1. BONE MARROW FAILURE SYNDROMES
H.A. MWAKYOMA, MD.

2. Hematopoiesis general
myeloid tissue in bone marrow
erythrocytes
platelets
granulocytes
monocytes
lymphoid tissue
thymus
lymph nodes
spleen

3. Development of Blood Cells
3 wk : formation of blood islands from yolk sac
6 wk : liver becomes hematopoietic organ
6-8 wk : spleen (until 8th month)
12-14wk : bone marrow (life-long)

4. Development of Blood Cells
3 wk : formation of blood islands from yolk sac
6 wk : liver becomes hematopoietic organ
6-8 wk :spleen (until 8th month)
12-14wk : bone marrow (life-long)
Bone Marrow
red marrow
yellow marrow

5. Hematopoiesis pluripotent stem cell trilineage myeloid stem cell
lymphoid stem cell
committed stem cells

6. Hematopoiesis
Proliferative potential
differentiation

7. Normal Marrow Composition
60%
20%
10%
unidentified or disintegrated cells
Erythroid precursors
Lymphocytes, monocytes
Granulocytes & precursors

8. Normal Marrow dominant myeloid cells Myelocytes Metamyelocytes
myeloid to erythroid ratio = 3 : 1
dominant myeloid cells
Myelocytes
Metamyelocytes
granulocytes
dominant erythroid cells
Polychromatophilic normoblasts
orthochromic normoblasts

9. Granulocyte maturation
stem cell: <0.1%
myeloblasts: ~2% promyelocytes: ~5%
myelocytes: %
metamyelocytes: ~22%
granular leukocytes

10. Lifespan of blood cells
RBC days
platelet 10 days
granulocytes circ : 9 hours
tissue : days
lymphocyte circ : variable (hours to years)
tissue : weeks to years

11. Hematopoietic Response
hypoxia
RBC
infection
granulocyte/monocyte
antigen
lymphocyte
hemorrhage
platelet

12. Hematopoietic Microenvironment
Stromal cells:
fibroblasts
endothelial cells
adipocytes
Growth Factors

13. GROWTH FACTORS
ERYTHROPOIESIS
GRANULOPOIESIS
MEGAERYTHROPOIESIS
LYMPHOPOIESIS
generation of each specific lineage of mature blood cells is regulated by a specific set of hematopoietic growth factors

14. Erythropoiesis erythropoietin-independent stage: marrow stromal cells
IL-3 (activated T-cells )
GM-CSF
SCF
hypoxia(liver, kidney)
erythropoietin-dependent stage:
erythropoietin
hypoxia(liver, kidney)

15. Granulopoiesis Neutropoiesis: Monopoiesis: Eosinopoiesis:
Basopoiesis,Mastpoiesis:early phase:
GM-CSF
SCF
IL-3

16. Megakaryopoiesis
may also play a role

17. Lymphopoiesis B-cells: T-cells: CD8 cells: initial stage: later stage:
final proliferation and Ab secretion:
T-cells:
CD8 cells:
CD4 cells:

18. Preview What does your bone marrow do? Why does it fail?
What can we do about it?
The Bone Marrow 
Your Blood Cell Factory
Blood is not forever

19. Blood Cell life spans : - RBC : 4 months - Platelet : 5 days
- WBC : 24 Hours   
Normally there is less than 5% variation in blood counts

20. The bone marrow works constantly to maintain balance
It’s all about supply and demand 
Demand is too high
Eg. bleeding                                   
Supply is too low
Bone marrow failure
- Aplastic Anemia
  - PNH(Paroxysmal nocturnal hemoglobinuria)
  - MDS (Myelodysplastic Syndromes)

21. DDx : Aplastic crisis Hereditary bone marrow failure
   DNA repair (Fanconi Anemia)
   Telomere (DC)
  Hypoplastic MDS
  PNH with aplasia
  Pancytopenia of other origin

22. BONE MARROW FAILURE SYNDROMES
Blood is continuously renewed
The Bone Marrow is the blood Factory May be exposed to damage or failure
Bone Marrow Failure
May involve one or more cell lines
Lymphocytes are usually spared

23. Pathophysiology of Bone marrow Failure
A decrease in or damage to the hematopoietic stem cells and their microenvironment, resulting in hypoplastic or aplastic bone marrow
Maturation defects, such as vitamin B-12 or folate deficiency
Differentiation defects, such as myelodysplasia.

