Drug Induced Hematological Disorders: An Undiscussed Stigma

Abstract

Drug Induced Hematological Disorders (DIHD) are one among the most frequently encountered Adverse Drug Reactions (ADRs) among the patients using the systemic drug therapy. These unwanted and noxious incidents are often unnoticed or even neglected most of the time during the clinical practices. However, they largely affect the compliance of the patients with their therapy and subsequently affecting the therapeutic outcome of the drug regimen. The inception of the concept of Pharmacovigilance has largely enlightened on this neglected issue and raised the concern over several scientific sessions. However, this serious issue remained unaddressed clinically. These noxious conditions frequently provoke the adverse events or precipitate the underlying medical complications affecting the safety of the patients. The wise and vigilant use of certain risky medication capable of inducing such clinical conditions can significantly reduce these incidences. Thus, the utilization of the skills and the expertise knowledge of the clinical pharmacist can play a pivotal role in preventing and minimizing such events.

1. Introduction

Drugs are now become part of our day-to-day life. The burden of disease in the ever-rising trend and the medical fraternity is progressing exponentially. The pharmaceutical industries are constantly expanding the spectrum of the pharmaceutical by carrying out the research and discovering the newer drugs or by synthesizing the molecule with the better efficacy. All the newer molecule or the formulations released in the market go through the strict regulatory process of their testing for safety and efficacy in the clinical subjects. However, it is not possible to the study the drugs completely. Thus, none of the drugs available in the markets are completely safe [1].

The molecule goes through the laboratory studies followed by the pre-clinical and clinical studies and the molecule able to demonstrate the sufficient safety along with the promising efficacy only will release in the market. This procedure generally takes the longtime of decade or even two-three decades [2]. Study of any marketed product after their release in the market is known as the post-marketing surveillance. Several of drugs with potentiality to threat the safety of the patients are continuously studied during this phase and the drugs with the established causality relationship with the adverse events are then recalled by the regulatory or the safety agencies. The Indian Pharmacopeial commission is one of the apex bodies to continuously monitor the safety of the drugs and collects the signals of the suspected adverse drug reactions [3].

Drug induced disorders are technically the adverse drug reactions occurred by that drug molecule or by the excipients used in the formulation of the drugs. The drug induces the adverse drug reactions by either pharmacokinetic or by the pharmacodynamic mechanism. Some of the most commonly occurring adverse drug reactions are drug induced liver disorders, drug induced pulmonary disorders, drug induced hematological disorders, drug induced renal disorders or any dermatological manifestations [4, 5]. Whatever may be the reactions, this incident possesses great risk to the patient safety and accounts for several injuries and casualties. These unwanted and noxious events generally remain undiagnosed or under-reported due to the various factors. However, the medical sciences are becoming vigilant toward such bitter event and continuously trying to detect, assess, manage, document, and prevent them [6, 7, 8].

Drug-induced hematological disorders (DIHD) are one among the major type of adverse drug reactions (ADRs) due to their severity rather than their incidence rate. The incidence rate of the DIHD is less compared to other ADRs, however, they posses the greater risk of morbidity and mortality. Thus, they are rare phenomenon occurring in the clinical setting. Some of the most frequently occurring DIHDs are Drug induced aplastic anemia, followed by drug induced agranulocytosis, megaloblastic and hemolytic anemia. There are few literatures in the scientific databases even reporting the incidences of drug induced thrombocytopenia. The incidence of these event is rare and the majority of ADRs are occurring after the chronic use of the medications. Thus, these ADRs are difficult to identify during the clinical trials and are best detected during the post-marketing surveillance [9, 10, 11].

