appunti del dott. Claudio Italiano
Granulocytopenia or neutropenia is defined by a decrease in neutrophil
granulocytes <2,500 / μl.
The most common cause is the alteration of the lateral medulla of neutrophils
due to the harmful action of chemical substances or lymphoproliferative diseases
with invasion of the bone marrow by malignant cells (see Leukocytes). We can
therefore have conditions of altered production of neutrophils as follows will
be reported. The task of neutrophils, as we know, is to intervene in the defense
of the organism against bacterial infections and, therefore, they take part in
the process of phagocytosis. Next you can see the pattern of a neutrophil at
work that incorporates a bacterium.
There are three types of cells in the blood:
• red blood cells (erythrocytes) that transport oxygen from the lung to the
different tissues of the body
• platelets (thrombocytes) that are essential for blood coagulation
• white blood cells (leukocytes) that intervene in the body's defense mechanisms
against infections. There are three types of white blood cells: granulocytes,
monocytes and lymphocytes. Neutrophils make up most of the granulocytes.
The production of blood cells is precisely controlled in the bone marrow, so as
to maintain, in the healthy subject, a constant number of each type of cell.
Every second are produced, for example, about 3 million erythrocytes and 120,000
white blood cells, which replace cells removed from the blood after their
physiological aging process.
Neutropenia can be defined:
• mild neutropenia, when the absolute neutrophil count is less than 1500 per mm3
(1.5 x 109 / l), but remains above 1000 per mm3 (1.0x109 / l)
• moderate neutropenia, when the absolute neutrophil count is between 500 per
mm3 (0.5 x 109 / l) and 1000 per mm3 (1.0 x 109 / l).
• severe neutropenia, when the absolute neutrophil count is less than 500 per
mm3 (0.5 x 109 / l). In this last condition it is a good rule that the patient
is kept isolated from individuals carrying infections or who perform a treatment
of chemoprophylaxis against infections. This situation, for example, occurs in
patients who have recently been transplanted from bone marrow. Such patients can
easily undergo otitis media, tonsillitis, pharyngitis, oral mucosa ulcers,
gingival infections and skin infections.
A. Decreased granulocytopoiesis (aplastic alteration):
1. damage to the bone marrow:
- chemicals (eg benzol)
- drugs:
• dose dependent, toxicity (eg cytostatics, immunosuppressants, AZT,
chloramphenicol)
• independent of the dosage for reactions related to the type of drug (eg
phenylbutazone, gold salts, in rare cases also chloramphenicol)
- irradiations
- autoantibodies against stem cells (in some cases of autoimmune neutropenia)
2. infiltration of bone marrow: leukemia, carcinomas, malignant lymphomas
3. osteomyelosclerosis
B. Granulocytopoiesis maturation disorders
1. rare inborn myelopoiesis disorders:
Kostmann syndrome: maturational arrest of myelopoiesis at the pro-myelocyte
stage; cyclic neutropenia: periodic neutropenia every 3 weeks; both these forms
can be successfully treated with G-CSF
2. myelodysplasia syndrome
3. lack of vitamin B, and of folic acid with ineffective
granule-erytro-trombopoiesis. II. Granulocitopenie da aumentata distruzione cellulare
A. Immunological neutropenias (relatively rare)
1. From autoantibodies (infrequent)
- idiopathic (eg autoimmune neutropenia in young children)
- autoimmune neutropenia secondary to known basic diseases:
• acute phase after infections (eg mononucleosis)
• chronic phase in HIV infection
• malignant lymphomas
• Systemic lupus erythematosus (SLE), Felty's syndrome
• Sjogren's syndrome
- immunological granulocytopenia from drugs)
2. From iso-antibodies to granulocytes:
alloimmune neutropenia of the newborn from anti-maternal anti-granulocyte IgG
antibodies of the child.
B. Non-immunological granulocytopenias
1. by consumption: bacterial infections
distribution alterations:
hypersplenism (granulocyte pooling in the enlarged spleen)
3. viral infections.
