Lecture 7.0 Pancytopenia 2024 Flashcards
Name 2 approaches to pancytopenia
- Pancytopenia with hypercellular bone marrow
- Pancytopenia with hypocellular bone marrow
-Can be congenital, can be acquired
What are the acquired forms of hypocellular pancytopenia?
- Primary idiopathic aplastia anaemia
- Secondary aplastic anaemia
- Miscellaneous disorders (Myelofibrosis, extensive
granulomatous inflammation, marrow necrosis)
What are the congenital forms of hypocellular pancytopenia?
- Fanconi anaemia
- Dyskeratosis congenita
- Schwachman-Diamond syndrome
Primary idiopathic aplastic anaemia
Characterized by hypocellular marrow with a peripheral pancytopenia without a bone marrow infiltrate or increase in marrow fibrosis
- Presents with signs and symptoms of bone
marrow failure (i.e bleeding, symptoms of anaemia, infection) - Rare disease, with a relatively higher incidence in Asia
Name the 2 pathophysiologies seen with Primary AA, and their treatment
- Pathophysiology- Immune defect
*Oligoclonal
expansion of
cytotoxic T-cells
targeting
haemopoietic stem
cells
Treatment:
- Immunosuppressive
therapy
*Antithymocyte
globulin (ATG) +
Cyclosporin (CSA
- Pathophysiology- Decreased number and quality of haemopoietic stem cells
Treatment: Allogeneic
Haemopoietic stem
cell transplant (HSCT
Discuss the Biphasic age distribution of Primary idiopathic aplastic anaemia
1 peak between 10-25 years, and another >60 years
*M:F ratio ~1:1
Discuss the Severity grading of Primary AA
Severity grading of Primary AA:
- Severe:
–Bone marrow cellularity <25% + 2/3 of the following:
*Neuts: <0.5x10^9/l
*Plts: <20x10^9/l and/or
*Reticulocytes <20x10^9/l - Very severe:
–As above, but neuts <0.2x10^9/l - Non-severe:
–Not severe or very severe
A polyclonal IgG antibody preparation produced
by immunizing horses/rabbits with human
Thymocytes.
ATG
It causes profound T-cell depletion, and is a
powerful immunosuppressive
ATG
What’s are the possible side effects of ATG?
- Allergy and
- serum sickness (happens when your body reacts to certain medications, antiserum (used to treat infections or venom), or other proteins from non-human sources)
(7-14 days after therapy commencement).
*It is therefore always given with a corticosteroid and an antihistamine
Patients referred to as transfussion independent
Those responding to ATG (which is normally 2/3rd of patients)
*Up to ~1/3rd of these will relapse.
What are the problems that result with with HSCT among siblings (Hematopoietic Stem Cell Transplantation)?
- Potentially serious complications, particularly
graft vs host disease.
– At risk of secondary malignancies in later life.
– Many patients don’t have a matched sibling
What’s the response rate of the HSCT (Hematopoietic Stem Cell Transplantation) with best
results in young sibling matched transplants patients
90 %
Problems with HSCT
- Potentially serious complications, particularly
graft vs host disease.
– At risk of secondary malignancies in later life.
– Many patients don’t have a matched sibling
The 3 causes of 2ndary aplastic anemia/ aplasia
- Drugs
- Toxins
- Irradiation
- Infection (viral (EBV, CMV, Hepatitis B and C, HIV,
Parvovirus), Mycobacteria - Auto-immune pathology (such as SLE)
- Miscellaneous (Prolonged starvation (including
Anorexia nervosa), pregnancy, thymoma) - Clonal myeloid disorders (Including hypoplastic
MDS, hypoplastic AML and Paroxysmal nocturnal
haemoglobinuria (PNH))
hereditary pattern of Fanconi anaemia
Autosomal recessive disorder
What causes Fanconi anamia?
Caused by a mutation in one of the FANC genes:
(FANCA , FANCB , FANCC , FANCD1 , FANCD2 , FANCE , FANCF ,FANCG , FANCI , FANCJ , FANCL , FANCM or FANCN), whichencode proteins involved with DNA repair.
