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Clinical Pathological Conference
Elizabeth Ross, M.D.Elizabeth Ross, M.D. Chief Resident Chief Resident
Department of MedicineDepartment of Medicine October 12October 12thth, 2007, 2007
Chief Complaint
A 46 year old Dominican woman A 46 year old Dominican woman presents with 3 months of increasing presents with 3 months of increasing abdominal distention and one month of abdominal distention and one month of diffuse epigastric paindiffuse epigastric pain
History of Present Illness 2-3 years prior to admission: patient first noticed 2-3 years prior to admission: patient first noticed
easy bruisability, she was diagnosed with easy bruisability, she was diagnosed with “anemia” and iron supplementation was started. “anemia” and iron supplementation was started.
3 months pta: she noticed abdominal distention 3 months pta: she noticed abdominal distention and was started on a “water pill”. and was started on a “water pill”.
1-2 months pta: Her abdominal distention 1-2 months pta: Her abdominal distention progressed, she felt like she looked pregnant. progressed, she felt like she looked pregnant.
2-3 weeks pta: unrelenting diffuse epigastric pain 2-3 weeks pta: unrelenting diffuse epigastric pain and discomfort. and discomfort.
HPI, continued
Her pain persisted so she sought medical attention Her pain persisted so she sought medical attention and was admitted to an outside hospitaland was admitted to an outside hospital
Imaging and lab studies revealed abnormal LFTs Imaging and lab studies revealed abnormal LFTs and portal and splenic vein thrombosis and portal and splenic vein thrombosis
She was started on a heparin drip and transferred She was started on a heparin drip and transferred to Bellevue to Bellevue
Repeat imaging confirmed IVC and hepatic vein Repeat imaging confirmed IVC and hepatic vein thrombosis and also showed portal and splenic thrombosis and also showed portal and splenic vein thrombosisvein thrombosis
Additonal History
Past Medical HistoryPast Medical History: : As aboveAs above
Past Surg HistoryPast Surg History: : Tuboligation 15 years agoTuboligation 15 years ago
MedicationsMedications: : iron, multivitaminiron, multivitamin
On transferOn transfer: : heparin dripheparin drip
AllergiesAllergies: : nonenone
Family HistoryFamily History: : Denies history of: clotting disorders, Denies history of: clotting disorders, bleeding disorders, malignancybleeding disorders, malignancy
Social HistorySocial History: : Born in Dominican Republic, has lived in Born in Dominican Republic, has lived in the US for 10 years, no recent travel. Ten pack-year tobacco the US for 10 years, no recent travel. Ten pack-year tobacco history, quit 9 years ago. No etoh, no illicit drug use. Lives history, quit 9 years ago. No etoh, no illicit drug use. Lives with husband. Worked as HHA until four months ago.with husband. Worked as HHA until four months ago.
Review of Symptoms
Monthly, regular menstruation since Monthly, regular menstruation since menarche, with heavy bleedingmenarche, with heavy bleeding
Physical Exam General: well-developed woman with apparent General: well-developed woman with apparent
ascites, moaning in pain, appears stated age, ascites, moaning in pain, appears stated age, mildly jaundicemildly jaundice
Vital signs: BP 127/82, HR 108 and regular, RR Vital signs: BP 127/82, HR 108 and regular, RR 18, Temp 97.6, SpO2 97% room air18, Temp 97.6, SpO2 97% room air
HEENT: HEENT: oropharynx dry, mild scleral icterusoropharynx dry, mild scleral icterus Lymph: no cervical, axillary or inguinal Lymph: no cervical, axillary or inguinal
lymphadenopathy lymphadenopathy Neck: supple, no jugular venous distensionNeck: supple, no jugular venous distension Pulmonary: clear to auscultation bilaterallyPulmonary: clear to auscultation bilaterally
Physical Exam, continued Heart: tachycardic, regular rhythm, normal heart Heart: tachycardic, regular rhythm, normal heart
sounds, no murmurssounds, no murmurs Abdominal: Distended, diffusely tender, shifting Abdominal: Distended, diffusely tender, shifting
dullness present, fluid wave present, no masses dullness present, fluid wave present, no masses palpablepalpable
Extremities: trace lower extremity edema Extremities: trace lower extremity edema bilaterally, 2+ peripheral pulsesbilaterally, 2+ peripheral pulses
Skin: no rashesSkin: no rashes Rectal: guaiac negativeRectal: guaiac negative Neuro: Alert and oriented to person, place and Neuro: Alert and oriented to person, place and
timetime Asterixis presentAsterixis present
Hematology
11.711.7 9.3 59 9.3 59 MCV 85 (80-100)MCV 85 (80-100)
34.9 34.9 MPV 9.9 (7.4-10.4)MPV 9.9 (7.4-10.4)
