Drug-Induced Hematologic Disorders

• Drug-induced hematologic disorders are adverse effects on the blood and its components caused by medications.

Hematologic Disorders

• Granulocytopenia (agranulocytosis) was reported in association with sulfonamide in 1938
• Common drug-induced hematologic disorders include: Aplastic anemia, Agranulocytosis, Hemolytic anemia, Megaloblastic anemia, and Thrombocytopenia
• Estimated incidences from a multinational study: 0.38 cases per 1 million/year for agranulocytosis and 1.6 cases per 1 million/year for aplastic anemia
• These disorders are less common, but significant because they are associated with morbidity and mortality
• Tools like the Naranjo or WHO algorithm can assess causative agents in Adverse Drug Reactions (ADR)
• It can be difficult to establish a definite causative relationship without rechallenge.

Drug-Induced Aplastic Anemia

• First described by Ehrlich in 1888 after observing failed hematopoiesis in a pregnant woman
• Characterized by pancytopenia, hypocellular bone marrow, and no evidence of peripheral blood cell destruction
• Two broad categories include inherited (mostly present in the first decade of life) and acquired (25-40% can identify causative)
• Diagnosis (must have 2 of the following): WBC count ≤ 3,500 cell/mm³, Platelet count ≤ 55,000 cell/mm³, Hemoglobin ≤ 10 g/dL with reticulocyte count ≤ 30,000 cell/mm³

Classification in severity

• Very severe is defined as a Neutrophil count less than 200 cell/mm3
• Severe criteria includes: BM: cellularity <25% or 25-50% (w< 30% hematopietic cell), 2/3 of following: Neutrophil count < 500 cell/mm3, Platelet ≤ 20,000 cell/mm3, Reticulocyte count ≤ 20,000 cell/mm3 (corrected index <1%)
• Not severe: Not fulfilling criteria Mechanisms
• Damage is directly inflicted to pluripotent stem cells
• Carries a high mortality rate compared to other blood dyscrasias
• Manifests symptoms from days to months, with an average of 6.5 weeks
• Mechanisms proposed; Direct toxicity, Drug-induced immune reaction, and Idiosyncratic

Direct Toxicity

• Direct suppression of proliferation cell line
• The drug toxicity is dose dependent
• Indicates reversible marrow suppression
• Often caused by chemotherapy and radiotherapy
• Direct toxicity comes from suppression of the cell proliferation line, typically resulting in dose-dependent reversible marrow suppression

Drug-Induced Immune Reaction

• Most current evidence supports this hypothesis
• Early studies showed removal of T-lymphocytes improves blood disorders
• Overproduction of cytokines relates to bone marrow failure
• Improvement in hematologic data is seen after conditioning regimen treatment (ATG + Cyclophosphamide)

Idiosyncratic

• Dose independence
• Latent period prior onset
• Injury continues following drug discontinuation
• May operate through drug toxic metabolites

Chloramphenicol

• Results in dose-dependent and reversible bone marrow suppression
• Prototype of idiosyncratic reactions
• Believed to result from abnormal metabolism
• The nitrobenzene ring's reduction to a nitroso group leads to DNA damage
• Bacteria from the GI tract may metabolize the drug into a marrow toxic form

Treatment for Drug-Induced Aplastic Anemia

• Goals include improving peripheral blood counts, limiting the need for blood transfusions, and minimizing the risk for opportunistic infections
• Treatment approach is based on severity of cytopenia
• 1st step: Remove the suspected offending agents
• 2nd step: Adequate supportive care, blood transfusion as needed, Routine use erythropoietin ineffective, Prophylaxis antibiotic and antifungal in severe aplastic anemia, Granulocyte colony stimulating factor (G-CSF) may be considered in patients not responsive with ATB
• 3rd step (blood transfusion dependent or severe AA): Immunosuppressive therapy, Allogeneic bone marrow transplantation