Impact of Fanconi anaemia on bone marrow. What is Fanconi anaemia associated with in the bone marrow?
Associated with bone marrow failure and an increased predisposition to malignancy (especially AML)- Acute Myeloid Leukemia
What are the clinical features of fanconi anaemia?
- Pancytopenia develops insidiously and presents in most cases between the ages of 5 and 10 years.
- One or more associated somatic abnormalities in 2/3rds of cases:
–café - au - lait spots
–skeletal abnormalities (short stature, absent/fingerised thumbs, radial hypoplasia)
–micro-opthalmia
–genitourinary, gastrointestinal, cardiac and/or neurological anomalies.
Diagnoses of Fanconi anaemia
– Chromosome breakage studies
– Genetic testing for FANC
mutations
Treatment of Fanconi anaemia
– Supportive measures
– Androgens (oxymetholone) or corticosteroids (prednisone) therapy to boost haemopoeitic function.
– HSCT with a reduced intensity conditioning regimen
- Prognosis: Average life expectancy is ~24 yrs.
Features of hypercellular pancytopenia
- Bone marrow infiltration
- Ineffective haemopoiesis
- Hypersplenism (condition where the spleen becomes overactive and removes blood cells from circulation faster than normal)
- Other
–Haemophagocytic lymphohistiocytosis (HLH)
–Multifactorial effects
Two forms of bone marrow infiltration
- Benign
– Granulomata
(Mycobacterial infection,
fungal infection,
Sarcoidosis etc) - Malignant
– Acute leukaemia (AML
(particularly APL) or ALL)
– Lymphoma (Hodgkin or
non-Hodgkin)
– Hairy cell leukaemia
– Non-haemopoietic
tumours (small round blue
cell tumours of childhood,
Carcinomas etc)
Ineffective hemopoiesis
- Failure to achieve adequate bone marrow output
of mature haemopoietic cells- despite there being apparently normal/increased haemopoietic
activity in the bone marrow- due to increased intramedullary cell death. - The haemopoietic precursors in the bone marrow are usually well represented but morphologically abnormal, and there is increased intramedullary cell death.
Causes of ineffective haemopoiesis
- Megaloblastic anaemia
- Chronic infection
–Most notably HIV and TB in South Africa - Drugs
–Including folate antagonizing agents (such as Methotrexate) and drugs which interfere with
DNA synthesis /repair (such as Nucleoside analogues (commonly AZT) and
chemotherapeutic agents). - Myelodysplastic neoplasms (MDS)
- Other miscellaneous causes
– Multi-organ failure
– Starvation
Features of
- Associated with an increased risk of acute myeloid leukaemia
- Can occur at any age, but is much morecommon in the elderly.
- Diagnosis is made on the basis of morphologic dysplasia in the bone marrow
(>10% of the cells in one/more cell lines)
in the absence of other causes - Cytogenetic abnormalities are present in 50-90% of cases (commonly
del/monosomy(5q), del/monosomy(7q),
trisomy 8 or a complex karyotype). - Somatic mutations in a variety of genes are also present in most cases.
Myelodysplastic neoplasms (MDS)
- A clonal stem cell disorder (malignancies in the bone marrow) characterized by the presence of peripheral cytopenias as a
result of ineffective haemopoiesis
Proportions of blood cells sequestered in the spleen of healthy people
In healthy people:
– ~5% of the red cell mass
– ~30% of all platelets
– ~40% of marginating neutrophils
are sequestered in the spleen.
*If the spleen is enlarged, the proportion of each respective cell line pooled in the spleen may be increased
Characteristics of hypersplenism
Hypersplenism is characterized by:
– 1 or more cytopenia associated with enlargement of
the spleen
– The bone marrow is hypercellular
– The life span of the sequestered cells tends to be
attenuated (reduced)
– The cytopenias recover following splenectomy
- Usually, the cytopenias are mild/moderate.
eg. It is unusual for the platelet count to be <50x10^9/l
A rare life-threatening disorder associated with
excessive immune activation which causes
tissue damage and organ dysfunction
HLH
*Caused by a lack of normal downregulation of
activated macrophages and lymphocytes, which
results in excessive inflammation following an
initially appropriate immune response
Triggers of HLH
HLH is triggered by an incident which disrupts
immune homeostasis.
