3. Hematologic disorders have long been a potential risk of modern
pharmacotherapy.
Granulocytopenia (agranulocytosis) was reported in association with one of
medicine’s early therapeutic agents, sulfanilamide, in 1938.
Some agents cause predictable hematologic disease (e.g., anemia), but others
induce idiosyncratic reactions not directly related to the drugs’ pharmacology.
The most common drug-induced hematologic disorders include aplastic anemia,
agranulocytosis, megaloblastic anemia, haemolytic anemia, and
thrombocytopenia.
4. The incidence of idiosyncratic drug-induced hematologic disorders varies
depending on the condition and the associated drug.
Drug induced haematological disorder are more common in elderly than in the
young; the risk of death also appears to be a greater with increasing age.
Blood induced injuries of the blood are termed blood dyscrasias.
5. Drug induced Thrombocytopenia :
Thrombocytopenia is usually defined as a platelet count below 100,000
cells/mm3 or >50% reduction from baseline values.
6. Thrombocytopenia can be caused by numerous conditions such as blood loss, infection, intravascular
coagulation, and the use of some medications.
The annual incidence of drug-induced thrombocytopenia is approximately 10 cases per 1,000,000 population
Several mechanisms have been proposed for the development of drug-induced thrombocytopenia:
1. direct toxicity reactions,
2. platelet-reactive autoantibodies and
3. drug dependent antibodies.
Direct toxicity reactions, as often associated with chemotherapeutic agents, result in suppressed
thrombopoiesis and produce a decrease in the number of megakaryocytes in the bone marrow.
In contrast, immune reactions result in an increased peripheral destruction of platelets and an increased
number of megakaryocytes (mega+karyo+cytes= large nucleus cell)
7. Causative agents :
Drug-induced thrombocytopenia usually develops through an immunologic mechanism.
The agents most commonly implicated are-
1. quinine,
2. quinidine,
3. gold salts,
4. sulfonamide antibiotics,
5. glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonists,
6. heparin.
8. clinical presentations
Signs and symptoms usually occurs when platelet counts fall below 1,00,000.
You can observe :
Minor bleeding
Petechiae
Gingival bleeding
Purpura
Microscopic haematuria &
Epistaxis
9. Significant bleeding
Retroperitoneal
Gastro-intestinal bleeding may occurs when platelet counts falls under 50,000.
Bleeding from mucous membranes and severe purpura can appear later in the disorder.
The median onset of thrombocytopenia is approximately up to 14 days, with a range of 1 day to 3
years.
17. Heparin is associated with 2 types of
thrombocytopenia
TYPE 1 – HEPARIN INDUCED THROMBOCYTOPENIA (TYPE 1 HIT)
Generally it is a mild and platelet counts rarely fall below 1,00,000 .
Usually occurs within 48-72hrs of initiation of heparin therapy and platelet counts normalise
when few days after discontinuation of heparin therapy.
The risk of thrombosis is extremely low.
18. Type 2 HIT
Usually occurs after 5-7 days following first exposure to heparin and more rapidly occurs on
second exposure.
Platelet count decline to below 1,00,000 in patient with type 2 HIT.
A major clinical manifestation is the occurrence of thrombosis.
The major morbidity is bleeding.
19. Mortality risk is relatively low, however the risk of serious and potentially life
threatening bleeding is not negligible.
Death may occur in patient with Heparin induced thrombocytopenia, most
commonly as a result of a stroke or pulmonary embolism
20. Management
The primary treatment of drug-induced thrombocytopenia is removal of the
offending drug and symptomatic treatment of the patient.
The use of corticosteroid therapy in the treatment of drug induced
thrombocytopenia is controversial, although some practitioners recommend it in
severe symptomatic cases.
21. In the case of HIT, the main goal of management is to reduce the risk of
thrombosis or reduce thrombosis-associated complications in patients who have
already developed a clot.
All forms of heparin must be discontinued.
Start heparin flushes and alternative anti-coagulation must begin immediately.