Treatment: Severe Aplastic Anemia

• Treatment depends on the patient age
• If under 40 years and has a HLA identical sibling they need HLA id sib BMT
• If under 40 but does NOT have a HLA identical sibling they need ATG + CSA
• If yes the Maintain on CSA while FBC rising, then very slow taper, often over one/more years
• If no consider MUDBMT if < 50 years (or 50–60* and good performance status)
• If over 40 years old, they need ATG+CSA and possibly +G-CSF only as part of clinical study
• Yes the Response at 4 months (years) require Maintain on CSA while FBC rising, then very slow taper, often over one/more years
• If no the Response at 4 months (years) require 2nd ATG + CSA if no MUD

Drug-Induced Agranulocytosis

• Defined as a reduction in the number of mature myeloid cells in the blood
• Total count ≤ 500 cell/mm³
• Incidence is more common in females and the elderly
• Annual incidence is between 1.1-12 cases per million
• Overall mortality rate is between 3.5-16%
• Onset: 19-60 days and Recovery: 4-24 days

Cause of Drug-Induced Agranulocytosis

• Direct toxic effect, which results in Direct toxicity for pluripoten or bipotent stem cells as well as Clozapine and ticlopidine
• Antibody-mediated effect

Antibody-Mediated Effects

• Drug adsorption mechanism such as penicillin (large dose)
• Innocent bystander mechanism such as quinidine -Protein carrier mechanism

Drug-Induced Agranulocytosis From Antithyroid Medications::

• Early publications reported an incidence of 0.3-0.6%
• Recent incidence is reported as 7-23% and mechanism is unknown
• PTU has a more incidence 0.4% (No dose related) while PTU has less incidence 0.1% (dose related)
• Could be linked to an antineutrophil cytoplasmic antibody

Drug-Induced Agranulocytosis: Ticlopidine and Clozapine::

• Ticlopidine has an incidence of 2.4% for neutropenia, and 0.8% agranulocytosis, with Onset in 1-3 months, Recovery: 2-4 weeks
• Clozapine Incidence is 1.3% with Onset in 3 months which in vitro study cause from nitrenium ion unstable metabolite resulting oxidative stress

Drug-Induced Agranulocytosis: Treatment

• Remove the offending drug
• Symptomatic treatment and appropriate hygiene practices
• Sargamostim (GM-CSF) filgrastim (G-CSF) can be used, but Randomized trial did not confirmed the mortality benefit
• One systematic review ANC < 100 cell/mm³ higher rate of infection and mortality
• Some clinicians recommend use in patient with ANC < 100 cell/mm³

Drug-Induced Hemolytic Anemia

• Synthesis from erythroid stem cell in bone marrow
• Survive 120 days
• Occurs when the red blood cells are Removed by phagocytic cells of spleen and liver
• Drug-induced hemolytic anemia can divided into drug-induced immune hemolytic anemia and drug-induced oxidative hemolytic anemia

Immune Hemolytic Anemia (IHA)

• IgG and/or IgM binding to antigens on the surface of RBC initiates the destruction process
• Intravascular hemolysis : complement system
• Extravascular hemolysis : monoclonal phagocytic system
• Drug-induced antibodies may recognize the host's intrinsic RBC antigens or RBCs bound to drug
• Process of identifying foreign Ig either in the patient's serum or on the RBCS by adding the antidlobulin serum (by injecting rabbit with human complement, Ig) to patient's RBC and if RBC are coated by antibody or complement Antiglobulin serum will bind and create the lattice formation called “agglutination”
• Antibodies that have attached to normal RBCs will be identified The mechanism is classified into 4 categories, Drug adsorption mechanism, Innocent bystander mechanism, Drug-induced autoimmune hemolytic anemia, and Nonimmune protein adsorption (NIPA)
• Is the most common drug-induced hematological disease as well as the most common cause of acquired immune hemolytic anemia

Drug Adsorption Mechanism: Immune Hemolytic Anemia

• Antibodies attach to the drug without directly interacting with the erythrocyte
• Hemolysis is primarily extravascular, mediated by IgG
• Complement activation is rare, except with streptomycin
• Onset: 7-10 days
• Recovery: 2 weeks
• Direct Coombs test will be positive several weeks after exposure
• Examples: Penicillin (high dose), minocycline, tolbutamide