– Infection
*Viral (EBV, CMV, HSV, VZV, Measles, HIV)
*Bacterial (TB, GNB)
*Parasitic (Leishmaniasis)
– Lymphoma
*Hodgkin
*Non-Hodgkin (particularly T-cell neoplasms)
– Autoimmune pathology (Macrophage activation
syndrome)
HLH clinical features
HLH Clinical features
- Most patients are acutely ill with multiorgan involvement
- S&S related to cytokine excess
–Persistent fever
–Organ dysfunction (hepatitis, respiratory distress, renal dysfunction) - S&S due to accumulation of activated macrophages
– Hepatosplenomegaly
– Skin rashes
– Neurological manifestations
HLH Laboratory findings
- Cytopenias (due to haemophagocytosis)
- Elevation of serum Ferritin (particularly worrying if >10 000 ug/L)
- Deranged liver function
- Coagulopathy (DIC, low Fibrinogen)- Impaired body’s ability to coagulate or form clots
- Hypertriglyceridemia
- Haemophagocytosis on Bone marrow aspirate
*HLH typically has a high mortality rate (50 – 100%),
partly as a result of delayed diagnosis and treatment, it can mimic many other conditions in
its early stages so it’s missed
HLH treatment
– Immunosuppressive Rx (high dose Corticosteroids)
– Immunoglobulins (Ivig)
– Etoposide (Topoisomerase inhibitor)
– Treat the underlying trigger
INVESTIGATION OF PANCYTOPENIA
- FBC with a differential white cell count and peripheral
blood smear review - Reticulocyte count
- Vitamin B12 and folate levels
- Iron studies
- HIV testing
- Bone marrow aspirate and trephine biopsy (including samples for flow cytometry and cytogenetics)
- Further investigation depending on the clinical context (such as liver
function tests, other viral studies, testing for an underlying auto-immune disease etc)
Treatment of pancytopaenia
Treatment of pancytopaenia
1) Specific management depends on the
underlying cause
2) Supportive management:
-Blood product transfusion
-Neutropenic measures as infection prophylaxis
-Growth factor support
-Iron chelation therapy
Supportive treatment of
neutropenia
Patients with severe neutropenia (Neuts
<0.5x10^9/l) are at risk of life threatening sepsis
(particularly in those patients without good bone
marrow reserve).
- General neutropenic measures:
– Good dental hygiene to prevent oral infections and bacteraemia from an oral source.
– Hand and food hygiene and strict aseptic technique for medical procedures
– Isolation
– Age-appropriate immunizations and annual influenza vaccines.
– Isolation
– Digital rectal examination, suppositories and enemas should be
avoided
Supportive treatment specifically for patients
with severe chemotherapy-associated neutropenia cont.
- Infection prophylaxis:
– Patients should be closely monitored, and broad
spectrum empiric antibiotics started at any sign of
infection
– Antibiotic prophylaxis with a fluoroquinolone where the neutrophil count is expected to be <0.5x10^9/l for >10 days.
– Antifungal prophylaxis (oral Fluconazole)
Granulocyte colony stimulating
factor (G-CSF)
1) drives proliferation and
differentiation of neutrophil
progenitor cells.
2) Accelerates neutrophil
maturation
Granulocyte colony stimulating
factor (G-CSF) Indications for use
Not used universally in patients with neutropenia.
- Used in patients with profound febrile neutropenia (neutrophil count < 0.1 x10^9/L)
AND - Clinical signs indicating potential septic shock
(such as hypotension, organ dysfunction etc)
OR - Persistent pyrexia (elevated body temperature) despite appropriate antibiotics/ antifungals
OR - Invasive fungal infection