2. Types of drug-induced hematological disorders

There are several types of hematological disorders occurring as an adverse drug reaction of drugs, most common types of them are [12, 13]:

1. Drug-induced aplastic Anemia,

2. Drug-induced agranulocytosis

3. Drug-induced megaloblastic anemia

4. Drug-induced thrombocytopenia

5. Drug-induced hemolytic anemia [14, 15, 16, 17].

2.1 Drug-induced aplastic anemia

This is the clinical condition characterized by extremely low count of blood cells due to the inability of the bone marrow to produce the sufficient amount of new blood cells [18, 19, 20, 21]. This is an extremely condition and is generally life-threatening reactions associated with some category of drugs. These drugs are generally having their toxic effect toward the bone marrow and affect the process of blood cell synthesis. This is again life-threatening condition due to its impact on all types of blood cells including white blood cells (WBC), red blood corpuscles (RBC) and platelets (Thrombocyte). Thus, the condition is clinically interpreted by the decline in all types of blood cells.

2.1.1 Mechanism involved or pathophysiology of the drug-induced aplastic anemia

The underlying mechanism to induce the aplastic anemia is the activation of the immune complex by these suspected drugs and the patient’s own immune system is directed toward the bone marrow. The immune related injury to the bone marrow will results in the synthesis of limited number of blood cells (hypoplastic anemia) or sometime make them almost empty (aplastic anemia).

Another hypothesis states that there is the generation of the intermediate toxic compounds that binds to several functional proteins and deoxyribose-nuclease acid (DNA) of these hematopoietic bone marrow cells leading to the direct injury of bone marrow. However, the generation of these toxic intermediate is highly dependent to the genetic variability of an individual. Some of the other research suggests the generation of toxic intermediates as an idiosyncratic condition.

2.1.2 List of common drugs responsible for aplastic anemia

• Salicylates: Aspirin

• Antimalarial: Chloroquine

• Diuretics: Hydrochlorothiazide, furosemide, thiazide

• Antibiotics: Chloramphenicol, sulphonamides, penicillamines

• Anti-neoplastic agents: Propylthiouracil

• Anticonvulsants: Carbamazepine, phenytoin

• Miscellaneous: Benzene containing compounds, drugs containing heavy metals.

2.1.3 Clinical manifestations of drug-induced aplastic anemia

The most significant clinical presentation of aplastic anemia is the decline in the count of blood cells and the condition is widely termed as pancytopenia. Aplastic anemia can be clinical characterized by either decrease in one type of blood cells or by the overall decrease of blood cells in most of the cases. Some of the other clinical features are:

• White blood cells fall below 3500cells/mm³

• Hemoglobin level fall below 10gm%

• Complain of easy tiredness and fatigue by the patients

• Generalized weakness and feeling of drainage of energy

• Thrombocyte counts fall below 55,000 cells/mm³

• Incident of prolonged bleedings

• Epistaxis

• Gum bleeding

• Fever (Mild to moderate)

• High propensity for acquiring the infections

• Reticulocyte count fall below 30,000 cells/mm³

• There might be the fall of the blood cells counts signifying the severity of the aplastic anemia and the fall of reticulocyte index to 1%, neutrophil level to 500 cells/ mm³ and platelet levels to 20,000 cells/mm³ is the indication of severe aplastic anemia.

• The condition of aplastic anemia can be life threatening if its level goes beyond the levels of severe aplastic anemia.

2.2 Drug-induced agranulocytosis

This is a clinical condition where there is a decrease in the body’s total number of mature myeloid cells (Granulocytes and immature ones) to 500 cells/mm³ or fewer [22, 23, 24, 25]. Occurrence of agranulocytosis is mainly seen in females and aged people with an approximated yearly incidence rate of one to 12 cases per 10 lacs population. This hematological condition will generally settle over time with approving care and prevention and management of infection.

2.2.1 Mechanism involved or pathophysiology of the drug-induced agranulocytosis (DIA)

The exact reason for drug induced agranulocytosis is still not recognized but many mechanisms were put forward, nonetheless the recent studies revealed that medications may have a direct toxic effect on the bone marrow, neutrocytes or stem cells. The first mechanism involves the anti-thyroid drugs (ATD) such as methimazole and propylthiouracil which have been outlined to cause agranulocytosis. Apoptosis occur which activates inflammasomes (important for innate immune system). The following figure shows the direct toxicity of ATD-Induced agranulocytosis. In recent outline 7–23% of DIA cases occur due to anti-thyroid drugs. Higher dose of methimazole received by patient showed neutropenia.

