4-Drug induced hematological disorders

Views:
 
Category: Education
     
 

Presentation Description

No description available.

Comments

Presentation Transcript

PowerPoint Presentation:

By Minyahil A Woldu Bpharm., MSc in Clincal Pharmacy Drug-Induced Hematologic Disorders

Introduction:

Introduction Can be : Predictable hematologic disease (e.g., antineoplastics ), or Idiosyncratic reactions which is not directly related to the drugs’ pharmacology. Drug-induced hematologic disorders are generally rare adverse effects associated with drug therapy. Reporting during postmarketing surveillance of a drug is usually the method by which the incidence of rare adverse drug reactions is established. Because drug-induced blood disorders are potentially dangerous, rechallenging a patient with a suspected agent in an attempt to confirm a diagnosis may not be ethical.

Drugs may produce hematologic toxicity by one of three general mechanisms: :

Drugs may produce hematologic toxicity by one of three general mechanisms: Direct drug (or a metabolite ) toxicity Toxicity due to a drug effect on a genetic abnormality in the bone marrow Toxicity involving immune mechanisms .

The four major blood dyscrasias attributable to drugs are: :

The four major blood dyscrasias attributable to drugs are: Agranulocytosis or leukopenia (loss of the white blood cells) Aplastic anemia (loss of all the formed elements of the blood) Thrombocytopenia (loss of the platelets) Hemolytic anemia (loss of the red blood cells). The incidence of these adverse hematologic drug reactions, the relative importance of various etiologic chemicals, and their resultant morbidity and mortality vary.

PowerPoint Presentation:

Fig. Differentiation of the stem cell into committed cell lines, illustrating the origins of various drug-induced hematologic disorders.

The mechanisms of drug-induced hematologic disorders:

The mechanisms of drug-induced hematologic disorders The mechanisms of drug-induced hematologic disorders are the result of direct toxicity or an immune reaction.

FIGURE 112-2. Drug adsorption mechanism. The drug binds to the membrane of the blood cell. Antibodies are formed to the drug–membrane complex (hapten). The antibodies then attach to the complex, and cell toxicity occurs. (This article was published in Transfus Med Rev, Vol 7(Oct), Petz LD, Drug-induced autoimmune hemolytic anaemia, pages 242–254, Copyright © Elsevier 1993.) :

FIGURE 112-2. Drug adsorption mechanism . The drug binds to the membrane of the blood cell. Antibodies are formed to the drug–membrane complex ( hapten ). The antibodies then attach to the complex, and cell toxicity occurs. (This article was published in Transfus Med Rev, Vol 7(Oct), Petz LD, Drug-induced autoimmune hemolytic anaemia , pages 242–254, Copyright © Elsevier 1993.)

FIGURE 112-3. Innocent bystander mechanism. The drug induces antibody formation. The antibodies and drug form a complex in the serum, and the complex nonspecifically binds to the cell membrane. Complement is activated, and the cell is lysed. (This article was published in Ballieres Clin Haematol, Vol 91, Petz LD, Drug-induced haemolytic anaemia, pages 455–482, Copyright © Elsevier 1980.) :

FIGURE 112-3. Innocent bystander mechanism . The drug induces antibody formation. The antibodies and drug form a complex in the serum, and the complex nonspecifically binds to the cell membrane. Complement is activated, and the cell is lysed . (This article was published in Ballieres Clin Haematol , Vol 91, Petz LD, Drug-induced haemolytic anaemia , pages 455–482, Copyright © Elsevier 1980.)

FIGURE 112-4. Protein carrier mechanism. The drug combines with a plasma protein. The complex then attaches to the cell membrane, and antibody formation is stimulated. Antibodies later attach to the complex and activate complement. The cell is then lysed by the complement. (This article was published in Ballieres Clin Haematol, Vol 91, Petz LD, Drug-induced haemolytic anaemia, pages 455–482, Copyright © Elsevier 1980.):

FIGURE 112-4. Protein carrier mechanism . The drug combines with a plasma protein. The complex then attaches to the cell membrane, and antibody formation is stimulated. Antibodies later attach to the complex and activate complement. The cell is then lysed by the complement. (This article was published in Ballieres Clin Haematol , Vol 91, Petz LD, Drug-induced haemolytic anaemia , pages 455–482, Copyright © Elsevier 1980.)

