Transcript CPC Answer - Clinical Correlations

Clinical Pathological
Conference
Elizabeth Ross, M.D.
 Chief Resident
Department of Medicine
 October 12th, 2007
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
Chief Complaint
 A 46
year old Dominican woman
presents with 3 months of increasing
abdominal distention and one month of
diffuse epigastric pain
History of Present Illness
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2-3 years prior to admission: patient first noticed
easy bruisability, she was diagnosed with
“anemia” and iron supplementation was started.
3 months pta: she noticed abdominal distention
and was started on a “water pill”.
1-2 months pta: Her abdominal distention
progressed, she felt like she looked pregnant.
2-3 weeks pta: unrelenting diffuse epigastric pain
and discomfort.
HPI, continued
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Her pain persisted so she sought medical attention
and was admitted to an outside hospital
Imaging and lab studies revealed abnormal LFTs
and portal and splenic vein thrombosis
She was started on a heparin drip and transferred
to Bellevue
Repeat imaging confirmed IVC and hepatic vein
thrombosis and also showed portal and splenic
vein thrombosis
Additonal History
Past Medical History: As above
Past Surg History: Tuboligation 15 years ago
Medications: iron, multivitamin
On transfer: heparin drip
Allergies: none
Family History: Denies history of: clotting disorders,
bleeding disorders, malignancy
Social History: Born in Dominican Republic, has lived in
the US for 10 years, no recent travel. Ten pack-year tobacco
history, quit 9 years ago. No etoh, no illicit drug use. Lives
with husband. Worked as HHA until four months ago.
Review of Symptoms

Monthly, regular menstruation since
menarche, with heavy bleeding
Physical Exam
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General: well-developed woman with apparent
ascites, moaning in pain, appears stated age,
mildly jaundice
Vital signs: BP 127/82, HR 108 and regular, RR
18, Temp 97.6, SpO2 97% room air
HEENT: oropharynx dry, mild scleral icterus
Lymph: no cervical, axillary or inguinal
lymphadenopathy
Neck: supple, no jugular venous distension
Pulmonary: clear to auscultation bilaterally
Physical Exam, continued
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Heart: tachycardic, regular rhythm, normal heart
sounds, no murmurs
Abdominal: Distended, diffusely tender, shifting
dullness present, fluid wave present, no masses
palpable
Extremities: trace lower extremity edema
bilaterally, 2+ peripheral pulses
Skin: no rashes
Rectal: guaiac negative
Neuro: Alert and oriented to person, place and
time
Asterixis present
Hematology
11.7
9.3
59
34.9

MCV 85 (80-100)
MPV 9.9 (7.4-10.4)
Differential - wnl
INR 1.67, PT 21, PTT 66
HIT Antibody – Positive
Thrombin Time 133.6 (21.5 –29.9)
RVVT – No Inhibitor Detected
Chemistry
130
95
13
90
4.6
26
0.5
Ca 8.0
Mg 1.7
Phos 2.0
Chemistry/Serology
311
129
193
LDH – 783 (110-225)
ANA – positive
Hep Bs Ab – positive
Hep Bs Ag – negative
Hep Bc Ab – positive
Hep C Ab – negative
6.8
6.0
4.3
3.0

Urinalysis:
 orange colored, clear; no glucose,
moderate (2+) bilirubin, no ketones,
Specific gravity 1.048, trace blood, trace
protein, pH 6.5, Urobilinogen 4.0 eu/dL
(0-2), no nitrite, trace leukocyte esterase,
WBC 0-2, RBC 0-2
EKG, sinus tachycardia
Abd/Pelvic CT with contrast
 Hepatic
vein, portal vein, splenic
vein and IVC thromboses
 … A diagnostic
performed
procedure was
Student Discussants
Marty Wolf – Paroxysmal Nocturnal
Hematuria
 Leo Drozhinin – Anti-phospholipid
Antibody Syndrome
 Marci Cherit – Autoimmune Hepatitis
 Cristobal Gao – Gastric Cancer