The second kind of mechanism comprises antibodies, neutrophils, immune-mediated medications, or drug metabolites. This process suggests that the medication is adsorbing through the neutrophile membrane. The drug-containing membrane functions as a hapten to promote the production of antibodies. As a result of the antibodies’ binding to the drug-membrane complex, the phagocytic system activates complement, which in turn causes the WBC to be destroyed. When medications like penicillin derivatives are administered at larger doses, this hapten-type response occurs as depicted in Figure 1.

Figure 1.

Antibody and complement system-based mechanism of toxicity.

There are also several other immune-mediated processes that have been identified. The culprit medicine reforms the neutrophil membrane through the autoantibodies forming to a membrane mechanism. This alteration triggers the production of autoantibodies, which kill cells.

2.2.2 List of common drugs responsible for agranulocytosis

1. Anti-thyroid drug (ATD): Carbimazole, methimazole, propylthiouracil.

2. Beta-lactam antibiotics: penicillin, penicillamine, ampicillin.

3. Anticonvulsants: Carbamazepine.

4. Cardiac glycosides: Digoxin, digitalis.

5. Propranolol: beta blockers.

6. Corticosteroids: Prednisone.

7. ACE-inhibitors: Captopril.

8. Anti-infectives: Dapsone.

2.2.3 Clinical features of drug-induced agranulocytosis

Symptoms of agranulocytosis occurs rapidly in less than a weeks after the intake of culprit drug.

• Having a sore throat is a very common symptom

• Complains of discomfort, illness

• People being febrile

• Increased propensity toward infections

2.3 Drug-induced megaloblastic anemia

A condition where the growth of RBC precursors (Megaloblasts) in the bone marrow is aberrant [26, 27, 28]. Drugs including amino salicylic acid, colchicine, neomycin, and metformin can prevent the absorption of vitamin B12. Megaloblastic anemia from these agents is extremely uncommon because of how little B12 the body needs and how much of it is present in most diets.

2.3.1 Pathophysiology of drug induced megaloblastic anemia

Megaloblastic anemia is most frequently brought on by cobalamin (vitamin B12) or folate insufficiency (vitamin B9). For the development of healthy cells, such as the precursors of red blood cells, these two vitamins act as building blocks. Since most dietary causes of folate and vitamin B12 deficiency may be resolved, drugs have emerged as a more significant contributor to megaloblastic anemia. Megaloblasts-inducing medications are frequently employed in clinical settings, although the caused changes to DNA synthesis pathways aren’t always welcomed. The most crucial biochemical process during DNA synthesis is the synthesis of thymidine, which is a component of DNA but not RNA. As a result, it is susceptible to drug inhibition. Through the methylation of pyrimidine, which is a folate and vitamin B12 dependent process, thymidine is produced. Megaloblastosis is brought on by medications that physically destroy vitamins, compete with reducing enzymes, or obstruct folate or vitamin B12 absorption, transport, or delivery.

2.3.2 Causative drugs

• Anticonvulsants: Phenytoin

• Barbiturates: Phenobarbital

• Anticonvulsants: Primidone

• Antimetabolites: Methotrexate

• Sulphonamides: Cotrimoxazole

• Biguanides: Metformin

• Nucleoside reverse transcriptase inhibitors (NRTIs): Zidovudine

• Antimetabolites: 5-Flurouracil

2.3.3 Clinical manifestation

• Shortness of Breath

• Malaise

• Muscle Weakness

• Irregular Heartbeats

• Dizziness

2.4 Drug-induced thrombocytopenia

A disorder known as thrombocytopenia occurs when there are not enough platelets in the blood [29, 30, 31]. Blood cells called platelets aid in blood clotting. Bleeding risk is increased by a low platelet count. When thrombocytopenia is present, the platelet count falls below 104 cells/mm³ or falls below 50% of the normal level. About 10 cases/105 people are affected by drug-induced thrombocytopenia per year. Except for cases linked to heparin, none of the numerous epidemiological studies have been reported. Find patient-specific risk factors for medication-induced thrombocytopenia that do not just involve exposure to drug classes.

