, 2022. Accessed January 15, 2024. https://www.nhlbi.nih.gov/health/thrombocytopenia
7. George JN, Aster RH. Drug-induced thrombocytopenia: pathogenesis, evaluation, and management. Hematology Am Soc Hematol Educ Program. 2009;153-158. doi:10.1182/asheducation-2009.1.153
8. Gauer RL, Braun MM. Thrombocytopenia. Am Fam Physician. 2012;85(6):612-622.
9. Phillips J, Henderson AC. Hemolytic anemia: evaluation and differential diagnosis. Am Fam Physician. 2018;98(6):354-361.
10. Tefferi A, Hanson CA, Inwards DJ. How to interpret and pursue an abnormal complete blood cell count in adults. Mayo Clin Proc. 2005;80(7):923-936. doi:10.4065/80.7.923
11. Adewoyin AS, Nwogoh B. Peripheral blood film - a review. Ann Ib Postgrad Med. 2014;12(2):71-79.
12. Chen KY, Brunk KM, Patel BA, et al. Pharmacists’ role in managing patients with chronic lymphocytic leukemia. Pharmacy (Basel). 2020;8(2):52. doi:10.3390/pharmacy8020052

About the Authors

Nana Kwesi Owusu-Boakye is a PharmD candidate in the Department of Pharmacy Practice at the Irma Lerma Rangel School of Pharmacy and an MBA candidate at Texas A&M University in Kingsville.

Chinonso Paul is a PharmD candidate in the Department of Pharmacy Practice at the Irma Lerma Rangel School of Pharmacy and an MBA candidate at Texas A&M University in Kingsville.

Taylor Roberson is a PharmD candidate in the Department of Pharmacy Practice at the Irma Lerma Rangel School of Pharmacy at Texas A&M University in Kingsville.

Shreya Kumar is a PharmD candidate in the Department of Pharmacy Practice at the Irma Lerma Rangel School of Pharmacy at Texas A&M University in Kingsville.

Yulianna Laurencin is a PharmD candidate in the Department of Pharmacy Practice at the Irma Lerma Rangel School of Pharmacy at Texas A&M University in Kingsville.

Sara Rogers, PharmD, BCPS, is a clinical assistant professor of precision medicine and ambulatory care at the Irma Lerma Rangel School of Pharmacy at Texas A&M University in Kingsville; a clinical specialist at Texas A&M Physicians Clinic; and a cofounder of the American Society of Pharmacovigilance.