Innocent Bystander Mechanism: Immune Hemolytic Anemia

• Drugs bind weakly to the normal RBC membrane
• Primary mechanism of hemolysis is intravascular, triggered by the complement system
• Direct Coombs test results are positive for complement
• The clearance leads the direct Coombs test to be become negative
• The low affinity means a small amount of drug can cause the reaction
• Examples: Quinidine, sulfonamides and phenacetin are prototypes

Drug-Induced Autoimmune Hemolytic Anemia: Immune Hemolytic Anemia

• Drugs can interact with RBCs and cause antibodies production specific to RBCs
• Antibodies can still be identified even with drawl of the offending drug
• Onset after 6-12 months of use
• Duration is 4-6 months, or lasting longer than 2 years
• Direct Coombs test may be positive for several months post drug wothdrawl
• Example: Methyldopa

Non-Immune Protein Adsorption (NIPA):: Immune Hemolytic Anemia

• Drugs alter the RBC membrane leading the resulting plasma protein (IgG) absorbed to the RBC membrane
• The IgG coated RBCs interact with macrophages with leads to The IgG coated RBCs interact with macrophages with leads to extravascular hemolysis

Oxidative Hemolytic Anemia

• Most often arises in individuals with glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency
• G6PD gene is located on the X chromosome, inherited through a sex-linked recessive mode, meaning both homozygotes and heterozygotes can be symptomatic
• Deficiency is most common in African blacks, Mediterranean area and Asia
• Drugs that place oxidative stress on RBC can cause hemolytic anemia

Drug-Induced Hemolytic Anemia; Treatment

• Drug-induced Immune Hemolytic Anemia
• Adsorption and the autoimmune mechanism tend to have a milder onset and severity
• The Drug-induced treatment plan would Removing the offending drug for with Corticosteroid to be used If needed to treat severe cases.
• The Drug-induced with Immune hemolysis treatment plan would Removing the offending drug for with Corticosteroid to be used If needed to treat severe cases In addition patients can also use Anti-CD20 monoclonal antibody antibody therapy . -Innocent Bystander induced issues can have more serve symptoms with shorted the treatment plan is would Removing the offending drug

Drug-Induced Megaloblastic Anemia::

• When the development of RBC precursors called megaloblast in the bone marrow are abnormal. can be treated with vitamin B12 or folate
• Impaired proliferation and maturation of RBC resulting Anemia
• Peripheral blood test will show Peripheral blood show with Anemia (Hb, Hct), Megaloblastic blood picture, Increase in Mean Corpuscular Hemopglobin Concentration (MCHC), Increase in Mean Corpuscular volume (MCV)
• Antifolate chemotherapy is the most frequently causative drug of Megaloblastic Anemia with Methotrexate is an irreversible inhibitor dihydrofolate
• Active Folate syntesis with Cotrimoxazole, Sulfamethoxazole, and Trimetoprim
• (phenytoin, phenobarbital) can also treat Barbitulate Inhibit folate absorption or by increasing folate catabolism

Para-Aminobenzoic Acid + Pteridine

• Dihydropteroate Synthetase requires Sulfamethoxazole and Dapsone
• Dihydrofolate Synthetase reqires Dihydrofolic Acid
• Dihydrofolate Reductase reqires Trimethoprim Which turns to Tetrahydrofolic Acid, Other precursors, Thymidine and Purines and finally creates DNA

Drug-Induced Megaloblastic Anemia: Treatment

• Mostly cause mild anemia and usually does NOT therapeutic needed
• Antifolate chemotherapy (No therapeutic needed) with High dose methotrexate which Folinic acid used to help prevent anemia with 5-10 mg by times with Cotrimoxazole
• Folate 1mg a day can correct Barbiturates issues but Some clinician concern about folic acid can decrease effectiveness of antiepileptic drug