2.4.1 Mechanism involved or pathophysiology of the drug-induced thrombocytopenia anemia

DITP is a distinctive immune-mediated reaction. Medication-dependent antibodies are a rare family of antibodies that bind securely to platelet surface glycoprotein epitopes only when a sensitizing drug is present. Drug-dependent antibodies are very sensitive to the chemical makeup of drugs. According to this hypothesis, medicines bind non-covalently and reversibly to antibodies as well as platelets, generally at locations on GP IIb-IIIa and/or GP Ib-V-IX. The resulting “sandwich” (seen in Figure 2) encourages the development of strong interactions between the antibody and platelet epitopes. The Fab domains’ capacity to identify medicines bound to platelet epitopes is used to select the antibodies that are produced because of exposure to sensitizers. Antiplatelet antibodies that are dependent on a medicine typically start to show up 1 to 2 weeks after first exposure. Drug-dependent antibodies may also develop following prolonged, irregular drug use. Unlike neutrophils and erythrocytes, platelets are significantly more frequently the target of drug-dependent antibodies for unexplained reasons.

Figure 2.

Drug-dependent model with specific affinity with thrombocytes.

2.4.2 Clinical features of drug-induced thrombocytopenia

The most significant clinical feature of thrombocytopenia is significant drop in the platelet count (<50% of normal platelet range). Due to the platelet count drop lots of sign and symptoms may noticed in patients like,

• In this case platelet count in the blood drops below 10,0000 cells/mm³

• Abnormal bleeding.

• Bleeding when brushing teeth.

• Easy bruising

• Red spots (petechiae) on the skin.

2.5 Drug-induced Hemolytic Anemia

Haemolytic anemia is a blood condition that occurs primarily when red blood cells are destroyed faster than they can be replaced [32, 33, 34]. Red blood cells are normally released from the bone marrow and survive for about 120 days before being cleared by phagocytic cells in the spleen and liver. The process by which immature red blood cells are destroyed is called haemolysis. This haemolysis occurs due to red blood cell defects or abnormal changes in the intravascular environment. Both processes may facilitate drug-induced haemolysis. It can develop rapidly or slowly and can be mild or severe.

2.5.1 Mechanism involved or pathophysiology of drug induced hemolytic anemia

Drug-induced haemolytic anemia is a type of blood disorder in which the body’s defense system is triggered by drugs, resulting in an attack on its own red blood cells. This leads to premature destruction of red blood cells, known as haemolysis. The drug causes the immune system to see its own red blood cells as foreign. The body responds by producing antibodies that destroy its own red blood cells. Immunoglobulin G (IgG) and/or immunoglobulin M (IgM) bind to antigens on the surface of red blood cells and begin to destroy them.

2.5.2 List of common drugs responsible for hemolytic anemia

• Antibiotics: Cephalosporins, Beta-lactum antibiotics, Ciprofloxacin

• Diuretics: Hydrochlorothiazide

• Antihypertensives: Methyldopa,

• Antiarrhythmic: Qiunidine, Procainamide

• NSAIDS: Diclofenac,

• Insulin secretagogues: Sulfonylureas

• Proton-pump inhibitors: Omeprazole, lansoprazole

• Miscellaneous: Acetaminophen, levodopa, probenecid, erythromycin

2.5.3 Clinical features of drug-induced immune hemolytic anemia

The sign and symptoms resemble the clinical features like anemia, patient may complain of fever with chills and rigor, breathlessness etc.