Drugs Suspected of Inducing Agranulocytosis (Leukopenia):

Drugs Suspected of Inducing Agranulocytosis ( Leukopenia ) Defined as a reduction in the number of granulocytes to ≤500 cells/mm3. Drug-induced agranulocytosis is classified as Type 1 (due to an immune mechanism) and Type II (drug effect on bone marrow DNA synthesis). In Type I reactions, blood immunoglobins are directed against drug-related antigens located on circulating leukocytes.

Table: Drugs Associated with Agranulocytosis:

Table: Drugs Associated with Agranulocytosis

DRUG-INDUCED AGRANULOCYTOSIS:

DRUG-INDUCED AGRANULOCYTOSIS Occurs most commonly in females and the elderly (i.e. >60 years of age), Has an estimated annual incidence of 1.1 to 12 cases per million population. overall mortality rate of agranulocytosis is estimated to be 3.5% to 16%. Mortality rate is highest among the elderly and patients with renal failure, bacteremia, or shock at the time of diagnosis.

Clinical Picture:

Clinical Picture Sore throat, fever, malaise, weakness, chills, and other signs and symptoms of infection. Onset: can appear rapidly, within days to weeks after the initiation of the offending drug. But the time to onset is >1 month for most of these agents Median duration of exposure prior to the development of agranulocytosis ranges from 19 to 60 days for most drugs.

Etiology and Mechanisms:

Etiology and Mechanisms The cause is not fully understood. Several mechanisms have been proposed. Direct toxic effect or An antibody mediated effect on the bone marrow, neutrophils, or stem cells.

Types of immune mediated rxns:

Types of immune mediated rxns Involves the drug or drug metabolite, antibodies, and neutrophils interaction- hapten formation. Eg penicillin induced rxn The innocent bystander phenomenon- the drug combines with a drug-specific antibody. Eg . Quinidine induced rxn . Involves a protein carrier that combines with the drug and then attaches to the cell membrane. The production of autoantibodies to a spoiled membrane. Eg . High concentrations of β- lactam antibiotics, carbamazepine , and valproic acid.

Rx :

Rx Removal of the offending drug. Most cases of neutropenia resolve over time. Symptomatic treatment (e.g., antimicrobials for infections) and appropriate vigilant hygiene practices are necessary. Sargramostim (GM-CSF 300 mcg/day sc) and filgrastim (G-CSF) can be used.

DRUG-INDUCED APLASTIC ANEMIA:

DRUG-INDUCED APLASTIC ANEMIA First described by Ehrlich in 1888. It is a rare, serious disease of unclear etiology. An incidence of two to seven cases per million inhabitants reported. This incidence is different in different regions. The young and elderly are at increased risk. It is characterized by pancytopenia . It is considered the most serious drug-induced blood dyscrasia.

Drugs Suspected of Inducing Aplastic Anemia:

Drugs Suspected of Inducing Aplastic Anemia Severe aplastic anemia is seen with a bone marrow of less than 25% of normal cellularity or a bone marrow of less than 50% of normal cellularity with less than 30% of the hematopoietic cells and at least two of the following peripheral blood values: 1) granulocytes fewer than 500/mm3 2) platelets fewer than 20,000/mm3 3) anemia with reticulocytes fewer than 1%. About 65% of people with aplastic anemia die within 4 months of diagnosis; few die after this 4-month period

TABLE. Drugs Associated with Aplastic Anemias:

TABLE. Drugs Associated with Aplastic Anemias

Diagnosis :

Diagnosis Made by the presence of two of the following criteria: WBC count of 3,500 cells/mm3 or less, A platelet count of 55,000 cells/mm3 or less, or A hemoglobin value of 10 g/dL or less with a reticulocyte count of 30,000 cells/ mm3 or less. Can be classified as nonsevere, severe, or very severe. Severe -at least two of the following three peripheral blood findings: Neutrophil count of less than 500 cells/mm3, Platelet count of less than 20,000 cells/mm3, and Anemia with a corrected reticulocyte index of less than 1%.

Diagnosis cont….:

Diagnosis cont…. The onset is variable and insidious. Symptoms have been reported to appear from days to months after initiation of the offending drug, In some instances, symptoms appear after the drug has been discontinued. Neutropenia typically presents first, followed by thrombocytopenia and finally, anemia evolves slowly. The cause is damage to the pluripotential hematopoietic stem cells before differenciation to stem cells.

