2.3 Neutropenia Flashcards
NEUTROPHIL COUNT
The normal range of the neutrophil count is ____________, but may be dependent on:
• Ethnic background: ______________ have lower counts (1.0 – 5.8 x 109/L)
• Age: 2 month old babies have lower counts (0.7 – 4.7 x 109/L)
• Pregnancy: ______________ have higher counts (3.8 – 12.3 x 109/L)
2 – 7.5 x 109/L;
Afro-Caribbean males;
2nd trimester onwards
Neutropenia (low neutrophil count) may be caused by the following:
Decreased production • Post-viral infection (e.g. common viruses) → neutropenia may persist for several weeks post-infection • Chemotherapy/irradiation • Drugs (e.g. \_\_\_\_\_\_\_\_\_\_\_\_\_\_) • Vitamin deficiency (\_\_\_\_\_\_\_\_\_\_) • \_\_\_\_\_\_\_\_\_\_\_\_\_\_ (bone marrow failure)
Replacement of BM haematopoietic tissue • Leukaemia (replacement with \_\_\_\_\_\_\_\_), lymphomas • \_\_\_\_\_\_\_\_\_ (myelomas) • Fibrosis (\_\_\_\_\_\_\_\_\_\_\_\_\_) • Cancer
Increased peripheral destruction
• In patients with splenomegaly (enlarged spleen)
• In patients with immune conditions (e.g. collagen vascular diseases (SLE), autoimmune neutropenia)
*The causes of pancytopenia (decreased neutrophils, RBCs, platelets) are similar to neutropenia, except post-viral infections occur due to rarer infections like __________ (not common viruses).
penicillin, anticonvulsants;
B12 or folate;
Aplastic anaemia;
blasts;
Plasma cells;
myelofibrosis
hepatitis
FEBRILE NEUTROPENIC SEPSIS
As the neutrophil count decreases, the risk of sepsis increases (bacterial, viral and fungal):
• Neutrophils < 1.0 x 109/L: increased risk of infection
• Neutrophils < __________: markedly increased risk of infection
There are micro-organisms everywhere in the environment, so neutropenic patients cannot avoid getting an infection (hospital setting is not ideal):
• Difficult to prevent exposure because of microbes in the environment and on the patient themselves → often develop infection due to own gut flora
• Lack of neutrophils also blunts the inflammatory response to infections, so these patients do not show the typical clinical signs of infection:
o No pus, fever without localising signs, pneumonia without chest consolidation
• Must reduce unnecessary exposure to pathogens
• Treated with ______________ even if the source of infection has not been determined yet
0.5 x 109/L;
empirical antibiotics
[Reduction of Risk in Hospitals] Patient • Warded in isolation rooms • No flowers (increased risk of \_\_\_\_\_\_\_\_\_\_\_\_ infections) • ‘Clean diet’ (e.g. avoid \_\_\_\_\_\_\_\_\_)
Staff/ institution
• Personal protective equipment (gloves and gowns)
• Handwashing
• _________ airflow
The following steps should be taken when examining a febrile patient in the hospital:
Examination
- Is the patient known to be neutropenic?
- Has the patient recently had _________ (risk of neutropenia)
- How high is the temperature? (requires treatment if >38°C for more than 1 hour)
- Examine patient (avoid throat/rectal exams) including _______
- Commence broad spectrum antibiotics (according to febrile neutropenic sepsis policy of the hospital)
- Arrange tests (_________________)
History taking
• Presence of cough, sputum, diarrhoea, dysuria, skin lesions
• Examine mouth, chest, abdomen, venous access devices, peri-anal region
• Avoid ____________ to prevent the introduction of pathogens or provoke influx of gut flora into the bloodstream
Treatment • Broad spectrum antibiotics (empirical) given before investigation test results return → cover organisms which could kill the patient quickly (e.g. Pseudomonas) o \_\_\_\_\_\_\_\_\_\_\_\_\_\_ (synergistic) commonly prescribed
Pseudomonas;
blue cheese;
Laminar;
chemotherapy;
BP;
FBC, CXR, mid-stream urine/MSU, sputum culture, wound swab;
rectal examination;
Tazocin & gentamicin
Aplastic anaemia is a rare condition (affects about 2 – 5 people per million a year), which may affect all age groups (peak incidence from ages 15 – 24 and > 60):
• Presents with the triad of ________________________
• Diagnosis depends on pancytopenia in the blood and hypocellular bone marrow (failure to produce blood cells)
• Differentials: ____________, hypoplastic myelodysplastic syndrome, anorexia nervosa, ____________ (usually atypical)
Classification
- Idiopathic: Vast majority of patients with aplastic anaemia (70 – 80%)
- Inherited: Includes ____________________-
- Secondary: Due to chemotherapy, radiation, immune causes
anaemia (fatigue, breathlessness), neutropenia (prone to infections), and low platelet count (easy bruising/bleeding)
