Importent

1. APLAST ANEMIA
Dr Mohammad Yaqoob Bahar, MD, PGY2 Internal Medicine

2. ANEMIA
• Anemia:
• Hb <13.6 g/dL in males
• Hb <12 g/dL in females
• Or
• Hematocrit below 41% in males
• Hematocrit below 36% in females
• Hematocrit levels are less useful than hemoglobin levels in
assessing anemia because they are calculated rather than
measured directly

3. APPROACH TO ANEMIA
• Hemoglobin
• Hematocrit
• red cell indices:
• MCV: mean cell volume in femtoliters
• MCH: mean cell hemoglobin in picograms per cell
• MCHC: mean concentration of hemoglobin per volume
of red cells in grams per liter

4. • Reticulocyte count
• Peripheral Blood Smear
• Bone marrow biopsy

7. CLASSIFICATION OF ANEMIA
1. Marrow production defects (hypoproliferation)
1. low reticulocyte production index together
2. little or no change in red cell morphology (a normocytic,
normochromic anemia)
2. red cell maturation defects (ineffective erythropoiesis)
1. slight to moderately elevated reticulocyte production index
2. either macrocytic
3. Or microcytic
3. decreased red cell survival (blood loss/hemolysis).

8. RPI<2.5%
RPI<2.5% RPI > 2.5%
RPI < 2.5%
RPI: Reticulocyte
production index
1. Blood loss
2. Intravascular
hemolysis

10. • Definiation
• Epidemiology and Etiology
• Pathophysiology
• Clinical features
• Diagnosis and Lab Exam
• Differential Diagnosis
• Treatment

11. DEFINIATION
•Pancytopenia with hypocelluar bone marrow
•Men = women
•age distribution is biphasic
•the major peak in the teens and twenties
•a second rise in older adults

12. ETIOLOGY
• Most cases: Idiopathic
• Radiation
• Chemmicals
• Drugs
• Infections
• Immunologic diseases
• Hepatitis
• Pregnancy
• PNH
• Constitutional Syndromes
(mostly Genetic)

13. RADIATION
• Marrow aplasia
• DNA damage
• Nuclear accidents
• employees of hospitals, laboratories, and industry (food
sterilization, metal radiography, etc.),
• Innocents exposed to stolen, misplaced, or misused
sources

14. DRUGS AND CHEMMICALS
• Toxins:
• benzene,
• Toluene
• insecticides
• Medications:
• Chloramphenicol
• gold salts
• Sulfonamides
• Phenytoin
• Carbamazepine
• Quinacrine
• Tolbutamide
• Heavy metals
• Cholorquine
• CA inhibitors (acetazolamide)
• D- Pencillamines

15. INFECTIONS
•Rarely follow infectious mononucleosis (EBV
virus)
•Parvo virus
•CMV
•Echo virus
•…

16. IMMUNOLOGIC
•SLE: Pancytopenia with hypocellular bone marrow
•transfusion-associated graft-versus-host disease
(GVHD)
•Thymoma
•Idiopathic

17. HEPATITIS
• Post-hepatitis marrow failure accounts for ∼5% of etiologies in
most series
• Patients are usually young men who have recovered
from a bout of liver inflammation 1–2 months earlier
• the subsequent pancytopenia is very severe
• The hepatitis is seronegative (non-A, nonB, non-C)
• immune-mediated

18. PAROXYSMAL NOCTURNAL
HEMOGLOBINURIA
• Mutation of PIG-A gene mutation in hematopoietic stem cells
• Coombs ⊝ hemolytic anemia, pancytopenia, venous thrombosis
(eg, BuddChiari syndrome)
• episodic hemoglobinuria resulting in reddish-brown urine
• flow cytometry tests demonstrates deficiencies of CD55 and CD59
• Eculizumab is a humanized monoclonal antibody against
complement protein C5 given every 2 weeks

19. CONGENITAL
• Fanconi anemia
• congenital developmental anomalies
• progressive pancytopenia
• an increased risk of malignancy
• short stature, café au lait spots
• anomalies involving the thumb, radius, and
genitourinary tract
• DNA Repairs defects
• 17 different genetic defects

21. CONGENITAL
• Diamond Blackfon and Shwachman-Diamond syndrome
• are ribosomopathies
• early in life with neutropenia, pancreatic insufficiency,
and malabsorption
• Telemeopathies: defects in telomere length maintenance
• Dyskeratosis congenitalis

22. PATHOPHYSIOLOGY
Suppersion or injury to
hematopoeitc stem cell
Hypoplastic bone marrow
Fails to produce mature
blood cells
pancytopenia

23. • Direct hematopoietic stem cell injury: radiation, chemotherapy,
toxins, or pharmacologic agents.
• SLE: suppression of the hematopoietic stem cell by an IgG
autoantibody
• The most common pathogenesis of aplastic anemia appears to be
autoimmune suppression of hematopoiesis by a T-cell-mediated
cellular mechanism, so-called idiopathic aplastic anemia.