Mechanisms ::

Mechanisms : Direct, dose-dependent drug toxicity - Most often caused by chemotherapy(CAF, antineoplastics) or radiotherapy. Idiosyncratic and may operate through toxic metabolites of the parent drug- eg Chloramphenicol(CAF). A drug- or metabolite induced immune reaction specific to the stem-cell population- the most common. Eg. Methylprednisolone, cyclosporine

TREATMENT:

TREATMENT Remove the suspected offending agent. Then provide adequate supportive care; Appropriate antimicrobial therapy for the treatment of infection Transfusion support with erythrocytes and platelets. Do not include chemoprophylaxis, except in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Fever of unknown origin should be initially managed with broad-spectrum antibiotics.

If treatment is required;:

If treatment is required; The two major treatment options are Allogeneic HSCT – Rx of choice for young pts. Immunosuppressive therapy- Tends to be first-line therapy for older patients and those who are not candidates for HSCT . Combination therapy with antithymocyte globulin (ATG) and cyclosporine. Cyclosporine monotherapy Corticosteroids are sometimes added to ATG-based immunosuppression.

Drugs Suspected of Inducing Thrombocytopenia:

Drugs Suspected of Inducing Thrombocytopenia Drug-induced immune thrombocytopenia is characterized by acute purpura, confluent petechiae or ecchy-moses- particularly after mild trauma-and gastrointestinal, central nervous system, or urinary tract bleeding,all associated with a mild or severe lack of blood platelets. Drugs may induce marrow hypoplasia, destroy platelets directly, or be responsible for an immune reaction. Thrombocytopenia may be associated with several disease states (acute leukemia, Gaucher's disease, systemic lupus erythematosus, sarcoidosis); drug-induced thrombocytopenia usually remits 1 to 2 weeks after drug discontinuance. 

DRUG-INDUCED THROMBOCYTOPENIA:

DRUG-INDUCED THROMBOCYTOPENIA is usually defined as a platelet count below 100,000 cells/mm3 or >50% reduction from baseline values. The annual incidence of drug-induced thrombocytopenia is approximately 10 cases per 1,000,000 population.

TABLE. Drugs Associated with Thrombocytopenia:

TABLE. Drugs Associated with Thrombocytopenia

Mechanisms ::

Mechanisms : Direct toxicity reactions, Result in suppressed thrombopoiesis and produce a decrease in the number of megakaryocytes in the bone marrow. Mostly by cancer chemotherapy agents, often by organic solvents, pesticides, drugs that influence folic acid metabolism, and inamrinone. Hapten type immune reactions – eg. heparin induced reaction.

Mechanisms cont….:

Mechanisms cont…. Platelet-reactive auto antibodies Gold compounds and procainamide The causative drug does not have to be present for the reaction to occur. Drug dependent antibodies Requires the presence of the drug to allow antibody binding.

DRUG-INDUCED HEMOLYTIC ANEMIA:

DRUG-INDUCED HEMOLYTIC ANEMIA Causes: defective RBCs or abnormal changes in the intravascular environment. Mechanisms: immune or metabolic. The onset of drug-induced hemolytic anemia is variable and depends on the drug and mechanism of the hemolysis.

Table: Drugs Associated with Hemolytic Anemia:

Table: Drugs Associated with Hemolytic Anemia

DRUG-INDUCEDIMMUNE HEMOLYTIC ANEMIA:

DRUG-INDUCEDIMMUNE HEMOLYTIC ANEMIA Best diagnosed by Coombs test : Direct (or direct antiglobulin test [DAT])- involves combining the patient’s RBCs with the antiglobulin serum. Indirect - combining the patient’s serum with normal RBCs, then subjecting them to the direct Coombs test. Mechanisms: hapten mediated, innocent bystanders, autoimmune. Eg. Streptomycin, sulfonamides, semi synthetic penicillines. Rx: withdrawal, supportive, steroids, rituximab, immunoglobulin.

DRUG-INDUCED OXIDATIVE HEMOLYTIC ANEMIA:

DRUG-INDUCED OXIDATIVE HEMOLYTIC ANEMIA Most often accompanies a glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency. NADPH in RBCs keeps glutathione in a reduced state. Reduced glutathione is a substrate for glutathione peroxidase An enzyme that removes peroxide from RBCs, thus protecting them from oxidative stress. Without reduced glutathione, oxidative drugs can oxidize the sulfhydryl groups of hemoglobin, removing them prematurely from the circulation (i.e., causing hemolysis ). Rx: removal and avoidance of offending agents.

