Bone marrow failure syndromes (Approach to Cytopenias)- Goorha

Question 1

What is aplastic anemia?

Answer 1

refers to a syndrome of chronic primary hematopoietic failure and attendant pancytopenia (anemia, neutropenia, thrombocytopenia)

Question 2

What usually causes aplastic anemia?

Answer 2

Exposure to chemicals and drugs. Causes dose related bone marrow suppression and is reversible.

Question 3

Describe the two major etiologies of aplastic anemia.

Answer 3

1) An extrinsic, immune-mediated suppression of marrow progenitors.
2) An intrinsic abnormality of stem cells.

Question 4

Expound on the extrinsic mechanism that causes aplastic anemia. What are the molecular steps that cause aplasia?

Answer 4

1) Start with a stem cell.
2) Add an environmental insult (viruses, drugs, etc) that genetically alters the stem cell.
3) Now the stem cell can go one of two ways:
a) it can express new antigens that trigger its destruction by TH1 cells (via IFN-g, TNF)
OR
b) it can have reduced proliferation and differentiative capacity that results in apoptosis.
4) BOOM marrow aplasia!

Question 5

Looking at a bone marrow biopsy of aplastic anemia, what would you expect to see under the scope?

Answer 5

lost of adipocytes and bony spicules, severely reduced density of hematopoietic cells. Marrow aspirates often yield little material (a “dry tap”)

Question 6

Describe typical clinical manifestations of aplastic anemia.

Answer 6

progressive weakness, pallor, and dyspnea; thrombocytopenia is heralded by petechiae and ecchymoses; and neutropenia manifests as frequent and persistent minor infections or the sudden onset of chills, fever, and prostration.

Question 7

Does the present of splenomegaly favor a Dx of aplastic anemia?

Answer 7

No.

Question 8

What do the red cells look like in aplastic anemia?

Answer 8

slightly macrocytic and normochromic. Reticulocytopenia is the rule (reduced reticulocytes).

Question 9

What does the Dx of aplastic anemia rest on?

Answer 9

Bone marrow biopsy examination.

Question 10

In a bone marrow biopsy, what distinguishes aplastic anemia from a leukemia or myelodysplastic syndrome?

Answer 10

anemia: marrow is markedly hypocellular

neoplasia/dysplasia: hypercellular marrows filled with neoplastic progenitors (immature clones)

Question 11

What are the best treatments for aplastic anemia?

Answer 11

• Bone marrow biopsy if donor available. (5yr survival 75%)

- Immunosuppressive therapy for older pts and those without a suitable donor. (good response)

Question 12

What is pure red cell aplasia?

Answer 12

a primary marrow disorder in which only erythroid progenitors are suppressed. In severe cases, red cell progenitors are completely absent from the marrow.

Question 13

What causes most pure red cell aplasias?

Answer 13

With the exception of those with parvovirus infection, it is likely that most cases have an autoimmune basis.

Question 14

What are some good treatments for pure red cell aplasia?

Answer 14

• immunosuppressive therapy
• plasmapheresis may also be helpful in unusual pts with pathogenic autoAbs, such as neutralizing Abs to EPO that appear de novo or following the admin of recombinant EPO.

Question 15

T/F: The mechanisms that cause pancytopenia are bone marrow failure and destruction of blood cells in the peripheral blood.

Answer 15

True

Question 16

Pancytopenia is the reduction in blood cells of these three types:

Answer 16

RBCs (anemia), WBCs (leukopenia), platelets (thrombocytopenia)

Question 17

What is in your immediate differential Dx for pancytopenia?

Answer 17

1) increased destruction due to immune destruction, sepsis, hypersplenism
2) decreased production due to myelodysplasia, marrow infiltrate, B12 dificiency, aplastic anemia, drugs, viruses, radiation

Question 18

What do we do to determine what the cause of bone marrow failure is?

Answer 18

Bone marrow biopsy. Look to see if it is hyper or hypocellular.

Question 19

What could cause hypercellular marrow?

Answer 19

-Bone marrow infiltration by:
         hematologic malignancy, carcinoma.
-Storage disorders
-Myelodysplastic syndromes
-B12 or folate deficiency

Question 20

What could cause hypocellular marrow?

Answer 20

aplastic anemia
Congenital cond’s: Fanconi anemia
Acquired: idiopathic, MDS, drugs/chems/radiation, viruses

Question 21

What is the severe, life threatening syndrome in which production of erythrocytes, WBCs, and platelets has failed?

Answer 21

aplastic anemia

Question 22

In aplastic anemia, you would see hyper or hypocellular bone marrow?

Answer 22

Hypocellular. Lots of white space filled with fat cells.