24. PATHOPHYSIOLOGY CONT…
• defects in maintenance of the hematopoietic stem cell telomere
length (eg, dyskeratosis congenita) or in DNA repair pathways (eg,
Fanconi anemia) have been identified and are likely linked to both
the initiation of bone marrow failure and the propensity to later
progress to myelodysplasia, PNH, or AML.
• Complex detrimental immune responses to viruses can also cause
aplastic anemia

25. SYMPTOMS
• can appear abruptly or insidiously
• Bleeding is the most common early symptom;
• a complaint of days to weeks of easy bruising, oozing from the
gums, nose bleeds, heavy menstrual flow, and sometimes
petechiae will have been noticed.
• With thrombocytopenia, massive hemorrhage is unusual, but
small amounts of bleeding in the central nervous system can
result in catastrophic intracranial or retinal hemorrhage

26. • Symptoms of anemia: frequent, including lassitude, weakness,
shortness of breath, and a pounding sensation in the ears.
• Infection is an unusual first symptom in aplastic anemia (unlike in
agranulocytosis, where pharyngitis, anorectal infection, or frank
sepsis occurs early
• Systemic complaints and weight loss should point to other
etiologies of pancytopenia
• Prior medical drug use, chemical exposure, and preceding viral
illnesses must often be elicited with directed questioning

27. PHYSICAL EXAM
• Petechiae and ecchymoses are typical,retinal
hemorrhages may be present.
• Pallor of the skin and mucous membranes is common.
• Infection on presentation is unusual but may occur if the
patient has been symptomatic for a few weeks.
• Lymphadenopathy and splenomegaly are highly atypical
of aplastic anemia.

29. • Café au lait spots and short stature suggest Fanconi
anemia;
• peculiar nails and leukoplakia suggest dyskeratosis
congenita;
• early graying (and use of hair dyes to mask it!) suggests a
telomerase defect

30. •hepatosplenomegaly, lymphadenopathy, or
bone tenderness should not be present, and
their presence should lead to questioning
the diagnosis

31. LAB FINDINGS
• Hallmark is pancytopenia (but at first only one on 2 cell lines may
be reduced)
• Anemia may be severe
• always associated with reticulocytopenia
• Red blood cell morphology is unremarkable (Normocytic) , but
there may be mild macrocytosis (increased MCV)
• Neutrophils and platelets are reduced in number, and no
immature or abnormal forms are seen on the blood smear

32. LAB FINDINGS
• presence of immature myeloid forms suggests leukemia
or MDS;
• nucleated red blood cells (RBCs) suggest marrow fibrosis
or tumor invasion;
• abnormal platelets suggest either peripheral destruction
or MDS

33. BONE MARROW BIOPSY
• bone marrow aspirate and the bone marrow biopsy appear
hypocellular
• biopsy (which should be >1 cm in length) is superior for
determination of cellularity and shows mainly fat under the
microscope,
• with hematopoietic cells occupying <25% of the marrow space
• Residual hematopoietic cells should have normal morphology

34. NORMAL VS APLASTIC ANEMIA
BONE MARROW

36. DIFFERENTIAL DIAGNOSIS
• Aplastic anemia must be differentiated from other causes of pancytopenia

37. DIFFERENTIAL DIAGNOSIS
• Hypocellular forms of myelodysplasia or acute leukemia:
• presence of cellular morphologic abnormalities
• increased percentage of blasts
• abnormal karyotype in bone marrow cells typical of MDS or acute
leukemia.
• Hairy cell leukemia has been misdiagnosed as aplastic anemia:
• presence of splenomegaly
• abnormal “hairy” lymphoid cells in a hypocellular bone marrow biopsy.

38. DIFFERENTIAL DIAGNOSIS
• Pancytopenia with a normocellular bone marrow may be
due to systemic lupus erythematosus, disseminated
infection, hypersplenism, nutritional (eg, vitamin B12 or
folate) deficiency, or myelodysplasia.
• Isolated thrombocytopenia may occur early as aplastic
anemia develops and may be confused with immune
thrombocytopenia

39. SEVERE APLASTIC ANEMIA
•presence of two of three parameters:
•absolute neutrophil count <500/μL,
•platelet count <20,000/μL
•corrected reticulocyte count <1% (or absolute
reticulocyte count <60,000/μL)

40. TREATMENT
• stem cell transplant
• Immunosuppression:allow recovery of the patient’s
residual bone marrow function
• Glucocorticoids are not of value as primary therapy
• Suspect exposures to drugs or chemicals should be
discontinued