2.6 Identification of drug-induced hematological disorders

The adverse event of drug induced hematological disorders are best identified during the clinical use of the suspected drugs. The patients administrating the suspected drug with potential to induce these hematological events should be closely monitored and any suspicious events should be assessed for the causal relationship with the drugs using the causality assessment scale. There are several scales to establish the causal relationship, assess the severity and preventability of the drugs with these adverse effects. The suspected drug should be withdrawn immediately, and the drug should not be rechallenged as these incidences are severe in nature. The suspected adverse drug reactions are then submitted to the local, zonal, or regional pharmacovigilance centers. The reporting can also be done to the competent authorities by their website with the complete information of the events and product.

2.7 Diagnosis tools

2.7.1 History taking

The complete and detailed history taking helps in diagnosing most of the cases. The patients usually have the history of taking the medications susceptible to induce these adverse drug reactions.

2.7.2 Monitoring of therapy

The monitoring of the therapy containing these agents also help in the prevention or early detection of such events.

2.7.3 Laboratory findings

The other mean to diagnose the cases are to obtaining the laboratory report and clinical correlation to the past medication history. The laboratory reports show the decline in the blood cells post commencement of medication therapy. Laboratory tests mainly performed are:

2.7.3.1 Complete blood count (CBC)

This test measures the levels of platelets and other blood cells in the blood.

2.7.3.2 Blood smear

A portion of patients’ blood is placed on a glass slide under the microscope to observe the platelets.

2.7.4 Bone marrow examination

These tests check to see if the bone marrow is healthy.

2.7.5 Vigilant use of risky medication

Some drugs with the frequent occurrence of aplastic anemia are chloramphenicol and propyl thiouracil thus, these therapy needs to be monitored.

2.7.6 Study of factors affecting the ADRs

There are various intra and intersubjective variability including the immunological factors, genetic factors, pharmacokinetics, and pharmacodynamics factors. Such factors can be identified and documented for some vulnerable patients. Early diagnosis is important to limit the injury caused by the drugs and restore the peripheral count of blood cells.

2.8 Management

2.8.1 Goals of therapy of DIHD

• The mains’ goal of drug induced hematological disorder is to ameliorate the ADR by timely withdrawal of suspected medications.

• Timely assessment and identification of any insult to the hematopoietic system caused by any suspected drugs.

• Another goal is to ensure the safe therapy and warn the patients about the drugs and their probable ADRs in future.

• To limit the decline in the blood cells.

• To minimize the risk of infection and bleeding.

2.8.2 Specific treatment of drug-induced aplastic anemia

• Immediate withdrawal of the culprit drugs. The removal of the culprit drug will arrest the insult to the hematopoietic system and reverse the condition.

• Fever can be treated by use of antipyretics and broad-spectrum antibiotics. However, the recent evidence suggests that the patients should not be administered with broad spectrum antibiotics as a chemoprophylaxis.

• Treating the adverse drug reactions by administering another drug is not recommendable.

• Generally mild aplastic anemia will reverse over the time and no specific treatment is required. The nature of specific treatment depends upon the level of cytopenia. The extreme low level of blood cells needs to be replaced by the transfusion as per clinical need.

• Immunosuppressive therapy and use of corticosteroids (methylprednisolone and/or prednisolone 1 mg/kg/day up to months or 6 weeks) can be warranted in the typical case of drug induced aplastic anemia due to the involvement of immunological system. E.g., antithymocyte globulin and cyclosporine.

• Hemopoietic stem cell transplantation can be suggested in the extreme cases. But rejection of therapy is the major challenge in this approach.

2.8.3 Specific treatment of drug-induced agranulocytosis

• Immediate withdrawal of the culprit drug.

• Filgrastim and sargramostim lessen the timeline of neutropenia, and the line antibiotic therapy, with hospital stay.

• Fever can be treated by use of antipyretics and broad-spectrum antibiotics.

• Treating the adverse drug reactions by administering another drug is not recommendable.