24. BONE MARROW FAILURE SYNDROMES
Aplastic Anemia
Named so in 1904
The theoretical basis for marrow failure includes primary defects in or damage to the stem cell or the marrow microenvironment
A decrease in or damage to the hematopoietic stem cells and their microenvironment, resulting in hypoplastic or aplastic bone marrow
Distinction between congenital or acquired may be difficult
80 % of patients have acquired cause which is an autoimmune disease

25. APLASTIC ANEMIA (AA) Definition AA is characterized by
pancytopenia with
hypocellular marrow;
hematopoietic tissue replaced by fat cells,
in absence of abnormal infiltrate or increase in reticulin
Failure of the bone marrow percursors to produce mature cells.
Characterized by hypocellular marrow and pancytopenia

26. Causes of aplastic anemia (1)
Primary (idiopathic) 70-80%: immune-mediated disease
II. Secondary - drugs
1. Unpredictable (idiosyncratic reaction)
- antiepileptic drugs (hydantoins)
- oral antidiabetic agents (tolbutamide chlorpropamide)
- tranquillizers (chlorpromazine, chlordiazepoxide)
- antirheumatic drugs (gold, indomethacin,
phenylobutazone)
- antibacterial agents (sulfonamides, isoniazid, steptomycin, tetracyclines, chloramphenicol)
2. Unpredictable hypersensitivity (immune reaction)
- many drugs

27. Causes of aplastic anemia (2)
III. Associated diseases
1. viral hepatitis
2. CMV infection
3. EBV infection
4. Parvovirus B19
5. paroxysmal nocturnal hemoglobinuria
IV. Industrial and household chemicals:
benzene, some organicsolvents,trinitrotoluene,
certain insecticides (DDT, chlordane, lindane)

28. Causes of aplastic anemia (2)
Pure Red Cell Aplasia (PRCA)
May be caused by a thymoma.
It may occur transiently, resulting from a viral infection such as with parvovirus B19.
Pure red cell aplasia also may be permanent, as a result of viral hepatitis.
Finally, it may be the result of lymphoproliferative diseases (eg, lymphomas, chronic lymphocytic leukemia) or
collagen vascular diseases (eg, systemic lupus erythematosus, refractory anemia), or
it may occur during pregnancy

29. Causes of marrow aplasia
1. Ionizing radiation
2. Antineoplastic drugs:
- folic acid antagonists,
- alkylating agents,
- anthracyclines,
- nitrosoureas
- purine and pyrimidine analogous

30. PATHOGENESIS OF AA
Quantitative or qualitative abnormalities of pluripotent stem cell
Abnormal humoral or cellular control of hematopoiesis
Abnormal hematopoietic microenvironment
Immunologic suppression of hematopoiesis

31. Clinical Features Non-specific: Hematological findings:
Bruising, petechiae
Manifestations of anemia
Infections
Hematological findings:
Peripheral blood:
Pancytopenia: initially only 1 or 2 parameters.
WBC < 2.0, Hb < 10. Plat. < 100.
No gross morphological abnormalities.
Anemia is usually NCNC.
Reticulocytopenia.

32. Clinical Features Hematological findings: (Cont…) Bone Marrow:
Hypocellular:
<50% of normal cellularity Trephine biopsy is the most important for diagnosis.
Most of the cells present are lymphocytes, plasma cells and stromal cells.
Iron stores: increased

33. Diagnosis of aplastic anemia
1 Personal medical history; family history
2. Physical examination
3. Clinical symptoms:
- infections
- bleeding
- symptoms of anemia
4. Laboratory findings:
- anemia, neutropenia, thrombocytopenia
- bone marrow: hypocellular with fatty changes.