Abdominal/pelvic CT with
IV contrast
Dr. Kay Cho
Faculty Discussant
Dr. Mitchell Charap
A DIAGNOSTIC PROCEDURE
WAS PERFORMED
Hematologist/Hematopathologist
Dr. David Araten
Patient
FLOW CYTOMETRY
Normal
WBC
PNH 06-113.001
99%
68%
R1
M1
100
101
102
CD45 PerCP
103
0
4 10
10
M2
101 102 103
CD16- FITC
M1
M2
0
104 10
101 102 103
CD55 PE
M2
104 100
101
M1
102 103
CD59 PE
104
RBC
PNH 06-11 3.00 1
R2
75%
M2
0
200 400 600 800 100 0
Forward Sca tter
88%
M1
100 101 102 103 104
CD5 5 PE
100
101
102
CD5 9 PE
CD 59
103
104
M1
M2
100 101 102 103 104
Glycop horin A FITC
Flow Analysis of Red Cells
Normal Control
Patient
IR CD59 FITCÉFSC-H, SSC-H subset
PCV-Y CD59 FITC rbcÉFSC-H, SSC-H subset
500
2000
400
300
# Cells
# Cells
# Events
1500
1000
200
500
100
0
0
10
0
10
1
2
10
FL1-H
10
3
10
4
10
0
10
1
2
10
FL1-H
CD59 Expression
10
3
10
4
Flow Analysis of Red Cells
Patient
Normal Control
IR CD59 FITCÉFSC-H, SSC-H subset
PCV-Y CD59 FITC rbcÉFSC-H, SSC-H subset
500
65%
25%
400
2000
10%
300
# Cells
# Cells
# Events
1500
1000
200
500
100
0
0
10
0
10
1
2
10
FL1-H
10
3
10
4
10
0
10
1
2
10
FL1-H
CD59 Expression
10
3
10
4
Flow Analysis of Red Cells
Normal Control
Patient
IR CD59 FITCÉFSC-H, SSC-H subset
PCV-Y CD59 FITC rbcÉFSC-H, SSC-H subset
500
65%
25%
400
2000
10%
300
# Cells
# Cells
# Events
1500
1000
200
PNH
III
100
PNH
II
500
0
0
10
0
10
1
2
10
FL1-H
10
3
10
4
10
0
10
1
2
10
FL1-H
CD59 Expression
10
3
10
4
Paroxysmal Nocturnal Hemoglobinuria
More Typical PNH Patient
MA CD59 FITC rbcÉFSC-H, SSC-H subset
500
# Cells
400
300
200
PNH
III
100
0
10
0
10
1
2
10
FL1-H
10
3
10
4
CD55
CD59
CD14
CD48
CD87
TFPI
stem cell
lymphocyte
CD55
CD59
CD48
CD52
CD87
monocytes
red cell
CD55
CD59
acetylcholinesterase
neutrophil
CD55
CD59
CD66
CD24
CD16
platelets
CD55
CD59
C5
C5b
Eculizumab
Eculizumab
C3b
Classical pathway
C5 convertase
C4b C2a
C3b
C3b
C3b
C4b C2a
Alternative
Pathway
C5 convertase
Bb
X CD55
CD59
C2
C4
C1r/C1s
Classical
pathway
C3b
X
C3
Classical Pathway C3 convertase
Bb
C1q
GPI
GPI
X
C5b
C6
C8
C7
Antibody
C9 Membrane Attack
Complex (MAC)
Immune Lysis Test
Rosse 1974
Two populations of cells
Immune Lysis Test
Rosse 1974
Three populations of cells
Immune Lysis Test
PNH
II
PNH
III
Rosse 1974
Three populations of cells
Loss of all GPI-linked proteins
Extracellular
Intracellular
transmembrane
protein
O=C
N
GPI
CD48
GPI-linked CD55
protein CD59
Acquired Somatic Mutations in PIG-A (Xp22.1)
Large deletion
in PNH patients
del 735 bp
del exons 3-4-5
.
*
*
**
*
Ava I
polymorphism
in frame deletion
missense mutation
inherited mutation
nonsense mutation
splice site mutation
716
3
2
1
*
**
*
H
849
4
*
**
**
1
*
*
*
*
**
*
*
Null mutations
*
*
*
*
982
5
*1189
*
*
*
1452
6
50 bp
deletion insertion
non coding region
coding region
insertion/deletion
TM, Transmembrane domain (nt 1246-1326, aa 415-442)
insertion/duplication
GlcNAc transferase homologous region (nt 912-1185, aa 304-395)
changes very close to each other, presumably
H: Hot spot reported by Mortazavi et al 2003
resulting from a single mutational event
*
From Luzzatto & Nafa 2000
Marked Geographical Disparity
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High rates of thrombosis reported in the
United States, Europe and India
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Much lower rates in Mexico, Japan,
China, and Thailand
Ethnicity as a Risk Factor for Thrombosis and Death
Thrombosis-Free
1
0.9
B
0.8
0.7
0.6
0.5
0.4
Other
patients
LatinAmerican
0.3
0.2
AfricanAmerican
0.1
0
1
Other
Patients
0.9
Survival
0.8
C
LatinAmerican
0.7
0.6
0.5
0.4
0.3
AfricanAmerican
0.2
0.1
0
5
10
15
Years
20
25
Araten et al 2005
Wrap-Up
Dr. Elizabeth Ross
Final Diagnosis:
Paroxysmal Nocturnal Hemoglobinuria
-with granulocyte and erythrocyte clone
size greater than 50%
PNH
An acquired hemolytic anemia  somatic
mutation of the PIG-A gene in a multipotent
hematopoietic stem cell
 This results in the impaired synthesis of the
GPI anchor so proteins (CD 55, 59) can’t
link antigens to cell surface
 Used to be diagnosed with Ham’s test,
illustrating red cells’ susceptibility to lysis
by complement, now flow cytometry is used