Question 23

What is a primary mechanism of idiopathic aplastic anemia?
Infiltration of bone marrow by abnormal protein
Immune mediated destruction of hematopoietic stem cells
Immune mediated destruction of peripheral blood cells
Vitamin deficiency

Answer 23

Immune mediated destruction of hematopoietic stem cells

Question 24

Describe Fanconi’s anemia.

Answer 24

Chromosomal defect. Disorder usually becomes symptomatic @ ~ 5yo and is associated with progressive bone marrow hypoplasia. Congenital defects such as skin hyperpigmentation and small stature are also seen in affected individuals.

Question 25

List a few viruses known as causative agents of aplastic anemia.

Answer 25

Infectious mononucleosis (EBV), infectious hepatitis, parvovirus, and CMV. Also bacterial: miliary TB occasionally leads to aplastic anemia.

Question 26

Describe the lab microscopic findings in aplastic anemia.

Answer 26

Severe pancytopenia with **relative lymohocytosis (lymphocytes live a long time)
Decreased reticulocyte count
Hypocellular bone marrow with >70% yellow marrow

Question 27

What is/are treatment option(s) for aplastic anemia and why?
A) Immune suppression
B) Stem cell transpant
C) Transfusion
D) All of the above

Answer 27

All of the above.
First, withdraw all potentially offending agents such as drugs.
Supportive care includes transfusion, antibiotics.
PRIMARY TREATMENT: Immunosuppressive regimens such as anti-thymocyte globulin, cyclosporine, steroids are often effective at improving counts (this observation suggests that autoimmune destruction of hematopoietic stem cells is a primary cause of acquired idiopathic aplastic anemia.
Hematopoietic cell transplantation

Question 28

What is the primary difference between MDS and aplastic anemia?

Answer 28

presence or absence of neoplastic cells in the bone marrow.

In MDS, the presence of neoplastic cells is what defines it.

Question 29

T/F: MDS are promary, neoplastic stem cell disorders that tend to terminate in acute leukemia.

Answer 29

True

Question 30

In MDS, the bone marrow is usually hypo/hyper/normocellular with evidence of qualitative abnormalities in one or more cell lines resulting in ineffective erythropoiesis and/or granulopoiesis and/or megakaryopoiesis.

Answer 30

normocullular or hypercellular

Question 31

In MDS, the peripheral smear shown dusplastic cells including:

Answer 31

nucleatic RBCs, oval macrocytes, pseudo-Pelger-Huet PMNs with hyperchromatin clumping, hypogranulated neutrophils, and giant bizarre platelets.

Question 32

What is the bone marrow appearance in MDS under the scope?

Answer 32

presence of ringed sideroblasts and other dysplastic changes

Question 33

ringed sideroblasts are a hallmark of this condition:

Answer 33

MDS

Question 34

MDS that progresses to >20% blasts is called:

Answer 34

AML

Question 35

MDS pts who go untreated will develop:

Answer 35

AML

Question 36

How do we treat MDS pts?

Answer 36

Supportive care with blood product support and hematopoietic growth factors (eg. EPO) is the mainstay of therapy
Chemotherapy with the hypomethyating agents 5-azacytidine and decitabine has been shown to decrease blood transfusion requirements and to retard the progression of MDS to AML and increase survival.
Lenalidomide was approved only for use in the 5q- syndrome (subtype of MDS)
Hematopoietic stem cell transplantation, particularly in younger pts (<60yo), more severely affected pts, offers the potential for curative therapy.

Question 37

What is autologous stem cell transplantation?

Answer 37

Take stem cells from a pt about to undergo therapy that may wipe-out their hematopoietic cells.
Freeze it until needed.
Re-infuse cells to pt to restore hematopoietic stem cell populations post-therapy. Used mainly in the treatment of lymphomas and multiple myeloma.

Question 38

In allogenic stem cell transplantation, matching of HLA types is performed on the basis of variability at 3 or more loci of the HLA gene, and a perfect match at these loci is preferred to prevent:

Answer 38

Graft versus host disease (GVHD)

Question 39

If allogenic transplantation presents the problem of GVHD, in what ways is it advantageous over autologous stem cell transplantation?

Answer 39

Can be used when recipient’s bone marrow fails such as if they have aplastic anemia or MDS.
When recipient has certain disease such as leukemia adn lymphoma, the donor cells can attack these tumor cells via GVHD to prevent relapse of the tumor.

Question 40

What are hypomethylating chemotherapy agents?

Answer 40

agents that inhibit DNA methylation

Question 41

What is the Pelger-Huet anomaly?

Answer 41

Neutrophils have fewer (2) than the normal (3-4) number of nuclear segments. Granules are also absent.
Hint towards MDS.

Question 42

Two cell types associated with MDS?

Answer 42

Pelger-Huet

Ringed Sideroblasts