2.8.4 Specific treatment of drug-induced megaloblastic anemia

• Most individuals are treated with cobalamin or folate once drug-induced megaloblastic alterations and myelodysplasia-related megaloblasts have been ruled out. Due to the progressive development of megaloblastic anaemias, many patients can cope with low hemoglobin levels and do not need blood transfusions. Only individuals with severe, uncomplicated, and life-threatening anemia should get transfusion therapy.

• The causative agents of megaloblastosis must be identified to manage and treat drug-induced megaloblastic anemia. If there is an alternative, it will take the place of the cause. However, if the chemotherapeutic treatment that caused the anemia were to be stopped, there would be no real therapeutic alternative, and the anemia would then become a tolerable side effect. In this situation, ensuring appropriate consumption of folate and vitamin B12 is necessary. Additionally, when medical professionals utilize substances that prevent DNA synthesis, they should exercise additional caution. Folate antagonists and purine and pyrimidine analogues are stronger and can cause anemia very quickly. As a result, it is advised to employ less strong inhibitors; however, megaloblastic anemia may progress more slowly in this situation.

• There is no effective treatment for chemotherapy-related drug-induced megaloblastic anemia, hence the condition is tolerated as a side effect of treatment. If cotrimoxazole causes drug induced megaloblastic anemia, a trial course of folic acid, 5 to 10 mg up to four times per day, can treat the anemia. The megaloblastic anemia brought on by either phenytoin or phenobarbital is frequently treated with folic acid supplementation of 1 mg per day, but some practitioners contend that this can lessen the efficiency of the antiepileptic drugs.

2.8.5 Specific treatment of drug induced thrombocytopenia

• Immediate withdrawal of the culprit drug.

• Platelet interfering drugs should be avoided like Heparin, Clopidogrel etc.

• Corticosteroids or IV immunoglobulin may be given for suspected immune thrombocytopenia.

• If the patient’s thrombocytopenia condition in severe and bleeding in there, platelet transfusion can be given.

2.8.6 Specific treatment hemolytic anemia

• Immediate withdrawal of the culprit drugs. The removal of the culprit drug will stop the destruction it may be causing to red blood cells and reverse the condition.

• Glucocorticoids containing drug may find their clinical implications in the serious cases.

• Additional treatment contains the use of monoclonal antibodies like anti-CD20, rituximab and other modified immunoglobulins. However, they always possess the serious ADRs.

2.9 Prevention of drug induced hematological disorders

• Drug induced hematological disorders are often unpredictable, rare and life-threatening adverse drug reactions. These incidences can be minimized by adopting the following preventive measures.

• Obtain the detailed medical and medication history.

• Make a note of previous drug-allergy.

• Avoid designing the complex therapy by adding the multiple drugs as the polypharmacy is one among the major reason for ADRs.

• Patient should avoid taking the medication from the pharmacy store without any proper prescription.

• The patient prescribed with the potential drug needs to be counseled for the expected side effects and ADRs and educate them to report to the hospital immediately after occurrence of such events.

• Utilizing the specialist service of clinical pharmacist in educating the patients, creating awareness, drug therapy review and optimization of drug and individualizing the drug therapy can prevent the occurrence of these event.

• Timely prediction, assessment, and management of these event can prevent the magnitude of injury and helps in the prevention of occurrence.

• The patients with the known drug sensitivity can be alerted by providing the yellow card.

• Monitoring of the therapy for the prescribed time to find any unwanted events.

3. Conclusions

Drug use became a part of healthcare delivery system in the modern days. The marketed drugs pass the stringent approval process from the regulatory authorities. However, they carry the possible threat of serious adverse effects among the patients. All the drugs are associated with side effects ranging from mild to life threatening effect. The drug induced blood disorders are one among the major class of adverse drug reactions. The vigilant use of these medications may help in early detection and management of this drug induced events. These events are preventable in large scale by adopting the safe health care delivery system by adopting the expert knowledges in the multi-disciplinary team. The drug induced events are unavoidable, but the incidences can be prevented, or the severity can be flattened in majority of cases.