PNH
See intravascular hemolysis, cytopenias and
venous thrombosis
 Venous thrombosis occurs in ~50% of
patients which is the most common cause of
death
 When granulocyte clone size is larger than
50%, patients are at increased risk of
thrombosis (Hall et al, Blood, 2003)
 PNH accounts for 15-25% of patients with
hepatic venous thrombosis
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Hillmen et al, NEJM, 1995
PNH
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Management:
 Note – 15% spontaneous remission (Hillmen, 1995)
 Thrombolysis for hepatic vein thrombosis as soon
as possible – case reports with TPA (McMullin et al, Jrnl
of Int Med, 1994)
Warfarin should be used as primary prophylaxis in
patients if platelets >100 (Hall et al, Blood, 2003)
 Monoclonal Ab, Eculizumab – inhibit lytic effect
of complement by binding to C5 (Hillmen et al, NEJM,
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2006)
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Cure?: bone marrow transplant, gene therapy
Pathogenesis of Patient’s Disease
Acquire PIG-A mutation 
Defect of GPI anchor on cell surface 
GPI-linked proteins (CD 55, 59) can’t link antigens to cell surface 
Multipotent hematopoietic stem cells are susceptible to complement
Platelets
RBCs
Platelet activation
Intravascular hemolysis
Anemia
Thrombosis
Venous Thrombosis
(Budd Chiari)
Abdominal distention and ascites
Diffuse epigastric pain
Elevated aminotransferases and INR
Thrombocytopenia
Heparin gtt
HIT Ab
Progression
of thrombosis
Follow-up
The patient’s abdominal pain and distention
continued to cause her distress as an
inpatient
 She was evaluated by the transplant service
for liver transplant and GI for a portocaval
shunt but given the presence of extrahepatic
thrombosis, neither was pursued
 Once the HIT Ab was found to be positive
she was taken off of heparin and transferred
to the MICU so that she could receive TPA
based on hematology’s consultation
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Follow-up
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She received 6 cycles of tissue plasminogen
activator (Alteplase) – which was stopped
secondary to a thigh hematoma and she was
started on lepirudin (Refludan) and started on
warfarin with a goal INR 2.8-3.4
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Abd/Pel CT and doppler ultrasound 2 weeks
after admission (approximately 1 week after
the TPA) revealed some flow through the
hepatic vein
Follow-up
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Once her ascites and epigastric pain improved, and
her INR was at goal, she was discharged
Approximately one year later she had an abd
ultrasound with doppler which revealed:
-patent main portal vein, collateral flow
in the porta hepatis supplying the left portal
vein, patent hepatic and splenic veins. No
ascites.
Abd/pel CT showed: portal venous hypertension
Her platelets remain near 90,000
Thank You
Martin Blaser, MD
Mitchell Charap, MD
David Araten, MD
Kay Cho, MD
Josh Olstein, MD