Drug induced hematology

Lecturer Nin PrapongsenaHuachiew Chalermprakiet University

Objective

• สามารถจ าแนกความผดปกตของเมดเลอด หรอเกลดเลอดไดอยางถกตอง

• ทราบถงยาทเหนยวน าใหเกดความผดปกตของเมดเลอด หรอเกลดเลอด

• ทราบถงกลไกของยาทเหนยวน าใหเกดความผดปกตของเมดเลอด หรอเกลดเลอด

• สามารถประเมนความผดปกตทเกดโดยใช Naranjo’s algorithmไดอยางถกตอง

• สามารถวางแผนการจดการปญหาทเกดขนไดอยางเหมาะสมกบผ ปวยเฉพาะราย

Drugs induced hematology

Plateletdisorders

Blooddisorders

Anemia

Neutropenia

Thrombocytopenia

Thrombosis

Drugs induced platelet disorders

Thrombocytopenia Thrombosis

Thrombocytopenia

Severity Platelet count

Grade 1 75,001 – 150,000/ uL

Grade 2 50,001 – 75,000/ uL

Grade 3 25,001 – 50,000/ uL

Grade 4 < 25,000/ uL

Symptoms:-เลอดก ำเดำไหล - เลอดออกตำมไรฟน - มจ ำเลอดใตชนผวหนง - เกดภำวะเลอดออกทสมอง (stroke) ซงจะพบวำผปวยเกดอำกำรชก

Mechanisms

1. Drug as haptenie. penicillins, cephalosporins

2. Compound epitope formationie. quinine, quinidine,sulfonamides, NSAIDs

3. Drugs induced Autoantibodiesie. Gold, procainamide

4. Heparin-induce thrombocytopenia(HIT) or Heparin-associate Thrombocytopenia(HAT)heparin

5. Fibrinogen inhibitorsabciximab, tirofiban,eptifibatide

6. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS)

1. Drug as hapten

2. Compound epitope formation

PlateletsOr

Glycoprotein (hydrophobic domain)

Binding

Platelet change

conformation

Antigens

3. Drugs induced autoantibodies

IgG(specific to glycoprotein V)

synthesis

Induce

Destroyedplatelets

4. Heparin-induce thrombocytopenia

HAT HIT

5. Fibrinogen inhibitors

Antigen

6. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome

(TTP-HUS)Change pathophysiology (unknown mechanism)

Cause thrombocytopenia

ex. mitomycin C, cyclosporine, tacrolimus, sirolimus, quinine, ticlodipine, clopidogrel, simvastatin

ConditionProthrombin

time

Partial

thromboplastin

time

Bleeding timePlatelet

count

Vitamin K deficiency

or

warfarin

ProlongedNormal or

mildly prolonged-

-

Disseminated

intravascular

coagulation

Prolonged Prolonged Prolonged Decreased

Von Willebrand

disease- Prolonged Prolonged

-

Hemophilia - Prolonged - -

Aspirin - - Prolonged -

Laboratory findings in various platelet

and coagulation disorders

Thrombocytopenia - - Prolonged Decreased

Factor V deficiency Prolonged Prolonged - -

Factor X deficiency Prolonged Prolonged - -

Factor XII deficiency - Prolonged - -

Management

Thrombosis

Deep Vein Thromboembolism

(DVT)

Pulmonary Embolism(PE)

Stroke

Drugs induced thrombosis

- Hemostatic agents - Anticoagulants

- Hematopoietic agents - Estrogen-containing agents

- Antiandrogenic agents - Selective estrogen receptor modulators

- Aromatase inhibitors - Androgenic agents

- Follicle-stimulating hormone - Antineoplastic agents

- Immunologic agents - Antipsychotic agents

- COX2-inhibitor

- Miscellaneous (ex. procainamide, botox, ergotamine, sidenafil)

Mechanism of action

Hypercoagulability(Direct/Indirect)

Blood coagualationimpairment

Anticoagulant inhibition

Tissue factor pathway inhibitors

Antithrombin III

Protein C and protein S pathway

Inhibit fibrinolysis

Anticoagulant inhibition

Anticoagulant inhibition (continue)

Mechanism of action

Blood coagualationimpairment

Inhibit fibrinolysis

Activated plasminogenactivator inhibitor (PAI)

antiplasmin:plasmin complex activation

Inhibit plasminogen synthesis

1

2

3

4

Symptoms of thrombosis

Wells score for DVT/PE evaluation

Wells score for DVT/PE evaluation (continue)

DVT managementAmerican College of Chest Physicians (ACCP)’s Guidelines for Diagnosis & Management of DVT / PE, 9th Ed.

