Transcript CBL hema A Patient with Pancytopeniax

A Patient with Pancytopenia
HISTORY: Part 1
• A 34 year-old woman is seen by her dentist for bleeding from
her gums. The bleeding started on the day prior to evaluation
and seems to be getting steadily worse with time.
• After briefly evaluating the patient and noting diffuse
bleeding from the mucosal surfaces around multiple teeth,
the dentist refers her for further evaluation to the emergency
department at a nearby hospital where you are working.
What further information should
you request regarding
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the patient's history?
Have you ever had a similar episode in the past?
 Is there any family history of a bleeding disorder?
 Are you taking any prescribed or over-the-counter
medications?
 Do you smoke cigarettes or drink alcohol?
 Do you have any bruises or other areas of bleeding?
 Is anyone else in your family ill?
 Do you have any pets?
Answer
Have you ever had a similar episode in the past?
Is there any family history of a bleeding disorder?
Are you taking any prescribed or over-the-counter
medications?
Do you smoke cigarettes or drink alcohol?
Do you have any bruises or other areas of bleeding?
Is anyone else in your family ill?
Do you have any pets?
HISTORY: Part 2
• The patient notes that she has never had an episode of
anything similar in the past. Her past medical history is
remarkable only for a tonsillectomy at age 11 that was
entirely uncomplicated. There is no family history of a
bleeding disorder. She takes no medication regularly,
but on occasion takes acetaminophen for headaches.
She does not smoke or drink alcohol.
HISTORY: Part 2
• On a review of systems, you discover that over the past month she
has been feeling gradually more fatigued, which she attributes to
working overtime at her job as an administrative assistant. She
notes no fevers or chills, but does say that she may have lost a few
pounds unintentionally due to decreased appetite. She notes that
on her way to the emergency department, she noted some small
bruises on her forearms and thighs and that her ankles and feet
seem to have numerous small red dots on them. She denies any
chest pain, shortness of breath, abdominal pain, edema, headaches,
dizziness, or other neurologic symptoms.
•
After obtaining this information, you move on to perform a physical examination on the patient.
Any Question?
Discussion
PHYSICAL EXAM
General Pale appearing woman in no acute distress.
:
T 37.2℃, P 105, BP 94/64, RR 16.
Skin:
HEENT:
Notable for several 2-3 cm ecchymoses on the forearms and thighs
bilaterally; in addition, there is a petechial rash over the ankles and feet
bilaterally.
The oropharynx is notable for a small amount of fresh blood at the gum
line around the base of multiple upper and lower incisors and molars.
CV:
Normal S1, S2, regular, with a grade I/VI systolic murmur appreciated at
the left sternal border.
Pulm:
Unlabored respiration, clear to auscultation and percussion bilaterally.
Abd:
Soft, non-tender, non-distended, without organomegaly or mass.
Extr:
Warm, well perfused, no edema, but with the ecchymoses and petechiae
noted above.
Neuro: Alert and oriented to person, place, and time. No motor or sensory
defects.
Discussion
Can you list differential diagnosis
according to the history and PE?
What additional information would
you request at this time?
 Laboratory Data
 Radiologic Studies
Answer
Laboratory Data
Radiologic Studies
LABORATORY DATA
What laboratory data should you
request initially?
 CBC with differential
 Peripheral Blood Smear
 Prothrombin Time (PT)
 Activated Partial Thromboplastin Time (aPTT)
 Serum creatinine
 Liver function tests
Answer
CBC with differential
Peripheral Blood Smear
Prothrombin Time (PT)
Activated Partial Thromboplastin Time (aPTT)
Serum creatinine
Liver function tests
On Routine
Office Visit
3 Months Ago
Today
Normal Range
CBC
WBC count
7,800/µL
2,300/µL
4,100-10,900/µL
65%
29%
6%
38-80%
30-50%
2-12%
0%
13-15 g/dL
39-45%
80-100 fL
Differential
Neutrophils
Lymphocytes
Monocytes
Blasts
Hemoglobin
Hematocrit
MCV
13 g/dL
41%
89 fL
16%
37%
18%
29%
8 g/dL
26%
87 fL
Platelets
225,000/µL
7,000/µL
140,000-440,000/µL
---
Coagulation Studies
PT
---
16 seconds
12-14 seconds
aPTT
---
41 seconds
23-31 seconds
1.1 mg/dL
0.5-1.2 mg/dL
45 U/L
31 U/L
131 U/L
7.3 g/dL
3.7 g/dL
1.6 mg/dL
0.2 mg/dL
7-56 U/L
5-35 U/L
20-140 U/L
6.3-8.2 g/dL
3.5-5 g/dL
<1.20 mg/dL
<0.20 mg/dL
Serum Creatinine
0.6 mg/dL
Liver Chemistries
ALT
AST
Alkaline Phosphatase
Total Protein
Albumin
Total Bilirubin
Direct Bilirubin
---------------
Discussion
What is the finding of the lab data?
What is your differential diagnosis?
Peripheral blood smear:
Review of the peripheral blood smear reveals decreased platelets, 3 to 4
schistocytes per high powered field, and a population of cells such as the
one shown above.
III. LABORATORY DATA
Are there further laboratory data,
radiographic studies, or diagnostic
procedures that you would wish to
request at this time?
