Download Profound Normocytic Anemia in a 36-Year

Case Studies
Received 2.28.05 | Revisions Received 3.25.05 | Accepted 3.29.05
Profound Normocytic Anemia in a 36-Year-Old
Woman With Syncopal Episodes
Jonathan Baker, MD, Yin Xu, MD, PhD
(Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX)
DOI: 10.1309/HUXB7PKDREXEUJQW
Patient
36-year-old Hispanic female.
Family History
Unremarkable.
Physical Examination
She was notably pale, alert, and oriented. Her
vital signs were: temperature, 37.9°C; blood
pressure, 93/68 mmHg; pulse rate, 90 beats
per minute; and respiratory rate, 16 breaths
per minute. The remainder of the physical
exam was unremarkable.
Questions:
1. What are this patient’s most striking clinical and laboratory
findings?
2. How do you explain the patient’s most striking clinical and
laboratory findings?
3. What condition does this patient’s clinical and laboratory
findings suggest?
4. What is this patient’s most likely diagnosis?
5. What is the pathophysiology of this patient’s disease?
6. What is the most appropriate treatment for this patient?
Possible Answers:
1. Syncope; a profound normocytic, normochromic anemia
with frequent schistocytes; marked thrombocytopenia; elevated
indirect bilirubin; markedly elevated LD.
2. Syncope: Syncope is a transient loss of consciousness due
to reduced cerebral blood flow and is usually caused by 1 of 3
general mechanisms: disorders of vascular tone or blood volume
(eg, vasovagal, orthostatic hypotension, peripheral neuropathy,
antihypertensive or vasodilator drugs, anemia, or blood loss),
cardiovascular disorders, including cardiac arrhythmias, or cerebrovascular disease. Our patient had a profound anemia with low
blood pressure, which are the most likely causes of her syncopal
episodes. Anemia: A normocytic and normochromic anemia can
be seen in anemia of chronic disease, blood loss, reduced bone
marrow production of RBCs (such as marrow suppression
caused by viral infection, toxin, drugs, immunologic diseases,
marrow replacement by neoplastic infiltration, or myelodysplasia), or hemolysis (such as immune-mediated hemolytic anemia,
microangiopathic hemolytic anemia, or mechanical damage by
hypertension in patients with a prosthetic heart valve). In the
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Principal Laboratory Findings
(Table 1)
Additional Diagnostic Procedures and Tests
The patient’s blood smear revealed a
normocytic and normochromic anemia with
frequent RBC fragments, increased
polychromasia, and marked thrombocytopenia
(Image 1). An electrocardiogram showed
normal sinus rhythm. A chest X-ray revealed a
prominent right hilum, but was otherwise
normal. Her stool was guaiac negative and a
urine pregnancy test was negative.
absence of signs for bleeding, a normocytic anemia with
increased polychromasia (reticulocytosis), as occurred in our patient, suggests a hemolytic anemia. Thrombocytopenia: Thrombocytopenia is caused by 1 of 3 mechanisms: decreased bone
marrow production of platelets, increased splenic sequestration
of platelets, or accelerated destruction or consumption of
platelets.1 The most common causes of decreased platelet production are marrow aplasia, fibrosis, or infiltration by malignant
cells, all of which can be diagnosed by bone marrow examination. Approximately one-third of the total platelet mass is normally sequestered in the spleen. When the spleen enlarges, the
fraction of sequestered platelets increases and thrombocytopenia
results. The most common causes of splenomegaly are portal
hypertension due to liver disease and splenic infiltration by
tumor cells in myeloproliferative or lymphoproliferative disorders. The most common causes of platelet destruction are immunologic due to viral or bacterial infections, drugs (heparin),
and idiopathic thrombocytopenic purpura (ITP). Platelets can
be coated with antibodies or complement, and such platelets are
then rapidly cleared by macrophages in the spleen or other tissues. Platelet destruction or consumption can also be accelerated
by nonimmunologic causes such as abnormal vessels, intravascular prostheses, and fibrin thrombi.1 Marked thrombocytopenia
in conjunction with profound normocytic anemia with frequent
schistocytes strongly suggests a consumption of platelets in a
microangiopathic hemolytic process. Elevated indirect bilirubin:
Bilirubin exists in the blood predominantly in 2 fractions: conjugated (or direct) and unconjugated (or indirect). Elevation of
the conjugated fraction of bilirubin in the blood is commonly
due to liver diseases or biliary obstruction. An isolated elevation
of unconjugated bilirubin is infrequently seen in genetic disorders such as Crigler-Najjar and Gilbert’s syndrome, and primarily seen in hemolytic anemia, which occurred in our patient.