34. Criteria for diagnosis of AA (1)
Blood  peripheral smear : 
Pancytopenia and reticulocytopenia
1. Cytopenia - Hb <10g/dL
- ANC <1,5 G/L
- PL <100 G/L
Bone  marrow aspiration & biopsy :
Bone marrow histology and cytology
- decreased marrow cellularity (< 25%)
(Hypocellular / aplastic bone marrow with increased fat spaces)
- increased fat cells component
- no extensive fibrosis
- no malignancy or storage disease
Tests  for underlying cause ( viral titers)

35. Criteria for diagnosis of AA (2)
3. No preceding treatment with X-ray or antyproliferative drugs
4. No lymphadenopathy or hepatosplenomegaly
5. No deficiencies or metabolic diseases
6. No evidence of extramedullary hematopoiesis

36. Classification of aplastic anemia
1. Severe aplastic anemia is defined if at least two of the following criteria are present:
- ANC < 0.5 G/l
- PLT < 20 G/l
- RTC < 1% (20 G/l)
Hypoplastic bone marrow (less than 25%) on biopsy
2. Very severe aplastic anemia
- criteria as above but ANC < 0.2 G/l
3. Non-severe aplastic anemia.

37. Prognosis of SAA if supportive therapy are only applied
The overall mortality is 65-75% and the median survival 3 months

38. AA

39. AA

40. Management of severe aplastic anemia
1. Hematopoietic stem cell transplantation
2. Immunosuppressive treatment
- cyclosporine
- antilymphocyte/antityhymocyte globulin,
- methylprednisolone
- growth factors (G-CSF)
3. Androgens
4. Supportive therapy
5. Growth factors (GM-CSF, G-CSF, EPO)

41. Hematopoietic stem cell transplatation in severe aplastic anemia
1. Advantages
- correction of hematopoietic defect
- long-term survival: 80% - 90% (HLA-matched sibling donor)
- majority of the patients appear to be cured
2. Restrictions
- age below 40
- suitable donor available in less than 30% (sibling)
% risk of GVHD
- 5-15% risk of graft failure in multitransfused patients
- solid tumors (12%)

42. INHERIDETED BONE MARROW FAILURE SYNDRME

43. Inherited bone marrow failure syndromes
(IBMFS) are rare disorders in which there is usually some form of aplastic anemia (failure of the bone marrow to produce blood), associated with a family history of the same disorder.
Some of these conditions have typical changes in physical appearance or in laboratory findings which suggest a specific diagnosis.

44. Inherited bone marrow failure syndromes
There are several well-described syndromes, which can be recognized by health care experts.
There are also patients who are harder to classify, but who appear to belong in this category

45. IBMFS
Patients with these syndromes have a very high risk of development of cancer (either leukemia or certain solid tumors).
At the moment we cannot predict which specific patient with an IBMFS is going to develop cancer.

46. IBMFS What are the IBMFS disorders? Amegakaryocytic Thrombocytopenia
Diamond-Blackfan Anemia
Dyskeratosis Congenita
Fanconi Anemia
Pearson Syndrome
Severe Congenital Neutropenia
Shwachman-Diamond Syndrome
Thrombocytopenia Absent Radii
Other Bone Marrow Failure syndromes

47. Amegakaryocytic Thrombocytopenia (Amega)
These patients have bruising during the first year of life, due decreased production of platelets by the bone marrow (platelets are the cells which help the blood to clot).
The physical appearance is otherwise normal.
The gene for Amega has been identified. It is called MPL.
Males and females are affected equally.
What are the major findings on physical examination?
Bruises, bleeding,
– tiny spots of bleeding into the skin ("petechiae")
What is the age at diagnosis?
From birth to 9 years
The diagnosis is usually made by 1 month of age