Fibrinogen level
 LDH
 Uric Acid
 CT scan of the chest, abdomen, and pelvis
 Lumbar puncture
 Bone marrow aspirate and biopsy
Answer
Fibrinogen level
LDH
Uric Acid
CT scan of the chest, abdomen, and pelvis
Lumbar puncture
Bone marrow aspirate and biopsy
III. LABORATORY DATA
Fibrinogen
LDH
Uric Acid
Patient Result
74 mg/dL
694 U/L
7.5 mg/dL
Normal Range
150-450 mg/dL
118-242 U/L
3.5-7 mg/dL
DIFFERENTIAL DIAGNOSIS
While the bone marrow aspirate and biopsy is being
processed, what is the most likely diagnosis for this
patient based upon the all of the data provided?
 Aplastic anemia
 Paroxysmal nocturnal hemoglobinuria
 Sepsis syndrome
 Vitamin B12 deficiency
 Acute lymphoid leukemia
 Acute myeloid leukemia
Discussion
About your differential diagnosis
Answer
Aplastic anemia
Paroxysmal nocturnal hemoglobinuria
Sepsis syndrome
Vitamin B12 deficiency
Acute lymphoid leukemia
Acute myeloid leukemia
•
Acute myeloid leukemia may present with pancytopenia, leukocytosis, or a white
blood cell count within the normal range. In addition, sometimes when
pancytopenia is present, there are no circulating blasts, although many may be
found in the bone marrow (this is called aleukemic leukemia). In this case, the
combination of pancytopenia with blasts combined with the consumptive
coagulopathy (disseminated intravascular coagulation, DIC) indicates a diagnosis
of acute myeloid leukemia. The cell shown in the photomicrograph of the
peripheral blood is a myeloblast that has a heavily granulated cytoplasm. The
stick-like inclusions in the cytoplasm are Auer rods. These are stacks of lysosomes
that have collapsed on one another to form linear structures within the cytoplasm.
They are indicative of a myeloid disorder and are seen only in acute myeloid
leukemia and advanced myelodysplastic syndromes. The latter are disorders that
tend to transform into acute myeloid leukemia.
• The bone marrow
aspirate and biopsy
findings become available,
along with the flow
cytometric analysis
documenting acute
promyelocytic leukemia
(APL, also known as M3
AML by the older FrenchAmerican British
Classification scheme):
•
Overall, the blasts present in bone marrow are found to have the following phenotype:
Present : CD33
CD13 CD117
Absent : CD34, HLA-DR
•
The presence of CD33 and absence of CD34 and HLA-DR are consistent with a diagnosis of
acute promyelocytic leukemia (APL). The particular markers present also distinguish acute
lymphoid from acute myeloid leukemia and also distinguish different classes of myeloid
leukemias from one another.
•
Cytogenetic Analysis including Fluorescence in situ Hybridization (FISH)
•
Cytogenetic analysis and FISH analysis have become standard techniques in the analysis of
acute leukemia. Cytogenetic abnormalities, present in about 50% of cases of acute myeloid
leukemia, can have major prognostic implications. Cytogenetic abnormalities also have a major
impact on treatment decisions, including the type of chemotherapy administered and whether
or not to recommend hematopoietic stem cell transplantation in certain cases.
•
Giemsa banding of 20 metaphase chromosome spreads documents the presence of t(15;17)
translocation in 18 cells. FISH demonstrates the presence of a PML/RARA signal in 85% of 200
interphase nuclei examined.
•
Molecular Diagnostics
•
Using reverse transcriptase polymerase chain reaction (RT-PCR) on RNA prepared from the patient’s
white blood cells, a strong band is identified, indicating the presence of the PML/RARA gene fusion.
•
Molecular diagnostic testing is becoming increasingly important in leukemia diagnosis. Besides
facilitating rapid diagnosis of known translocations, it identifies abnormalities in about 75% of acute
myeloid leukemia that is otherwise cytogenetically normal. As with cytogenetics, identification of
such abnormalities can have major prognostic significance. For example, in otherwise cytogenetically
normal acute myeloid leukemia, the finding of internal tandem duplications in the FMS-like tyrosine
kinase 3 gene (FLT3-ITD mutation) is associated with a poor prognosis, whereas the finding of an
isolated abnormality in the nucleophosmin 1 gene (NPM1 mutation) is associated with a favorable
overall prognosis.
PATHOPHYSIOLOGY
• The molecular pathogenesis of APL is now understood and is
illustrated below. The fusion protein consists of the promyelocytic
leukemia gene (PML), a tumor suppressor normally found in nuclear
bodies, and the retinoid acid receptor alpha gene (RARA), a
transcription factor that is normally responsive to retinoid acid. The
juxtaposition of these two genes produces a protein that does not
respond to the usual form of retinoic. However, it does respond to a
specific type of retinoic acid, all-trans retinoid acid, leading to
restoration of gene transcription and thereby to cellular
differentiation. Interestingly, the substance arsenic trioxide leads to a
similar effect because it leads to aggregation and degradation of the
PML-RARA fusion protein, thereby promoting differentiation. Both
ATRA and arsenic trioxide are now used for the treatment of APL.
Treatment
•
•
•
•
•
All-trans retinoid acid
Daunomycin
Maintenance chemotherapy
Management of DIC
Follow up BM with PML/RARa to detect
minimal residual disease
Discussion
About treatment
• Reference: ASH teaching case
• http://teachingcases.hematology.org/