Elevated LD: The various isoenzymes of LD are present in various types of cells in liver, lung, myocardium, skeletal muscle,
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Chief Complaint
The patient presented to our emergency
department complaining of syncopal episodes
over the previous 2 days, resulting in a fall and
bruising of her left hip. The episodes were
preceded by dizziness and palpitations and
were accompanied by urinary incontinence.
She also complained of nausea, headache,
neck pain, and minor vaginal bleeding.
Past Medical History
The patient had no significant past medical
history. She was taking no medications and had
no known drug allergies.
Case Studies
and erythrocytes. Cellular injury causes release of LD into the
blood and an elevated serum LD concentration. The combination of our patient’s increased indirect bilirubin and normal liver
function test results (Table 1) suggests that our patient’s
hemolytic anemia is the most likely cause of her markedly elevated LD concentration.
Test
Hematology
WBC count
RBC count
Hemoglobin
Hematocrit
MCV
MCH
MCHC
RDW
Platelet count
Coagulation
PT
INR
PTT
Chemistry
Sodium
Potassium
Chloride
CO2
BUN
Creatinine
Calcium
Phosphorus
Magnesium
Total protein
Albumin
Bilirubin, total
Bilirubin, direct
AST
ALT
GGT
ALP
LD
Patient’s Result
“Normal” Reference Range
12.5
1.98
5.8
16.8
85.2
29.4
34.5
18.1
7
4.1-11.1 x103/µL
4.01-5.31 x106/µL
12.1-16.1 g/dL
36.8-48.7%
76.2-98.6 fL
24.6-33.4pg
31.6-35.4 g/dL
10.8-13.8%
174-404 x103/µL
10.7
1.0
24.1
9.2-12.5 sec
0.9-1.2
24.5-34.5 sec
136
4.0
101
27
21
0.8
8.4
3.2
1.6
7.1
4.3
2.9
0.4
34
32
23
105
1082
135-145 mmol/L
3.6-5.0 mmol/L
98-109 mmol/L
22-31 mmol/L
7-21 mg/dL
0.6-1.2 mg/dL
8.4-10.2 mg/dL
2.4-4.5 mg/dL
1.4-1.8 mEq/L
6.3-8.2 g/dL
3.5-5.2 g/dL
0.2-1.3 mg/dL
0.0-0.3 mg/dL
13-40 U/L
10-40 U/L
8-78 U/L
38-126 U/L
100-190 U/L
WBC, white blood cell; RBC, red blood cell; MCV, mean corpuscular volume;
MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration;
RDW, red cell distribution width; PT, prothrombin time; INR, International Normalized Ratio;
PTT, partial thromboplastin time; BUN, blood urea nitrogen; AST, aspartate aminotransferase;
ALT, alanine aminotransferase; GGT, gamma-glutamyl transferase; ALP, alkaline phosphatase; LD, lactate dehydrogenase.
4. Most likely diagnosis: Thrombotic thrombocytopenic purpura (TTP). Our patient had a microangiopathic hemolytic anemia, thrombocytopenia, and a low fever. Although renal
impairment and neurologic changes were not apparent at the
time of her admission, they appeared later when her TTP rapidly worsened.
5. Thrombotic thrombocytopenic purpura is caused by a
decrease or deficiency of the vonWillebrand factor (VWF)
cleaving protease, ADAMTS-13 [13th member of the
ADAMTS family of metalloproteases (ie, metalloproteases containing A Disintegrin-like And Metalloprotease with
ThromboSpondin type I motif)].4 VonWillebrand factor, a
large glycoprotein that is synthesized in endothelial cells and
megakaryocytes, promotes platelet adhesion and aggregation. It
is produced as a large multimer and assumes a globular form
under relatively static conditions, but normally exists in the
blood as a series of smaller multimers due to the action of
ADAMTS-13. When vascular injury occurs, VWF binds to
damaged endothelium and unfolds, enhancing its interaction
with platelets to form thrombi. VonWillebrand factor also unfolds in normal circulation when it is exposed to increasing
shear stress in arterioles and capillaries. Such unfolding exposes
VWF cleavage sites to the action of ADAMTS-13, which
cleaves the VWF into smaller multimers. When there is a deficiency of ADAMTS-13, the large VWF multimers unfold in
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Image 1_Patient’s peripheral blood smear demonstrating a profound
normocytic and normochromic anemia with reticulocytosis and frequent schistocytes (Wright-Giemsa stain; 500x magnification).
