Week 2 Lecture 4 - Cytopenia and Bone Marrow Failure Syndromes Flashcards
Pancytopenia
May manifest with symptoms/clinical signs related to anaemia, leukopenia, thrombocytopenia
May be asymptomatic/diagnosed incidentally
Can be an indication of an underlying disease
Commonly reflects trilineage hypoplasia in the bone marrow (= impaired production) but can reflect peripheral destruction or a combination of both
Trilineage Hypoplasia (Aplastic Anaemia)
Deceased presence of 3 haematopoietic cell lines
- erythroid
- myeloid
- megakaryocytic
BM morphology
- <25% cellularity with consideration of age & biopsy site
- commonly haematopoietic cells replaced by adipocytes
- may be also be replaced by: fibrous tissue, haematopoietic neoplastic cells, metastasised neoplastic cells
Inherited Bone Marrow Failure Syndromes
Inherited bone marrow failure syndromes
(IBMFS) are a group of disorders that result in:
- decreased bone marrow cellularity
- decreased cellularity in the peripheral blood
Include:
- Diamond-Blackfan anaemia
- Schwachman-Diamond syndrome
- Fanconi anaemia
- Severe congenital neutropenia
- Congenital amegakaryocytic thrombocytopenia
Diamond-Blackfan Anaemia
Autosomal dominant trait
~25% have mutation in RPS19 located on chromosome 19q13.2
In total 15 genes shown to have result in DBA
These mutations prevent the assembly of ribosomal proteins => ‘ribosomopathy’
Manifests during infancy
Clinical consequences
- haematological abnormalities
- physical abnormalities
- neoplasia
Diamond-Blackfan Anaemia - Haematological Findings
PB:
- anaemia (commonly)
- ± macrocytic RBC
- thrombocytopenia - thrombocytosis
BM:
- erythroid hypoplasia => trilineage hypoplasia
- trilineage dysplasia
- megakaryocytic hyperplasia
- fibrosis
Schwachman-Diamond syndrome (SDS)
Autosomal recessive disorder
Mutation in SBDS gene on chromosome 7q11.21
Clinical manifestation shortly after birth
- recurrent infections
- pancreatic exocrine insufficiency
- skeletal abnormalities
Clinical consequences
- haematological abnormalities
- physical abnormalities
Schwachman-Diamond syndrome (SDS) - Haematological Findings
PB:
- neutropenia (~100%)
- anaemia (~66%)
- thrombocytopenia (~25%)
BM:
- myelodysplasia (~33%)
- left shifted granulopoiesis
Fanconi Anaemia
Pathogenic variants in at least 20 genes are known to cause FA in humans
Many mutations documented
Clinical consequences:
- haematological abnormalities
- physical abnormalities
- neoplasia
Fanconi Anaemia - Haematological Findings
PB:
- cytopenia (70% by 7 y.o., ‘all’ by 40 y.o.)
- RBC; anisocytosis, poikilocytosis including dacrocytes, basophilic stippling
BM:
- trilineage hypoplasia
- dyserythropoiesis
- reactive mastocytosis
Severe Congenital Neutropenia (SCN)
Broad term that encompasses several disorders; all => neutropenia
Present early in infancy with severe infections
>50% due to mutations of ELANE gene, encoding for neutrophil elastase
Less frequent causes of SCN include pathogenic variants in GFI1, WASP, G6PC3, VPS45, JAG1, &TCRG1
Severe Congenital Neutropenia - Haematological Findings
PB:
- severe, constant neutropenia <0.5 x109/L
BM:
- ↓ myeloid precursors
- ↓ M:E
- myeloid maturation arrest
Haematological Neoplasia with IBMFS - Fanconi Anaemia
Have increased risk of hematologic malignancies, head and neck squamous cell carcinoma (HNSCC), gynecologic cancers, and other solid tumors.