Clinical: neutropenias> 1,000 / μl are almost always asymptomatic, while the
risk of infection constantly increases between 1,000 and 500 / pl; with values
<500 / μl there is always infection, especially of bacterial type up to sepsis.
In this case the inflammatory signs are not very evident.
1. anamnesis (of the drugs) / clinic
2. granulocyte counts (absolute values)
3. cytology and histology of the bone marrow
4. evtl. specialized examinations (eg anti-granulocyte autoantibodies).
1. causal: suspension of suspected drugs, treatment of any underlying disease
2. symptomatic:
- protection against infections, in case of high granulocytopenia (<500 / ul)
treatment in aseptic rooms, evtl. anti-bacterial remediation; in the event of
fever or infection, administer broad-spectrum antibiotics after blood culture
and tampons
- in case of myelopoiesis disorders administer granulocytopoiesis growth factors
(G-CSF and GM-CSF)
- in autoimmune neutropenia, the following sequence can be used:
• corticosteroids
• high dose immunoglobulins for e.v. (SRE block)
• immunosuppressants.
Definition: immunological granulocytopenia induced by drugs, with sudden
destruction of all granulocytes and partly also of granulopoiesis precursors.
Etiology:
the drugs that most often can induce such reactions are: analgesics and
antipyretics, especially derivatives of pyrazolone (metamizole); Thyrostatics;
sulphanilamides (including anti-diabetics, anti-epileptics, psychotropic drugs,
etc.).
Pathogenesis: the drug acts as hapten; when it is bound to plasma proteins, a
complete antigen is formed, able to stimulate the production of specific
antibodies. The antibody antigen complexes thus formed bind to the surface of
the granulocytes, causing a complement-mediated granulocytosis.
Clinic: acute onset, with fever accompanied by shaking chills, multiple
ulcerations of the mucous membranes and tonsils, possibly sepsis. Granulocyte
counts can drop to 0, then increase after one week after discontinuation of the
drug.
Bone marrow: inhibition of granulocyte maturation with prevalence of
promyelocytes (promyelocyte medulla) with normal erythro- and thrombopoiesis.
Therapy: suspension of all the drugs hitherto taken; place the patient in an
aseptic room; in case of fever, antibiotic therapy with broad-spectrum
antibiotics (see chapter on fever), administration of G-CSF (granulocyte colony
stimulating factor) and GM-CSF (granulocyte macrophage colony stimulating factor).
Alterations of granulocyte function
Epidemiology: they are rare forms, mainly congenital, with increased
susceptibility to bacterial infections. Defects of leukocyte adhesion (LAD):
lack of adhesion and adhesion proteins. Autosomal recessive inherited deficiency
of the 3 adhesion molecules (integrins). The mutations in the chain (3 of the
molecules of adhesion are the molecular basis.The consequences are alterations
on chemotaxis, adherence and phagocytosis function of granulocytes.These are the
delay of fall of the umbilical cord, the persistence of physiological
granulocytosis of the newborn and increased susceptibility to infections These
defects can be corrected by bone marrow or stem cell transplantation.
Hyper-IgE syndrome (Job syndrome):
marked increase in IgE. Typical staphylococcal infections of skin ("cold"
abscesses, without signs of inflammation) and lungs (pneumonia).
Chediak-Steinbrinck-Higashi syndrome:
autosomal recessive alteration of granulocytes, with presence of giant granules,
increased susceptibility to infections, partial albinism.
Progressive septic granulomatosis:
hereditary predominantly X-linked affection, related to an alteration of the
NADPH-dependent granulocyte oxidase activity; as a consequence, the bacteria,
after a normal phagocytosis, can not be destroyed in the intracellular site.
"Lazy leukocyte syndrome": reduced mobility of granulocytes.
Granulocyte myeloprossase deficiency with ease to fungal infections.