18
Major medications with a definite association with agranulocytosis
Age >65 years ANC at the time of diagnosis <100/microL Severe infection (eg, septicemia, septic shock) Pre-existing comorbidities (eg, renal, cardiac, respiratory, systemic inflammatory diseases) • mortality rate has fallen over the past 20 years
The autoimmune mechanism
Legend:
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 Clin Haematol, Vol 9(Oct), Young GA, Vincent PC, Drug-induced agranulocytosis, pages 483–504, Copyright © Elsevier 1980.)
11
From: eChapter 24. Drug-Induced Hematologic Disorders
Pharmacotherapy: A Pathophysiologic Approach, 9e, 2014
The hapten mechanism
Legend:
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.)
12
Date of download: 8/19/2014 Copyright © 2014 McGraw-Hill Education. All rights reserved.
From: eChapter 24. Drug-Induced Hematologic Disorders
Pharmacotherapy: A Pathophysiologic Approach, 9e, 2014
• Mechanisms are varied
• The propensity to infection depends upon the adequacy of bone marrow reserve
3
Definitions
• Neutropenia中性粒细胞减少症 : ANC<1500/microL • Agranulocytosis中性粒细胞缺乏症: ANC <500/microL
Drug-induced neutropenia and agranulocytosis
Outline
• • • • • • • • • Introduction Epidemiology Definitions Pathogenesis Clinical presentation Drug induced neutropenia/agranulocytosis Prevention and screening Treatment Summary and recommendation
ANC = WBC (cells/microL) x percent (PMNs + bands) ÷ 100
ANC:absolute neutrophil count：绝对中性粒细胞计数 WBC:white blood cell count ：白细胞计数 PMNs:polymorphonuclear cells：多形核粒细胞（=segment 分叶核粒细胞） Bands:杆状核粒细胞
– 1-5 /million/year – Europe:1.6-9.2 /million – United States: 2.4-15.4 /million
• Age
– 10 % children and young adults – 50% over age 50 • Women : Men=2:1
the immune-complex mechanism
Legend:
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.)
13
Date of download: 8/19/2014 Copyright © 2014 McGraw-Hill Education. All rights reserved.
From: eChapter 24. Drug-Induced Hematologic Disorders
Pharmacotherapy: A Pathophysiologic Approach, 9e, 2014
– ANC < 1,000/microL – most clinically significant : ANC < 500/microL
5
Definitions
6
Relation of ANC to risk of infection
7
Agranulocytosis
• Incidence rate
4
Definitions
• e.g:
– A patient with a total WBC of 2,500/microL, 30 % PMNs and 6 % bands – ANC= 2,500 x (30 + 6) ÷ 100 = 900/microL
• The risk of infection increases
15
Clinical presentation
• Immune-mediated destruction
– Present： days to weeks after beginning the drug – often with acute and explosive symptoms – Rechallenge：prompt recurrence even with low doses.
16
Clinical presentation
• • • • • Fever Oral ulcerations with or without fever Sore throat Gingival disease inflammation Malaise, weakness, and chills
– 10% -20% to 5% – because of improvements in infection prophylaxis and supportive care
10
– – – –
Pathogenesis
1. Immune-mediated destruction
– the drug or more commonly a reactive metabolite of the drug, irreversibly binds to the neutrophil membrane. – the reactive metabolite results in the production of antibodies or T cells directed against the altered membrane structure – Examples of propylthiouracil (PTU) can bind to the neutrophil membrane and act as haptens then produced autoantibodies
2
Introduction
• Most cases of neutropenia in adults are acquired and are due to decreased granulocyte production or increased destruction. • Predictable and dose related