acute leukaemia (AML/ALL);
Mycobacteria;
dyskeratosis congenita (DC) and Fanconi anaemia (FA)
CLASSIFICATION
Aplastic anaemia is divided into severe aplastic anaemia (SAA) and non-severe aplastic anaemia (NSAA) determined based on the _______________:
• At least 2 of 3 of the following peripheral blood features must be present with a hypocellular bone marrow to be diagnosed as SAA
Bone marrow
- < 20% cellularity
Peripheral blood
- Reticulocytes < 20 x 109/L
- Neutrophils < _____ x 109/L
- Platelets < 20 x 109/L
INVESTIGATIONS
There are many investigations that should be performed in aplastic anaemia to ascertain the underlying cause of the patient’s symptoms:
Blood tests • FBC & reticulocyte count • Blood film examination • \_\_\_\_\_\_ in children (prognostic factor) • Vitamin B12 & folate levels • Liver function tests • Anti-nuclear antibody and anti-dsDNA tests • Viral studies (HAV, HBV, HCV, EBV, HIV, CMV)
Biopsies
• Bone marrow aspirate & ________ (with cytogenetics)
Inherited disorders
• _________________ if < 50 years of age (to exclude Fanconi anaemia)
• ________________- for dyskeratosis congenita (in presence of clinical features or lack of response to immunosuppressive therapy) Imaging
• Chest X-ray
• Abdominal ultrasound and echocardiogram
Camitta criteria;
0.5;
HbF%;
trephine;
Peripheral blood chromosomal breakage analysis;
Peripheral blood mutation analysis (DKC1, TERC, TERT)
The management of bone marrow failure includes the following factors:
- Supportive blood/platelet transfusions (must be _____________________) along with antibiotics (due to neutropenia) and iron chelation therapy (multiple transfusions lead to high iron)
- Drugs promoting marrow recovery (____________ (androgens) and growth factors)
- Immunosuppressive therapy*
- ________________
There are late complications following immunosuppressive therapy for aplastic anaemia:
- Relapse of aplastic anaemia: 35% of patients over 15 years
- Clonal haematological disorders (myelodysplasia, acute leukaemia): 20% risk over 10 years
- Solid tumours: 3% risk
leucodepleted, CMV-negative, and irradiated;
oxymetholone;
Stem cell transplantation
FANCONI ANAEMIA
Fanconi anaemia is an autosomal recessive condition (with at least 13 mutations identified in the DNA repair pathway → genes for FA-A, -B, -C, -D act through final common pathway involved in DNA repair mechanisms):
• Patient may appear normal until _____________, after which progressive bone marrow failure occurs over an extended period of time
• 10% of patients terminate in _________
• Treatment includes supportive measures, _____________ (transient improvement of cell counts, but with side effects like hepatotoxicity) and stem cell transplantation
Fanconi anaemia is a multi-system disease associated with chromosomal instability (exquisitely sensitive to radiation → avoid exposure like X-rays) and high incidence of ________________ (mainly head, neck and gynaecological tract):
Abnormalities
- skeletal e.g. radial ray, congenital hip, vertebral, rib (71%)
- skin pigmentation (cafe au lait, hyper/hypo pigmentation) (64%)
- short stature (63%)
- eyes (micropthalmia) (38%)
- male genital (20%)
5 – 10 years of age;
acute leukaemia;
androgens;
squamous cell carcinomas
FACONI ANAEMIA
Patients with Fanconi anaemia have spontaneous chromosomal breakage and hypersensitivity to DNA cross-linking agents (e.g. _____________, _________):
• Basis of screening for Fanconi anaemia (cross-linking agents used)
• CT scans and X-rays are avoided as they are highly sensitive to irradiation
• If they undergo a stem cell transplant, radiotherapy should be avoided/reduced dose
diepoxybutane (DEB);
mitomycin C (MMC)
DYSKERATOSIS CONGENITA Dyskeratosis congenita (Zinsser-Engman-Cole syndrome) presents with skin pigmentation, \_\_\_\_\_\_\_\_\_\_\_\_ and \_\_\_\_\_\_\_\_\_\_\_\_:
There are also other somatic and congenital abnormalities associated with DC:
- ________________: 30.5%
- Learning difficulties/development/mental retardation: 25.4%
- Pulmonary disease: 20.3%
- Short stature: 19.5%
- Extensive dental caries/loss: 16.9%
- Oesophageal stricture: 16.9%
- Hair loss/grey hair/sparse eyelashes: 16.1%
- Hyperhidrosis (excessive sweating): 15.3%
- Malignancy: 9.6%
The treatment of DC is the same with other types of aplastic anaemia, including supportive treatments with transfusions and antibiotics, and drugs to promote marrow recovery and haematopoietic stem cell transplantation.