PE managementAmerican College of Chest Physicians (ACCP)’s Guidelines for Diagnosis & Management of DVT / PE, 9th Ed.

Drugs induced blood disorders

Anemia Neutropenia

Aplastic anemia

Hemolytic anemia

Macrocytic anemia

Anemia evalulation

Mild to Moderate:

- Hb < 12.3 (F) or 14 (M) g/dL

- Fatigue

- Shortness of breath

- Dizziness

- Pallor

Severe:

- Respiratory rate (> 20/min)

- O2 saturation (< 95%)

- Hb (< 7 g/dL)

- Hct (< 21%)

- Tachycardia

- Hypoxia or cyanosis (yes)

Anemia evalulation

Blood Transfusion

Aplastic anemia

Directtoxic

Hematopoietic stem cell

Immune mediated

Antigen

Non-immune mediated(ex. chemotherapy)

Drug Incidence

*Acetazolamide 1:18,000 each year

Captopril Not known

*Carbamazepine 4:100,000

*Felbamate 127:1,000,000

Furosemide Not known

*Gold salt Death1.5:10,000

pescriptions

Imatinib Not known

Nonsteroidal anti-inflammatory

drugs

Diclofenac

Ibuprofen

Indomethacin

Salicylates

Sulindac

Not known

Phenytoin Not known

Sulfonamides

Sulfisoxazole

Sulfasalazine

Mesalamine

Not known

Temozolomide Not known

Ticlodipine Not known

Aplastic anemia

Disorders of pluripotent stem cell

Neutropenia(Low WBC)

Thrombocytopenia(Low platelets)

Pancytopenia(Low RBC)

Cytotoxic drugs,radiations,antimicrobials, pesticides, viral infection

Genetic disorder(Fanconi anemia)

Aplastic anemia: symptoms

NCCN guideline

NCCN guideline

Hemolytic anemia

Hemolytic anemia (life span < 120 d)• Generate autoantibody

Autoantibodyspecific to RBC

Generate

RBC Destruction

Methyldopa,levodopa, procainamide

• Neoantigen

Antigen

Activated complement

RBC destructed by spleen

• Induce RBC destructive

quinine, quinidine

penicillins, cephalosporins, tetracyclines

Drug Incidence

*Carbamazepine 4:100,000 pescriptions

Cephalosporins

Cefazolin

Cefotaxime

Cefotetan

Cefoxitin

Ceftizoxime

Ceftriazone

Cefuroxime

Cephalothin

Ceftazidime

Not known

Fluroquinolones

Ciprofloxacin

Levofloxacin

Not known

H2-antagonist

Cimetidine

Famotidine

Ranitidine

Nizatidine

Not known

Isoniazid Not known

Methyldopa/Levodopa Not known

Nonsteroidal anti-inflammatory drugs

Diclofenac

Ibuprofen

Indomethacin

Salicylates

Sulindac

Not known

Piperacillin/tazobactam Not known

Probenecid Not known

Quinidine/Quinine Not known

Hemolytic anemia

S & O in hemolytic anemia

• Found after receive drugs 2 wk -3 mth

• Severe stomachache

• Jaundice: (increased bilirubin)

• Splenomegaly

• Hepatomegaly: (Increased free iron)

- ferritin (คาปกต 15-200 ng/mL)

- transferring saturation (TSAT; คาปกต ≥ 20%)

Hemolytic anemia management

• Hgb < 7g/dL:

recommend blood transfusion

• Iron overload (ferritin ≥ 1,000 ng/mL): recommend deferoxamine, deferiprone หรอ deferasirox

• Immune mediated hemolytic anemia:recommend corticosteroids or IVIg

Macrocytic anemia(MCV > 100 fL)

Folic acid and

Vit B12 Depletion

Macrocytic anemia (How induced ???)