41. STEM CELL TRANSPLANT
• first choice for the younger patient with a fully histocompatible sibling donor
• may also benefit from allogeneic bone marrow transplantation using an
unrelated donor
• In transplant candidates, transfusion of blood from family members should
be avoided so as to prevent sensitization to histocompatibility antigens
• allogeneic transplant from fully matched siblings, long-term survival rates for
children are ∼90%.
• Transplant morbidity and mortality are increased among adults, due to the
higher risk of chronic GVHD and infections

42. IMMUNOSUPPRESION
• adults over age 40 years
• those without HLA matched hematopoietic stem cell donors
• Anti-thymocyte Globulin (ATG) plus cyclosporine
• equine ATG 40 mg/kg/day intravenously for 4 days in
combination with cyclosporine, 6 mg/kg orally twice daily
• Equine ATG is superior to rabbit ATG, resulting in a higher
response rate and better survival

43. IMMUNOSUPPRESION
• ATG should be used in combination with corticosteroids (prednisone or
methylprednisolone 1–2 mg/kg/day orally for 1 week, followed by a taper
over 2 weeks) to avoid ATG infusion reactions and serum sickness
• Responses usually occur in 1–3 months and are usually only partial,
but the blood counts rise high enough to give patients a safe
and transfusion-free life.
• The full benefit of immunosuppression is generally assessed at 4 months
post-equine ATG.
• Cyclosporine and eltrombopag are maintained at full doses for 6 months and
then stopped in responding patients

44. IMMUNOSUPPRESION
• Relapse (recurrent pancytopenia) is frequent, often occurring as
cyclosporine is tapered or discontinued
• Overall survival is equivalent with transplantation and
immunosuppression
• older patients do better with immunoauppresion (ATG and
cyclosporine) whereas transplant is preferred in children and if
neutropenia is profound

45. ELTROMBOPAG
• Hematopoietic growth factors (HGFs) such as erythropoietin
(EPO) and granulocyte colony-stimulating factor (G-CSF) are not
effective in aplastic anemia
• Endogenous levels are high
• Eltrombopag (a thrombopoietin mimetic) is now being added to
ATG plus cyclosporine with tri-lineage hematologic responses as
high as 90%

46. ANDROGENS
• Androgens (such as fluoxymesterone 10–20 mg/day orally
in divided doses or danazol 200 mg orally twice daily)
have been widely used in the past, with a low response
rate, and may be considered in mild cases

47. SUPPORTIVE CARE
• First and most important, infection in the presence of severe
neutropenia must be aggressively treated by prompt institution of
parenteral, broad-spectrum antibiotics
• Therapy is empirical and must not await results of culture
• foci of infection such as oropharyngeal or anorectal abscesses,
pneumonia, sinusitis, and typhlitis (necrotizing colitis) should be
sought on physical examination and with radiographic studies
• Indewelling plastic catheters: Vancomycin

48. SUPPORTIVE CARE
• Persistent or recrudescent fever implies fungal disease: Candida
and Aspergillus are common, especially after several courses of
antibacterial antibiotics
• Granulocyte transfusions can be effective when bacterial or fungal
infection is progressive or refractory to antibiotics.
• Hand washing, the single best method of preventing the spread of
infection

49. SUPPORTIVE CARE
• platelet and erythrocyte numbers can be maintained by
transfusion
• goal is to maintain the platelet count >10,000/μL
• Menstruation should be suppressed either by oral estrogens or
nasal follicle-stimulating hormone/luteinizing hormone
antagonists.
• Aspirin and other nonsteroidal anti-inflammatory agents must be
avoided in the presence of thrombocytopenia

50. SUPPORTIVE CARE
• RBCs should be transfused
• hemoglobin value of 70 g/L (90 g/L if there is underlying cardiac
or pulmonary disease);
• a regimen of 2 units every 2 weeks will replace normal losses in a
patient without a functioning bone marrow.
• In chronic anemia, the iron chelators deferoxamine and
deferasirox should be added at approximately the fiftieth
transfusion to avoid secondary hemochromatosis

51. PROGNOSIS
• severe aplastic anemia have a rapidly fatal illness if left untreated
• major prognostic determinant is the blood count
• Allogeneic bone marrow transplant from an HLA-matched sibling
donor produces survival rates of over 80% in recipients under 20
years old and of about 65–70% in those 20 to 50 years old

52. • Equine ATG-cyclosporine immunosuppressive treatment leads to a
response in approximately 70% of patients (including those with
hepatitis virus–associated aplastic anemia) and in up to 90% of
patients with the addition of eltrombopag
• Up to one-third of patients will relapse with aplastic anemia after
ATG-based therapy
• Factors that predict response to ATG-cyclosporine therapy are
patient’s age, reticulocyte count, lymphocyte count, and age-
adjusted telomere length of leukocytes at the time of diagnosis

53. WHEN TO ADMIT
• Treatment of neutropenic infection
• The administration of ATG
• Allogeneic bone marrow transplantation

54. Thanks