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Block 3 > Lecture 7.0 Pancytopenia 2024 > Flashcards

Lecture 7.0 Pancytopenia 2024 Flashcards

1
Q

Name 2 approaches to pancytopenia

A
  • Pancytopenia with hypercellular bone marrow
  • Pancytopenia with hypocellular bone marrow
    -Can be congenital, can be acquired
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2
Q

What are the acquired forms of hypocellular pancytopenia?

A
  • Primary idiopathic aplastia anaemia
  • Secondary aplastic anaemia
  • Miscellaneous disorders (Myelofibrosis, extensive
    granulomatous inflammation, marrow necrosis)
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3
Q

What are the congenital forms of hypocellular pancytopenia?

A
  • Fanconi anaemia
  • Dyskeratosis congenita
  • Schwachman-Diamond syndrome
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4
Q

Primary idiopathic aplastic anaemia

A

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
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5
Q

Name the 2 pathophysiologies seen with Primary AA, and their treatment

A
  1. Pathophysiology- Immune defect
    *Oligoclonal
    expansion of
    cytotoxic T-cells
    targeting
    haemopoietic stem
    cells

Treatment:
- Immunosuppressive
therapy
*Antithymocyte
globulin (ATG) +
Cyclosporin (CSA

  1. Pathophysiology- Decreased number and quality of haemopoietic stem cells

Treatment: Allogeneic
Haemopoietic stem
cell transplant (HSCT

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6
Q

Discuss the Biphasic age distribution of Primary idiopathic aplastic anaemia

A

1 peak between 10-25 years, and another >60 years

*M:F ratio ~1:1

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7
Q

Discuss the Severity grading of Primary AA

A

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
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8
Q

A polyclonal IgG antibody preparation produced
by immunizing horses/rabbits with human
Thymocytes.

A

ATG

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9
Q

It causes profound T-cell depletion, and is a
powerful immunosuppressive

A

ATG

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10
Q

What’s are the possible side effects of ATG?

A
  • 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

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11
Q
A
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12
Q

Patients referred to as transfussion independent

A

Those responding to ATG (which is normally 2/3rd of patients)

*Up to ~1/3rd of these will relapse.

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13
Q

What are the problems that result with with HSCT among siblings (Hematopoietic Stem Cell Transplantation)?

A
  • Potentially serious complications, particularly
    graft vs host disease.
    – At risk of secondary malignancies in later life.
    – Many patients don’t have a matched sibling
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14
Q

What’s the response rate of the HSCT (Hematopoietic Stem Cell Transplantation) with best
results in young sibling matched transplants patients

A

90 %

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15
Q

Problems with HSCT

A
  • Potentially serious complications, particularly
    graft vs host disease.
    – At risk of secondary malignancies in later life.
    – Many patients don’t have a matched sibling
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16
Q

The 3 causes of 2ndary aplastic anemia/ aplasia

A
  • 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))
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17
Q

hereditary pattern of Fanconi anaemia

A

Autosomal recessive disorder

18
Q

What causes Fanconi anamia?

A

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.

19
Q

Impact of Fanconi anaemia on bone marrow. What is Fanconi anaemia associated with in the bone marrow?

A

Associated with bone marrow failure and an increased predisposition to malignancy (especially AML)- Acute Myeloid Leukemia

19
Q

What are the clinical features of fanconi anaemia?

A
  • 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.
20
Q

Diagnoses of Fanconi anaemia

A

– Chromosome breakage studies
– Genetic testing for FANC
mutations

21
Q

Treatment of Fanconi anaemia

A

– 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.
22
Q

Features of hypercellular pancytopenia

A
  • 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
23
Q

Two forms of bone marrow infiltration

A
  • 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)
24
Q

Ineffective hemopoiesis

A
  • 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.
25
Q

Causes of ineffective haemopoiesis

A
  • 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
26
Q

Features of

A
  • 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.
26
Q

Myelodysplastic neoplasms (MDS)

A
  • A clonal stem cell disorder (malignancies in the bone marrow) characterized by the presence of peripheral cytopenias as a
    result of ineffective haemopoiesis
27
Q

Proportions of blood cells sequestered in the spleen of healthy people

A

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

28
Q

Characteristics of hypersplenism

A

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
29
Q

A rare life-threatening disorder associated with
excessive immune activation which causes
tissue damage and organ dysfunction

A

HLH

*Caused by a lack of normal downregulation of
activated macrophages and lymphocytes, which
results in excessive inflammation following an
initially appropriate immune response

30
Q

Triggers of HLH

A

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)

31
Q

HLH clinical features

A

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
32
Q

HLH Laboratory findings

A
  • 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

33
Q

HLH treatment

A

– Immunosuppressive Rx (high dose Corticosteroids)
– Immunoglobulins (Ivig)
– Etoposide (Topoisomerase inhibitor)
– Treat the underlying trigger

34
Q

INVESTIGATION OF PANCYTOPENIA

A
  • 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)
35
Q

Treatment of pancytopaenia

A

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

35
Q

Supportive treatment of
neutropenia

A

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
35
Q

Supportive treatment specifically for patients
with severe chemotherapy-associated neutropenia cont.

A
  • 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)
36
Q

Granulocyte colony stimulating
factor (G-CSF)

A

1) drives proliferation and
differentiation of neutrophil
progenitor cells.
2) Accelerates neutrophil
maturation

37
Q

Granulocyte colony stimulating
factor (G-CSF) Indications for use

A

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

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