Drug-Induced Thrombocytopenia

• Thrombocytopenia is defined as a platelet count below 100,000 cells/mm³ or a reduction of 50% or more from baseline
• Excluding heparin patients, The Incidence is 10 cases per 1,000,000 population
• Immune mediated mechanism which includes that Direct toxicity result to a decrease from direct toxicity megakaryocytes & Nonimmune mediated mechanism which includes direct toxicity Increase peripheral destruction and Increase number of megakaryocyte

Immune Mediated Thrombocytopenia

• Mechanism classified into 4 categories: Drug adsorption mechanism, Drug-dependent antibody mechanism, Drug induced autoimmune thrombocytopenia, and Immune complex induced thrombocytopenia

Drug Adsorption Mechanism: Drug-Induced Thrombocytopenia

• Onset: at least 7 days, Recovery when over after 1 week
• Eg: Penicillin, Cephalosporin, Abciximab.

Drug-Dependent Antibody Mechanism: Drug-Induced Thrombocytopenia

• Antibody Pre-exsist in patient
• Drug use helps to better it with the ab platelet complex
• Quinine, Anticonvulsants, NSAIDs, Vancomycin

Drug Induced Autoimmune Thrombocytopenia: Drug-Induced Thrombocytopenia

• Drug causes platelet platelet characteristic which drug is not present when the complex created
• Cause antibody to patient's blood
• Eg, GP IIb/IIIa or antagonist and and Gold

Immune Complex Induced Thrombocytopenia: Drug-Induced Thrombocytopenia

• Most serious type of Heparin-induced thrombocytopenia (HIT type II)
  • HIT type I : Most common, less severe, MOA unknown
  • Most serious type of Heparin-induced thrombocytopenia (HIT type II) Heparin induced thrombocytopenia classified as one of 2 types. -HIT type I: Most common, less severe, MOA unknown
    • HIT type II : Less common, more severe, MOA immune reaction

HIT type II mechanism::

  - Heparin bind to Platelet factor 4 (PF-4) present in endotherial cell (EC)
        - Heparin bind to Platelet factor 4 (PF-4) present in endotherial cell (EC)
  - Specific IgG occur and form complex in the plate
        - Heparin bind to Platelet factor 4 (PF-4) present in endotherial cell (EC)
        - Specific IgG occur and form complex in the plates
  -The formed binded complex bind to platelet, activation follows due to complex binding to to platelet which is caused by Fc receptor
        - Heparin bind to Platelet factor 4 (PF-4) present in endotherial cell (EC)
       - Specific IgG occur and form complex in the plates

HIT Types 1 and 2

• Frequency 10-20% from type 1 and 2-30% from type 2
• Timing of the onset 1-4days by type one, or 5-10 with type 2 - Nadic Plate: greater the 100,000 mcl -Nad Plate type 2 is more common 1000 miclo type1 no ab, where type two has a positive AB Throm type one = none throm type 2= 38 %
• Hemo with type 1 has none
• Hemo with type 2 is rare
• When the patient is dealing with a type 1 issue observe
• When the patient is dealing with a type 2, Cession with heparin, alternative antico, additional therapy

Drug-Induced Thrombocytopenia: Treatment

• Remove offending the drug
• Symptomatic treatment
• HIT need to switch to another antithrombotic with Lepirudin, Argatroban, Bivalirudin and Fondaparinux
• The Lepirudin is an analogue of hirudin which runs the risk of antibody development but helps clear the drug
• (Argatroban) Met Liver
• LACKk OF STUDY FOR Argatroban
• Bivalirudin is an analogue of hirudin and requires dose adjustment in severe renal dysfunction Fondaparinux: Inhibit factor Xa which Vitro study not cause reactivity with HIT

Drug-induced hematologic disorders involve adverse effects of medications on blood components. Common disorders include aplastic anemia, agranulocytosis, and thrombocytopenia. Tools like the Naranjo algorithm help assess causative agents in adverse drug reactions, though establishing a definite causative relationship can be challenging.