48. Amega 3. What is the pattern of bone marrow failure?
The bone marrow problems typically start with a low platelet count.
Patients may eventually develop aplastic anemia when all 3 types of cells (red cells, white cells and platelets) are abnormally low because the bone marrow is not producing them.
4. What specific kinds of cancer develop?
Leukemia (cancer of the blood and bone marrow

49. Amega 5. How is Amega specifically diagnosed?
Characteristic medical history
Mutation analysis (genetic testing)
Laboratories can now identify the genetic "error" (mutation) in some patients, which occurs in the gene called MPL.
The disease occurs only if a person has two abnormal (mutant) genes.
The inheritance is therefore thought to be of the autosomal recessive type

50. Diamond-Blackfan Anemia (DBA)
DBA patients have primarily low red cell counts (anemia).
The rest of their blood cells (the platelets and the white cells) are usually normal.
~25% of DBA patients have physical abnormalities, often involving malformations of the thumbs.
Most patients are diagnosed within the first year of life.
Detecting a mutation in a known DBA gene confirms the diagnosis.

51. (DBA
However, failure to find a mutation in a DBA gene does not eliminate the diagnosis of DBA.
This is because the genes which have been identified so far explain less than half of the disease occurrences.
Currently, DBA is diagnosed by clinical findings after exclusion of other known causes of pure red cell anemia.
Males and females are affected equally

52. DBA 1. What are the major findings on physical examination?
Short stature
Abnormal thumbs
2. What is the age at diagnosis?
Anytime from birth to 60 years of age.
90% are less than 1 year old when the diagnosis is made.
3. What is the pattern of bone marrow failure?
Pure anemia (low red blood cell count, often with large red cells)
Normal platelet count usually (Platelets are the cells in the blood which help the blood to clot)
Normal white cells usually (White cells help the body fight off infection)

53. DBA 4. What specific kinds of cancer develop?
Leukemia (cancer of the blood and bone marrow)
Sarcomas (cancer arising in bone, fat, cartilage, tendons or connective tissue)
5. How is DBA specifically diagnosed?
Patients with DBA usually have an increase in a specific red cell enzyme called adenosine deaminase (ADA).
Mutation analysis (genetic testing)
Laboratories can now identify the genetic "error" (or mutation) in some patients.
There are now 9 different genes responsible for DBA: RPS19, RPS26, RPS10, RPS24, RPS17, RPS7, RPL5, RPL11, RPL35a; about 50% of patients do not have mutations in the known genes, and more genes await discovery.
The disease is inherited in an autosomal dominant fashion.
This means that illness may occur if a person has only one copy of the abnormal (mutant) gene

54. Dyskeratosis Congenita (DC)
DC patients have characteristic
abnormal shapes to fingernails and toenails,
a lacy rash on the face and chest, and
More than half of the patients are males.
About half of DC patients develop bone marrow failure.
Onset may be in early childhood, but diagnoses are often made later, because the findings on physical examination become more obvious with age and the complications increase with age.
Several genes have now been identified as causing DC, but there are more still to be discovered.

55. DC 1. What are the major findings on physical examination?
Abnormal fingernails and toenails (dyskeratosis)
Lacy rash on the face, neck, and chest
White patches in the mouth (leukoplakia)
2. What is the age at diagnosis?
From birth to 60 years of age or older
The diagnosis is usually made between the ages of 10 to 30 years.