The direct thrombin inhibitors are the alternative anticoagulants most
commonly used in current practice.
22. Lepirudin – 50mg the first drug that was approved for the treatment of HIT,
When Lepirudin prescribes in Renal Dysfunction patient, Dose adjustment is
necessary.
23. Argatroban –
50mg/50mL
Argatroban is another intravenous thrombin
inhibitor indicated for the management of HIT.
But unlike lepirudin, argatroban is metabolized
in the liver and can be used in patients with
end-stage renal disease. However, dosage
adjustment is needed for patients with
significant hepatic impairment.
26. Thromboembolic Disease :
Thromboembolic disease is a collective term for thrombotic and embolic disorders.
Thrombotic disorders are characterised by the formation of a clot produced from the blood that
attach to the vessel or heart wall causing an incomplete occlusion.
When complete occlusion occurs, the clot is then called embolism.
Venous thromboembolism (VTE) is a common thromboembolic disorder, which may present as a
deep vein thrombosis means a clot in the leg or groin, or a pulmonary embolism (PE) that clot
ledged in a vessel of lung.
28. Clinical presentation & diagnosis
The sign and symptoms of VTE vary depending on the length, time between development of DVT
or PE.
29. Symptoms associated with drug induced
VTE
DVT PE
Unilateral warmth Dyspnea
Redness Hemoptysis
Swelling Cough
Skin discoloration Pleuritic pain
Cynosis
Pain or tendorness
30. Morbidity & mortality
PE is associated with a 30% mortality rate.
Death has occurred within 1 hr to 30 days.
Although oral contraceptives are well known culprit of drug induced
VTE.
31. Management
To decrease preventable risk factors such as smoking & obesity.
Treatment goals are to prevent death from PE,
Relieve form associated symptoms of VTE
Prevent recurrence of VTE.
33. Aplastic anemia occurs when the bone marrow fails and production of red blood
cells, white blood cells and platelet ceases. (i.e. pancytopenia)
A drug induced aplastic anemia accounts for 7 – 86% of total cases of aplastic
anemia.
Some practitioners have reported a peak incidence in patients younger than 30
years of age, although others report the highest incidence in those older than
60years of age.
The causes of drug induced aplastic anemia is damage to pluripotential
hematopoetic stem cells, before their differentiation to committed stem cells. This
damage effectively reduces the normal level of circulating erythrocytes,
neutrophills and platelets.
36. Diagnosis
Complete blood counts (CBC)
Bone marrow biopsy.
A diagnosis of aplastic anemia can be made by the presence of following criteria :
A WBC count of 3500/mm3 or less
A platelet count of 55,000/mm3 or less,
A Hb value of 10g/dL or less with a reticulocyte count of 30,000/mm3 or less.
37. A severe aplastic anemia is defined by following peripheral findings :
Neutrophil count of less than 500/mm3
Platelet counts of less than 20,000/mm3
38. Risk factors
Drug induced aplastic anemia is rare, and risk factors are not well defined.
Exposure to pesticides and chemical.
Exposure to specific drug known to cause the disorder.
Occupational radiation exposure.
Viral exposure (i.e. hepatitis)
39. Morbidity & mortality
The major cause of mortality in patient with aplstic anemia are infection and bleeding.
One case series estimated the mortality rate for patients with drug induced aplastic anemia to
be 51%.
One study showed that 62% death were due to infections consisting mostly of bacteria and
fungal pathogenes.
40. Prevention
Drug induced aplastic anemia is rare and unpredictable, so prevention is challenging.
Careful haematological investigation monitoring should be routinely conducted.
Patient should be educated regarding the sign and symptoms of aplstic anemia.