DRUG-INDUCED MEGALOBLASTIC ANEMIA:

DRUG-INDUCED MEGALOBLASTIC ANEMIA In this case the development of RBC precursors called megaloblasts in the bone marrow is abnormal. May be 2 0 to the direct or indirect effects of the drug on DNA synthesis. Antimetabolite class of chemotherapeutic agents is most frequently associated with it. Other drugs are cotrimoxazole, phenytoin, or the barbiturates.

Rx::

Rx: The anemia becomes an accepted side effect of therapy if it is 2 0 to chemotherapy Folinic acid 5 to 10mg qid if it is 2 0 to SMX-TMP. Folic acid supplementation of 1 mg every day if it is 2 0 to antiepileptic agents (phenytoin, phenobarb).

Table: Drugs Associated with Oxidative Hemolytic Anemia:

Table: Drugs Associated with Oxidative Hemolytic Anemia

Drugs Associated with Megaloblastic Anemia:

Drugs Associated with Megaloblastic Anemia

Heparin –induced thrombocytopenia:

Heparin –induced thrombocytopenia At least two types: HIT Type I- most common, occurs in approximately 10% to 20% of patients treated with heparin. It is a mild, reversible, nonimmunemediated reaction that usually occurs within the first 2 days of therapy. Is usually an asymptomatic condition and is thought to be related to platelet aggregation.

HIT cont….:

HIT cont…. HIT type II- is less common but more severe and can be associated with more complications. Approximately 1 to 5% of patients receiving unfractionated heparin and up to 0.8% of patients receiving lowmolecular - weight heparin (LMWH) can develop HIT. The platelet count generally begins to decline 5 to 10 days after the start of heparin therapy. patients who have had recent, major surgery are one of the highest risk groups

Causes of HIT:

Causes of HIT HIT is caused by the development of antibodies against platelet factor-4 (PF-4) and heparin complexes. LMWHs bind less well to PF-4 than unfractionated heparin, and therefore antibody formation is less common. Thrombosis is one of the major complications of HIT…..anticoagulants needed. Less common complications are heparin-induced skin necrosis and venous gangrene of the limbs. RX: Remove heparin, symptomatic rx, steroids???

FIGURE 112-5. Proposed explanation for the presence of both thrombocytopenia and thrombosis in heparin-sensitive patients who are treated with heparin. Injected heparin reacts with platelet factor-4 (PF-4), which is normally present on the surface of endothelial cells (ECs) or released in small quantities from circulating platelets, to form PF-4–heparin complexes (1). Specific immunoglobulin G (IgG) antibodies react with these conjugates to form immune complexes (2) that bind to crystallizable fragment (Fc) receptors on circulating platelets. Fc-mediated platelet activation (3) releases PF-4 from α-granules in platelets (4). Newly released PF-4 binds to additional heparin, and the antibody forms more immune complexes, establishing a cycle of platelet activation. PF-4 released in excess of the amount that can be neutralized by available heparin binds to heparin-like molecules (glycosaminoglycans) on the surface of ECs to provide targets for antibody binding. This process leads to immune-mediated EC injury (5) and heightens the risk of thrombosis and disseminated intravascular coagulation. (Aster RH. Heparin-induced thrombocytopenia and thrombosis. N Engl J Med 1995;332:1374–1376. Copyright © 1995 Massachusetts Medical Society. All rights reserved.) :

FIGURE 112-5. Proposed explanation for the presence of both thrombocytopenia and thrombosis in heparin-sensitive patients who are treated with heparin. Injected heparin reacts with platelet factor-4 (PF-4), which is normally present on the surface of endothelial cells (ECs) or released in small quantities from circulating platelets, to form PF-4–heparin complexes (1) . Specific immunoglobulin G (IgG) antibodies react with these conjugates to form immune complexes (2) that bind to crystallizable fragment (Fc) receptors on circulating platelets. Fc-mediated platelet activation (3) releases PF-4 from α -granules in platelets (4). Newly released PF-4 binds to additional heparin, and the antibody forms more immune complexes, establishing a cycle of platelet activation. PF-4 released in excess of the amount that can be neutralized by available heparin binds to heparin-like molecules (glycosaminoglycans) on the surface of ECs to provide targets for antibody binding. This process leads to immune-mediated EC injury (5) and heightens the risk of thrombosis and disseminated intravascular coagulation. (Aster RH. Heparin-induced thrombocytopenia and thrombosis. N Engl J Med 1995;332:1374–1376. Copyright © 1995 Massachusetts Medical Society. All rights reserved.)

Thank You!:

Thank You!

authorStream Live Help