56. DC 3. What is the pattern of bone marrow failure?
Aplastic anemia is diagnosed when all 3 types of cells (red cells, white cells and platelets) are abnormally low because the bone marrow is not producing them.
Anemia (low red blood cell count) may develop (often with large red cells).
Low platelet count (platelets are the cells which help the blood to clot)
Low white cell count (white cells help the body fight off infection)

57. DC 4. What specific kinds of cancer develop? Solid organ cancer
Tongue, mouth and throat cancer ("head and neck")
Cancer of the esophagus, stomach, colon, and rectum ("gastrointestinal")
Perhaps others (all of the types of solid cancers associated with DC have not been completely identified)
Leukemia (cancer of the blood and bone marrow)

58. DC 5. How is DC specifically diagnosed?
Characteristic findings on physical examination
Telomere length testing (repeated sections of DNA at the ends of chromosomes are short in patients with DC).
Mutation analysis (genetic testing)
Laboratories can now identify the genetic "error" (mutation) in some patients.
The type of DC that is inherited only by males (X-linked inheritance) is usually due to mutations in the gene called DKC1.

59. Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH), sometimes referred to as Marchiafava-Micheli syndrome, is a rare, acquired, potentially life-threatening disease of the blood characterised by
complement-induced intravascular hemolytic anemia (anemia due to destruction of red blood cells in the bloodstream),
red urine – haematuria (due to the appearance of hemoglobin in the urine) and
thrombosis.

60. PNH
PNH is the only hemolytic anemia caused by an acquired (rather than inherited) intrinsic defect in the cell membrane (deficiency of glycophosphatidylinositol leading to absence of protective proteins on the membrane.
It may develop on its own ("primary PNH") or in the context of other bone marrow disorders such as aplastic anemia ("secondary PNH").
Only a minority have the telltale red urine in the morning.

61. Pathophysiology - PNH
All cells have proteins attached to their membranes that are responsible for performing a vast array of functions.
There are several ways for proteins to be attached to a cell membrane.
PNH occurs as a result of a defect in one of these mechanisms

62. Pathophysiology- PNH
The enzyme phosphatidylinositol glycan A (PIGA) is needed to make glycosylphosphatidylinositol (GPI), a molecule that anchors proteins to the cell membrane.
The gene that codes for PIGA is located on the X chromosome, which means that only one active copy of the gene for PIGA is present in each cell (initially, females have two copies, but one is silenced through X-inactivation)

63. Pathophysiology PNH -
If a mutation occurs in this gene then PIGA may be defective, which leads to a defect in the GPI anchor.
When this mutation occurs in a bone marrow stem cell (which are used to make red blood cells as well as white blood cells and platelets), all of the cells it produces will also have the defect.[

64. Pathophysiology- PNH
Several of the proteins that anchor to GPI on the cell membrane are used to protect the cell from destruction by the complement system, and, without these anchors, the cells are more easily targeted by the complement proteins

65. Pathophysiology- PNH
The complement system is part of the immune system and helps to destroy invading microorganisms.
Without the proteins that protect them from complement, red blood cells are destroyed.
The main proteins that carry out this function are decay-accelerating factor (DAF) (CD55), which disrupts formation of C3 convertase, and protectin (CD59), which binds the membrane attack complex and prevents C9 from binding to the cell.

66. Pathophysiology -PNH
The increased destruction of red blood cells results in anemia.
The increased rate of thrombosis is due to dysfunction of platelets due to binding by complement, or possibly due to low nitric oxide levels

67. Pathophysiology- PNH
The symptoms of esophageal spasm, erectile dysfunction, and abdominal pain are attributed to the fact that hemoglobin released during hemolysis binds with circulating nitric oxide, a substance that is needed to relax smooth muscle.
This theory is supported by the fact that these symptoms improve on administration of nitrates or sildenafil (Viagra), which improves the effect of nitric oxide on muscle cells

68. Pathophysiology- PNH
There is a suspicion that chronic hemolysis causing chronically depleted nitric oxide may lead to the development of pulmonary hypertension (increased pressure in the blood vessels supplying the lung), which in turn puts strain on the heart and causes heart failure

69. Signs and symptoms
Most people with "primary PNH" have red urine at some point in their disease course.
Many of them continue to have low-grade breakdown of red blood cells, leading to anemia.
Typical symptoms of anemia are tiredness, shortness of breath, and palpitations.
On laboratory examination of the urine, breakdown products of red blood cells (hemoglobin and hemosiderin) may be identified

70. Signs and symptoms A small proportion of patients report
abdominal pain,
dysphagia (difficulty swallowing) and
odynophagia (pain during swallowing),
as well as erectile dysfunction in men - this occurs mainly when the breakdown of red blood cells is rapid.