The most frequent hematological malignancies are MDS and AML
The cumulative incidence of AML at 40 years is 15%-20%
The cumulative incidence of MDS at 50 years is 40%
Haematological Neoplasia with IBMFS - Diamond-Blackfan Anaemia
Associated with elevated risk of MDS, AML, colon cancer, osteosarcoma, and female genital cancers
Haematological Neoplasia with IBMFS - Severe Congenital Neutropenia
Cumulative incidence of MDS/AML is estimated at 11% at 20 years of age and at 22% after 15 years on G-CSF treatment
Although it is clearly demonstrated that G-CSF dramatically improved survival of SCN patients, it is also likely that G-CSF itself affects clonal evolution
Haematological Neoplasia with IBMFS - Schwachman-Diamond Syndrome
MDS and/or AML has been reported
Cumulative risk of MDS/leukaemia was 36% at 30 years of age
Aplastic Anaemia
Defined as pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate or marrow fibrosis
Diagnosis requires at least two of the following:
- [Hb] <100 g/l, [platelet] <50 x109/l, [neutrophil] <1.5x109/l
The majority of cases are idiopathic
Clonal Haematopoiesis
HSCs have the capacity for self-renewal for the lifetime of an individual, consequently mutations arising in HSCs will persist for the lifetime of that individual
If any of these mutations is capable of providing a selective advantage to the HSC in which it arises then clonal expansions results
Clonal Haematopoiesis of Indeterminate Potential (CHIP)
CHIP is defined by the presence of a neoplasm-associated somatic mutation in the blood or bone marrow of persons without a known hematologic neoplasm
Used to distinguish the presence of these mutations in non-malignant settings from malignant clonal haematopoiesis
The most common mutations in CHIP are:
- loss-of-function alleles in DNMT3A & TET2
- both encode enzymes involved in DNA methylation
These mutations are found nearly always in circulating granulocytes, monocytes, & NK cells
CHIP and Haematopoietic Neoplasia
CHIP predisposes to neoplasia
Commonly myeloid phenotype
Usually results from acquisition of a stronger driver mutation on a background CHIP clone
After stem cell transplantation donor CHIP can contribute to cytopenias, and may also result in donor-derived leukemia
Similarly, after autologous hematopoietic cell transplant clonal haematopoiesis is associated with adverse outcomes
Inherited Thrombocytopenias
These represent a group of inherited bone marrow disorders affecting platelet production
Typically:
- platelet concentration is decreased
- platelet size (volume) may be affected
- platelet function is often normal
Several inherited disorders that result in decreased [platelet] have been reported including:
- congenital amegakaryocytic thrombocytopenia
- thrombocytopenia with absent radii syndrome
- radioulnar synostosis with amegakaryocytic thrombocytopenia
- X-linked thrombocytopenia with dyserythropoiesis
Congenital Amegakaryocytic Thrombocytopenia
Characterised by severe thrombocytopenia and an almost complete absence of megakaryocytes in the bone marrow
Typically presents within the first month of life with bleeding disorder
The underlying defect causing CAMT is a mutation in the MPL gene causing abnormal expression or function of the thrombopoietin (TPO) receptor
Affected individuals have severe thrombocytopenia with median platelet levels of 20 × 10^9/L
A bone marrow that has normal cellularity but significantly reduced or absent megakaryocytes is suggestive of CAMT
Plasma TPO levels are uniformly elevated in CAMT patients
Thrombocytopenia with Absent Radii Syndrome (TAR)
Presents with thrombocytopenia in association with bilateral absent radii & frequently additional congenital abnormalities
TAR is related to an abnormal response of megakaryocytes to TPO
Caused by a microdeletion of 11 genes on chromosome 1q21.1
Diagnosis made by observing severe thrombocytopenia at birth, associated with bilateral radial aplasia and occasionally other skeletal abnormalities in the arms but not in the hands and fingers
Thrombocytopenia can fluctuate from 10-100 × 10^9/L
Accompanied by increased concentrations of plasma TPO
Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia
Patients present similarly to congenital amegakaryocytic thrombocytopenia, with early neonatal thrombocytopenia bleeding that eventually progresses to pancytopenia
Mutation in the homeobox gene HOXA11 has been implicated
X-linked Thrombocytopenia with Dyserythropoiesis
A group of X-linked disorders characterised by thrombocytopenia associated with RBC defects
Linked to mutations in the GATA1 gene located on Xp11–12
GATA1 encoding GATA-1 protein is an erythroid & megakaryocyte specific transcription factor required for the development of these two lines of haematopoietic cells
Clinically, patients typically have significant bleeding and bruising that can be spontaneous or after a haemostatic challenge
The bone marrow is typically hypercellular with dysplasia in both erythroid and myeloid lines
The diagnosis should be suspected when thrombocytopenia is accompanied by anaemia
How to Distinguish X-linked Thrombocytopenia with Dyserythropoiesis from Wiskott-Aldrich Syndrome
X-linked has normal-large sized platelets whereas Wiskott has small platelets