the arterioles and capillaries and induce aggregation of platelets
and the formation of microvascular thrombi, which
subsequently fragment red cells passing through these areas and
result in microangiopathic hemolytic anemia. The deficiency of
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3. The patient had an unremarkable past medical history
and a normal physical examination except for paleness. Her clinical, laboratory, and morphologic peripheral blood smear findings indicate a microangiopathic hemolytic anemia, possibly due
to thrombotic thrombocytopenic purpura (TTP), hemolytic
uremic syndrome (HUS), or disseminated intravascular coagulation (DIC).2 Thrombotic thrombocytopenic purpura is a rare
disorder that has been classically characterized by the pentad of
findings: fever, thrombocytopenia, microangiopathic hemolytic
anemia, transient neurologic deficits, and renal failure.1 However, only microangiopathic hemolytic anemia and thrombocytopenia are required for the diagnosis of TTP. Hemolytic uremic
syndrome and TTP are often difficult to distinguish from each
other clinically. Thrombotic thrombocytopenic purpura typically
occurs in adults and spares the kidneys, while HUS typically
occurs in children and is characterized by the absence of neurologic symptoms and the dominance of acute renal failure. The
clinical manifestations of TTP and HUS in adults and children
seem to be due to differences in the distribution of microvascular thrombi.3 Disseminated intravascular coagulation is characterized by widespread intravascular coagulation and the
formation of microthrombi that cause bleeding from the consumption of platelets and coagulation factors and the anticoagulant effects of fibrolytic products. In addition to
thrombocytopenia, the peripheral blood smear of patients with
DIC demonstrates the presence of both schistocytes and spherocytes and coagulation tests (ie, PT and PTT) are commonly abnormally increased. Notably, our patient’s PT and PTT values
were not increased (Table 1).
Table 1_Principal Laboratory Findings
Case Studies
ADAMTS-13 can be congenital, resulting in chronic relapsing
TTP. More commonly, however, the deficiency of ADAMTS-13
is acquired, triggered by infection, drugs (Ticlopidine),5 and immune system abnormalities [eg, systemic lupus erythematosus
(SLE), human immunodeficiency virus (HIV) infection], which
lead to an autoimmune reaction to ADAMTS-13 mediated by
IgG antibodies. This reaction is usually transient and confined to
a single episode.
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LABMEDICINE 䊏 Volume 36 Number 6 䊏 June 2005
Keywords
thrombotic thrombocytopenic purpura, hemolytic uremic syndrome,
disseminated intravascular coagulation, von Willebrand factor,
schistocyte
1. Handin, RI. Harrison’s Principles of Internal Medicine, 16th ed. Chapter 101:
Disorders of the Platelet and Vessel Wall. The McGraw-Hill Companies, Inc.
2005.
2. Kjeldsberg C, Kojo E-J, Foucar K. Practical Diagnosis of Hematologic
Disorders, 3rd ed. Chicago: ASCP Press. 2000;796-798.
3. Hosler GA. Thrombotic thrombocytopenic purpura and hemolytic uremic
syndrome are distinct pathologic entities. Arch Pathol Lab Med. 2003;127:834839.
4. Tsai, H-M. Advances in the pathogenesis, diagnosis, and treatment of
thrombotic thrombocytopenic purpura. J Am Soc Nephrol. 2003;14:10721081.
5. Tsai H-M, Rice L, Sarode R. Antibody inhibitors to von willebrand factor
metalloproteinase and increased binding of von willebrand factor to platelets in
ticlopidine-associated thrombotic thrombocytopenic purpura. Annals of Int
Med. 2000;132:794-799.
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6. Management: The goals of treatment for TTP are to
replace the ADAMTS-13 protease and remove the antibodies
against it. Plasma exchange accomplishes both of these goals,
and should be initiated as early as possible in the treatment of
patients with TTP. The introduction of plasma exchange as a
treatment for TTP has decreased mortality rates to less than
10%. Previously, TTP was fatal in the majority of cases. Fresh
frozen plasma (FFP) infusion can also be used to replace the
protease, but it is not as effective as plasma exchange in the treatment of patients with acquired TTP because the antibodies to
ADAMTS-13 remain in the patient’s plasma. However, FFP
infusion has the advantage of speed, and should be utilized until
plasma exchange can begin. Moreover, regular FFP or cryo-poor
plasma infusions are sufficient for the treatment of TTP caused
by a congenital deficiency of ADAMTS-13. Immunosuppression therapy has also been used with some success in the treatment of TTP, including the use of steroids, Rituxan, and
Vincristine. Platelet transfusion is strongly contraindicated in
patients with TTP, as it will increase platelet thrombi formation
and exacerbate the condition. Moreover, TTP patients generally
do not bleed, and therefore, platelet transfusion should only be
considered in cases of life-threatening hemorrhage. LM