Genetic basic
Telomeres are repeated DNA segments at the tip of each chromosome, which prevent ___________________:
• Become shorter as the cell divides → cell dies via apoptosis when it shortens to a certain length (Hayflick limit)
• Telomerase is an enzyme important in the maintenance of telomere length (found in stem cells) → lengthens cell lifespan if telomeres do not shorten In DC, mutations in two genes (_______________) result in defective telomerase function, resulting in progressive telomere shortening and early loss of cells (e.g. stem cells):
• Progressive development of features (most pronounced in rapidly dividing tissues)
Inheritance
- X-linked recessive: Most common; due to __________ mutations leading to defective telomerase function (some carriers have less severe forms of DC)
- Autosomal dominant Due to __________ (encodes RNA component of telomerase)
- Autosomal recessive: Not identified
nail dystrophy, leukoplakia (white plaques);
Epiphora (watering eyes; tearing);
chromosomal fusion or rearrangements during chromosomal replications;
DKC1 and TERC;
DKC1;
TERC mutations
MYELODYSPLASTIC SYNDROMES (MDS) Myelodysplastic syndromes (MDS) are a biologically heterogeneous group of acquired haematopoietic stem cell disorders (occurs in 4 per 100000 people; typically elderly): • Abnormal blood cell maturation leads to \_\_\_\_\_\_\_\_\_\_\_, functional defects and increased risk of transformation to leukaemia • May have single cytopenia (e.g. anaemia, isolated neutropenia) or signs and symptoms of \_\_\_\_\_\_\_\_\_\_\_\_ which may develop over weeks or months
MORPHOLOGICAL FEATURES
All the peripheral blood features tend to show morphological distortion of cell lines:
- Pelger-Huet anomaly: Bilobed neutrophils with ______________ (thin strand connecting lobes)
- ___________: Absence of granules or abnormal granules in neutrophils.
- Dyserythropoiesis: ______________ (nuclear bridging is highly abnormal) - Dysplastic megakaryocytes: Micro-megakaryocytes
- Increased proportion of blast cells in BM: Normal value < _____
cytopenias;
general marrow failure;
pince-nez appearance
Dysgranulopoiesis;
Cytoplasmic bridge;
5%
MYELODYSPLASTIC SYNDROMES (MDS)
CLASSIFICATION
Myelodysplastic syndromes (MDS) can be classified into the following categories:
- Refractory anaemia: ___________ anaemia with few other findings
- Refractory cytopenia with multilineage dysplasia (RCMD): Morphological changes in more than 1 cell line in the peripheral blood
- Refractory anaemia with excess blasts (RAEB): Leads to ________________
- Unclassified MDS: Includes MDS with bone marrow fibrosis, childhood MDS
PROGNOSIS
In the international prognostic scoring system for MDS, higher scores indicate a higher risk category (shortest median survival rate and highest risk of evolution into AML):
The main concerns of MDS patients are the deterioration of blood counts and development of AML (very poor prognosis if developed from preceding MDS → usually not curable):
• One-third of MDS patients die from infection, another third die from ___________, and the last third die from acute leukaemia
Currently, the only two treatments which can prolong survival are allogeneic stem cell transplantation (SCT) (not viable for ____________) and intensive chemotherapy (only a minority can really benefit):
Supportive care:
• Blood product support (when patient bleeds in thrombocytopenia);
• Antimicrobial therapy (due to increased risk of infections)
• Growth factors (___________): Biological modifiers
Immunosuppressive therapy
- Azacytidine (cytidine analogue – inhibits __________________)
- Lenalidomide (___________ derivative used in multiple myeloma and MDS)
Unexplained ;
leukaemia (bad prognosis);
bleeding;
elderly patients;
EPO, G-CSF;
DNA methyltransferase;
thalidomide