71. Signs and symptoms
40% of patients develop thrombosis (a blood clot) at some point in their illness.
This is the main cause of severe complications and death in PNH.
These may develop in common sites (deep vein thrombosis of the leg veins and resultant pulmonary embolism when these clots break off and enter the lungs),

72. Signs and symptoms
but, in PNH, blood clots may also form in more unusual sites:
the hepatic vein (causing Budd-Chiari syndrome),
the portal vein of the liver (causing portal vein thrombosis),
the superior or inferior mesenteric vein (causing mesenteric ischemia),
and veins of the skin.
Cerebral venous thrombosis, an uncommon form of stroke, is more common in PNH

73. Diagnosis
Blood tests in PNH show changes consistent with intravascular hemolytic anemia:
low hemoglobin,
raised lactate dehydrogenase,
raised reticulocytes (immature red cells released by the bone marrow to replace the destroyed cells),
raised bilirubin (a breakdown product of hemoglobin), and
decreased levels of haptoglobin.

74. Diagnosis
The direct antiglobulin test (DAT, or direct Coombs' test) is negative, as the hemolysis of PNH is not caused by antibodies

75. Diagnosis
Today, many labs use flow cytometry for CD55 and CD59 on white and red blood cells.
Based on the levels of these cell proteins, erythrocytes may be classified as type I, II, or III PNH cells.
Type I cells have normal levels of CD55 and CD59;
type II have reduced levels; and
type III have absent levels.

76. Diagnosis
The fluorescein-labeled proaerolysin (FLAER) test is being used more frequently to diagnose PNH.
FLAER binds selectively to the glycophosphatidylinositol anchor and is more accurate in demonstrating a deficit than flow cytometry for CD59 or CD55.

77. Myelodysplastic Syndromes ( MDS )
Definition: Myelo = marrow in Greek
Dys = irregular in Greek
Plasia = proliferation in Greek
MDS is a heterogenous stem cell disease with
a very active and abnormal proliferation of hematopoiesis in the bone marrow with
asynchronous and delayed maturation of the different cell lines and
early apoptosis ( cell death ) leading to
ineffective hematopoiesis and peripheral blood (PB) cytopenia

78. MDS What is MDS? Ineffective Hematopoiesis
Reduction of peripheral blood counts
Normal or increased bone marrow cellularity
“Dysplasia”
Propensity to evolve into AML

79. MDS Lack of Skilled Workers Too much quality control!
Bone marrow is working hard
Most blood cells are defective
   - not exported to the blood

80. MDS 50 ~ 100 per million per year
Causes: radiation, chemotherapy, organic solvents
- usually cause is unknown
Blood cells develop abnormally
prevented from entering blood by overly vigilant quality control

81. Myelodysplasia (MDS) Patho-physiology
1. Since the stem cell is diseased any or all of the erythroid, myeloid or megakaryocytic cell lines may be affected.
2. An acquired somatic mutation of the stem cell CD 34 may cause one or several cytogenetic anomalies, influencing to a great extent the clinical evolution of the disease.
3. In addition to peripheral cytopenia, there is also shortened survival of the affected cells as well as qualitative deficiencies of these cells:
e.g. defic. Chemotaxis of granuloc., bleeding, etc

82. Myelodysplasia (MDS) Nucleo – Cytoplasmic asynchrony
Hemoglobinized orthochromic
erythroblast with still immature
Nucleus with visible
Chromosomes ready to
Divide.
Giant metamyelocyte
Immature nucleus,loose
Chromatin.
Alk. PO4-ase granules
Peroxidase granules