• Inhibited folate synthesis

TrimetoprimMTX

• Interfered folate absorptionor increased folate excretion

Phenytoin

• Interfered heme synthesis

Zidovudine

Macrocytic anemia

Drug Incidence

Azathioprine Not known

Leflunomide Not known

Metformin Not known

Phenytoin Not known

Sulfonamides

Sulfisoxazole

Sulfasalazine

Mesalamine

Not known

Trimetroprim-

sulfamethoxazole

Not known

Zidovudine Not known

• Recommend prevent macrocytic anemia (folate/ Vit B12 deficiency)

Add Folic acid oral 5 mg/d

or Vit B12 oral 1-2 mg/d

• Recommend stop drug that inhibited heme synthesis + supportive care

Macrocytic anemia (Management)

Drugs induced blood disorders

Anemia Neutropenia

Aplastic anemia

Hemolytic anemia

Macrocytic anemia

Neutropenia

• Classified neutropenia by National Cancer Institute (NCI) risk category:

Mild: ANC (1000-1500/µL)

Moderate: ANC (500-1000/µL)

Severe: ANC (<500/µL)

How drugs induced Neutropenia???

• Immune mediated

Generated autoantibodyspecific to

- granulocytic precursor- neutrophils

Ex. chlorpropramide, methimazole,propylthiouracil

• Direct toxic- Damaged to myeloid precursors:(cimetidine, quinidine)

- Intefered development process:(ticlodipine)

- Damaged to neutrophils:(sulfonamides)

• Multiple mechanisms

Flecainide, clozapine

- Alkylating agents - Antimetabolites,- Anthracyclines - Topoisomerase inhibitors- Taxanes - Vinca alkaloids

- Antithyroids - Antirheumatic- Antiarrythmic - Antipsychotic- Tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib) - Nonsteroidal anti-inflammatory drugs (NSAIDs)

Drugs induced Neutropenia

Risk factors of neutropenia

-อายมากกวา 50 ป-โรคประจ าตวทเกยวกบ autoimmune disease

-การไดรบการรกษาดวยการฉายรงส (radiation)

-เพศหญงมความเสยงมากกวาเพศชาย 2 เทา-ความผดปกตทางพนธกรรม-การตดเชอจลชพหรอไวรสบางชนด-ไดรบยาตานมะเรงหลายชนด-ใชยาหลายตว-ขาดสารอาหาร-ไตหรออวยวะอนๆ มการท างานผดปกต

Clinical presentation-ไข (fever)-หนาวสน (chills)-งวงซม (lethargy)-ปวดกลามเนอ (myaglia)-ออนเพลย (weakness)-หลอดลมอกเสบ (bronchitis)-เหงอกอกเสบ (gingivitis)-คออกเสบ (pharyngitis)-ตดเชอในกระแสเลอด (sepsis)-ไซนสอกเสบ (sinusitis)-เยอบทางเดนอาหารอกเสบ (stomatitis)-Etc.

Drugs induced neutropenia management

Reduced dose or stopped drug use

+

Antibiotic

±

CSF/ GCSF/ GMCSF

Evalulated prophylactic by CSFs

Addition to initial empiric regimen

Addition to initial empiric regimen

Addition to initial empiric regimen

Addition to initial empiric regimen

Reference

1. Patton WN., and Dufful SB., Idiosyncratic drug-induced hematological abnormalities:

incidence, pathogenesis, management, and avoidance. Drug Saf. 1994; 11: 445-462.

2. Thalassemia International Federation. Guidelines for The Clinical Management of

Thalassemia. 2nd ed. Cyprus; Thalassemia International Federation, 2008 : 14-63. 3. รศ. นพ. กตต ตอจรส. Thalassemia: iron overload, clinical consequences and iron chelators. 1-14.

4. Rizzo JD., Somerfield MR., Hagerty KL., et al. Use of epoietin and darbepoietin in

patients with cancer: 2007 American society of hematology American society of clinical

oncology clinical practice guideline update. Blood. 2008; 111: 25-41.

5. National Comprehensive Cancer Network®. NCCN guidelines® Cancer – and

Chemotherapy-Induced Anemia. Version 2. National Comprehensive Cancer Network, Inc.,

2012.

6. Crawford J. Neutropenia in cancer patients: risk factor and management. Cancer World.

2012

7. National Comprehensive Cancer Network®. NCCN guidelines® myeloid growth factor.

Version 1. National Comprehensive Cancer Network, Inc., 2012.

8. National Comprehensive Cancer Network®. NCCN guidelines® Prevention and Treatment

of Cancer-Related Infections. Version 2. National Comprehensive Cancer Network, Inc.,

2012.