41. Management
Hematopoietic stem cell transplantation
Blood transfusion if necessary
Immune suppressive agents
Antithymocytes globulin
Cyclosporin – 50mg or 100mg oral therapy, 4-12 hr pre-transplant : 15mg /kg PO for 1 dose
Azathaiprine – 100mg IV therapy, Maintenance dose is 1-3mg/kg/day
Cyclophosphamide – 1-2gm IV therapy, maintenance dose is 1-5mg/kg/day
43. Hemolytic anemia is a normocytic anemia that occurs when RBCs are prematurely destroyed
(Hemolysis), which can occurs either because of defective RBCs or abnormal changes in RBCs.
Estimates of the annual evidence of drug induced hemolytic anemia in general population range
from 1.1 – 1.6% cases per million people.
44. Signs & symptoms
Intravascular hemolysis : it is the state when RBCs rupture as a result of complex of complement
autoantibodies attached(fixed) on surfaces of RBCs attack and rupture RBCs membrane.
Extravascular hemolysis : It occurs when RBCs are phagocytized by macrophages in the spleen,
liver and bone marrow. It always present in animal with hemolytic anemia in animal.
Fatigue
Headcahe
Lethargy
Tachycardia
Weakness
46. Diagnosis & risk factors
The direct coombs test (Anti-human globulin test), used to determine the presence of antibodies on red cells.
Risk factors :
Infections, particularly in those patients with hereditary disorders.
Presence of rare inherited disorders like :
G6PD deficiency
Hereditary spherocytosis
Sickle cell anemia
Thalassemia
Exposure to traumatic and micro-angiographic conditions :
Valve replacement
47. Morbidity & mortality
It result in significant morbidity as a result of fatigue, shortness of breath, dizziness, arrythmia
and heart failure.
A case series suggests that the mortality rate is approximately 4%.
48. prevention
Since it is frequently related to G6PD deficiency, careful screening of patient for this deficiency
can be an important preventing step.
G6PD testing should be done whenever the use of drug known to cause haemolytic anemia is
being contemplated.
49. Management
The first step includes the removal of THE OFFENDING AGENT and start supportive care.
RBC transfusion for patients with low haemoglobin and haemodialysis for those whom acute
renal failure develops may be necessary in some clinical situations.
Use Immunoglobulins and steroids.
Sargramostim: 250mcg/kg/ day IV or SC over 4 hours
Filgrastim: 5 mcg/kg/day IV or SC
51. Megaloblastic anemia are characterised by increase in the average volume of RBC (increase in
MCV) and increase in the diameter and thickness of erythrocytes.
Megaloblastic anemias are produced by disorders of DNA synthesis, most commonly as a folic
acid and Vit. B12 deficiencies.
Methotraxate, an irreversible inhibitor of dihydrofolate reductase, cause megaloblastic anemia
in 3% - 19% of patients.
53. Mechanism
The normal proliferation of red cells require adequate folate and vit. B12
Folate is necessary for production of DNA.
Trimethoprim and methotrexate disrupt the folate pathways by inhibiting
dihydro folate reductase, while phenytoin may decrease absorption of folate or
facilitate its clearance.
Zidovudine appears to interfere with the synthesis of heme proteins, possibly by
inhibiting DNA polymerase.
54. Diagnosis
Patient with macrocytic anemia present an elevated MCV in the presence of low haemoglobin.
The diagnostic evaluation of patients with suspected drug induced macrocytic anemia must
include determination of folate and Vit. B12 concentratin.
56. Mortality & morbidity
Drug induced macrocytic anemia is usually does not result in significant
morbidity and mortality.
Prevention:
Primary prevention of drug induced macrocytic anemia involves avoidance of
agents known to cause the disorder.
Careful hematologic monitoring is recommended.
58. Conclusion :
A drug induced hematological disorders are rare but sometimes will lead to a life
threatening conditions.
Clinicians should recognise the medications with the potential of causing
hematologic disorders and educate patients to recognise the symptoms
associated with such events.
Frequent laboratory monitoring of patients taking medications associated with
severe hematologic events can facilitate diagnosis and treatment.
Identifying the Etiology of the event and documenting the causative agents may
severe to prevent a recurrence secondary to the use of a related medications.