83. Myelodysplastic bone marrow – Patient No.1

84. Myelodysplasia : Bone marrow hemosiderin with ringed sideroblasts

85. Myelodysplasia (MDS): Pt. No 2

86. MDS : Clinical and lab. characteristics
Early on asymptomatic and incidentally discovered as anemia or multilineage cytopenia.
Anemia symptoms: fatigue, dyspnea, palpitations, dizziness, angina, CHF, slowing of mental processes.
Leuco-Neutropenia: also impaired chemotaxis, phagocytosis, bactericidal activity, often skin inf.
Thrombocytopenias and impaired hemostasis.
Paraneoplastic autoimmune manifestations: vasculitis, arthritis, edema, pulm. Infiltrates, pleural and peric. Effusions, iritis, myositis, skin ulcers , chloromas, neuropathies,
Acquired Pure Red Cell Aplasia

87. MDS – Laboratory characteristics
Normo – or – macrocytic anemia, aniso-poikilocytosis.
Normal B12, folate.
Leuco-erythroblastosis may be present, when MDS advanced.
Basophilic stippling, Howell-Jolly bodies, giant bands and hypogranular granuloc., Pelger-Huett anomaly, hypersegmentation.
BM – hypercell., megaloblastoid = nucleo-cytoplasmic asynchrony, micro- and- very polyploid megakaryocytes.
PNH – like defects in RBC-s ( CD55 and CD59 )-high complement sensitivity.

88. MDS – Lab. Characteristics continued
Lymphopenia, esp. CD 4 after many transf., elev. CD 8
Hypo-or – hypergammaglob.
Lympho-plasmacytic neoplasms may coexist or follow.
Immuno-cytochemistry: Myeloperoxidase in myeloid cells.
Alpha Naphtyl Esterase in Monocytes,
CD 13, CD 14, CD33 - in myeloid precursors
Antibodies to F.VIII & v.W.F in Megakaryocytes

89. MDS – Necessary diagnostic criteria
1. Persistent, unexplained cytopenia with the known morphologic anomalies.
2. Older adults with normo- or – macrocytic anemia without B12, folate deficiency.
3. Hyper ( rarely hypo ) cellular BM with megaloblastoid and asynchronous maturation features. Ineffective hematopoiesis.
4. Cytogenetic anomalies in 40-60% of pts.: 5q -; 7 – etc.
5. Blast count: Myeloblasts or monocytes over 1,000 / ul., CD34 is proof of blast, but not all blasts are CD 34 +.

90. Myelodysplasia (MDS) Etiopathogenesis.
1. Genetic somatic mutations and abnormal DNA repair, more frequent as age advances,
2. Heritable predisposition:
Fanconi’s Pancytopenia,
Congenital Neutropenia ( Schwachman-Diamond )
Down Syndrome ( trisomy 21 )
Familial Monosomy 7 (7 - )
Trisomy 8 Mosaicism ( 8 + )
Neurofibromatosis. etc

91. Myelodysplasia (MDS) Etiopathogenesis (cont.)
3. Acquired:
Vit. B12 and /or folate deficiency, +/- chr. Liver dis.
Chemotherapy : Alkylators – mutagenic, antimetabolites e.g. – Methotrexate, Purine – 6MP or Pyrimidine DNA intercalators
Radiation – therapeutic or nuclear ( Chernobyl 1986 )
Benzene and its derivatives,
Bone Marrow conditioning and transplantation,
Paroxysmal Nocturnal Hemoglobinuria (PNH) with clonal expansion of cells hypersensitive to Complement

92. Myelodysplasia – Summary and Conclusions
1. MDS are quite frequent in aging populations, but are occas. present in young persons and children.
2. Since MDS involves the pluripotential stem cell, any or all hematopoietic progenitors may be affected.
3. MDS in elderly is often accompanied by comorbidities, thus detracting our attention from symptoms and signs of MDS – cause of anemia, bleeding tendency, recurrent infections.

93. Thank You

94. Thank You For Your Attention!