Differential - wnlDifferential - wnl
INR 1.67, PT 21, PTT 66INR 1.67, PT 21, PTT 66HIT Antibody – PositiveHIT Antibody – PositiveThrombin Time 133.6 (21.5 –29.9)Thrombin Time 133.6 (21.5 –29.9)RVVT – No Inhibitor DetectedRVVT – No Inhibitor Detected
Chemistry
130 95 13130 95 13
90 Ca 8.090 Ca 8.0
4.6 4.6 26 26 0.5 0.5 Mg 1.7 Mg 1.7
Phos 2.0Phos 2.0
Chemistry/Serology
311 129 6.8 6.0311 129 6.8 6.0 193 4.3 3.0193 4.3 3.0
LDH – 783 (110-225)LDH – 783 (110-225)ANA – positiveANA – positiveHep Bs Ab – positiveHep Bs Ab – positiveHep Bs Ag – negativeHep Bs Ag – negativeHep Bc Ab – positiveHep Bc Ab – positiveHep C Ab – negativeHep C Ab – negative
Urinalysis:Urinalysis: orange colored, clear; no glucose, orange colored, clear; no glucose,
moderate (2+) bilirubin, no ketones, moderate (2+) bilirubin, no ketones, Specific gravity 1.048, trace blood, trace Specific gravity 1.048, trace blood, trace protein, pH 6.5, Urobilinogen 4.0 eu/dL protein, pH 6.5, Urobilinogen 4.0 eu/dL (0-2), no nitrite, trace leukocyte esterase, (0-2), no nitrite, trace leukocyte esterase, WBC 0-2, RBC 0-2 WBC 0-2, RBC 0-2
EKG, sinus tachycardia
Abd/Pelvic CT with contrast
Hepatic vein, portal vein, splenic Hepatic vein, portal vein, splenic vein and IVC thrombosesvein and IVC thromboses
… … A diagnostic procedure was A diagnostic procedure was performedperformed
Student Discussants
Marty Wolf – Paroxysmal Nocturnal Marty Wolf – Paroxysmal Nocturnal HematuriaHematuria
Leo Drozhinin – Anti-phospholipid Leo Drozhinin – Anti-phospholipid Antibody SyndromeAntibody Syndrome
Marci Cherit – Autoimmune HepatitisMarci Cherit – Autoimmune Hepatitis Cristobal Gao – Gastric CancerCristobal Gao – Gastric Cancer
Abdominal/pelvic CT with Abdominal/pelvic CT with IV contrastIV contrast
Dr. Kay ChoDr. Kay Cho
Faculty Discussant
Dr. Dr. Mitchell CharapMitchell Charap
A DIAGNOSTIC PROCEDURE A DIAGNOSTIC PROCEDURE WAS PERFORMEDWAS PERFORMED
Hematologist/Hematopathologist
Dr. David AratenDr. David Araten
100 101 102 103 104
CD16- FITC
M1M2
100 101 102 103 104
CD55 PE
M1M2
100 101 102 103 104
CD59 PE
M1M2
PNH 06-113.001
100 101 102 103 104
CD45 PerCP
R1
PNH 06-113.001
0 200 400 600 800 1000Forward Scatter
R2
100 101 102 103 104
Glycophorin A FITC
M1M2
WBC
RBC
CD 59
Normal
Patient
68% 99%
100 101 102 103 104
CD55 PE
M1M2
75%
100 101 102 103 104
CD59 PE
88%
FLOW CYTOMETRY
100 101 102 103 104
0
100
200
300
400
500
IR CD59 FITCÉFSC-H, SSC-H subset
FL1-H
# C
ells
100 101 102 103 104
0
500
1000
1500
2000
PCV-Y CD59 FITC rbcÉFSC-H, SSC-H subset
FL1-H
# C
ells
Normal ControlPatient
# E
vent
s
CD59 Expression
Flow Analysis of Red Cells
100 101 102 103 104
0
100
200
300
400
500
IR CD59 FITCÉFSC-H, SSC-H subset
FL1-H
# C
ells
100 101 102 103 104
0
500
1000
1500
2000
PCV-Y CD59 FITC rbcÉFSC-H, SSC-H subset
FL1-H
# C
ells
Normal ControlPatient
25% 65%10%
# E
vent
s
CD59 Expression
Flow Analysis of Red Cells
100 101 102 103 104
0
100
200
300
400
500
IR CD59 FITCÉFSC-H, SSC-H subset
FL1-H
# C
ells
100 101 102 103 104
0
500
1000
1500
2000
PCV-Y CD59 FITC rbcÉFSC-H, SSC-H subset
FL1-H
# C
ells
Normal ControlPatient
25% 65%10%
# E
vent
s
CD59 Expression
Flow Analysis of Red Cells
PNH III
PNH II
Paroxysmal Nocturnal Hemoglobinuria
100 101 102 103 104
0
100
200
300
400
500
MA CD59 FITC rbcÉFSC-H, SSC-H subset
FL1-H
# C
ells
More Typical PNH Patient
PNH III
red cell neutrophilplatelets
monocytes
stem cell lymphocyte
CD55CD59acetylcholinesterase
CD55CD59CD66CD24CD16
CD55CD59
CD55CD59CD48CD52CD87
CD55CD59CD14CD48CD87TFPI
CD59
C6
C7C8
C9 Membrane AttackComplex (MAC)
Antibody
C1q
C1r/C1s
C4 C2
C4b C2a CD55
XC3
C3bBb
Classicalpathway
Alternative Pathway
C3 convertase
C4b C2a
C3b
Classical Pathway C3 convertase
BbC3b C3b
AlternativePathwayC5 convertase
Classical pathwayC5 convertase
C5b
C5b
C5
C5
XX
GPI GPI
C3b
Eculizumab
C3
C3b
Eculizumab
Immune Lysis Test
Two populations of cellsRosse 1974
Immune Lysis Test
Three populations of cellsRosse 1974
Immune Lysis Test
Three populations of cellsRosse 1974
PNH III
PNH II
Loss of all GPI-linked proteins
Extracellular
Intracellular
GPI
O=CN
GPI-linkedprotein
CD48 CD55CD59
trans-membrane
protein
4
982 11898497161
1
1452
3
Ava Ipolymorphism
*
****
*
** *
*
***
**
50 bp
**
652
H
** *** **
**
** **
GlcNAc transferase homologous region (nt 912-1185, aa 304-395)
non coding region coding regionTM, Transmembrane domain (nt 1246-1326, aa 415-442)
deletion insertioninsertion/deletioninsertion/duplicationinherited mutation
missense mutationin frame deletion
nonsense mutationsplice site mutation
* changes very close to each other, presumablyresulting from a single mutational event
.
Null mutations
del exons 3-4-5del 735 bp
Large deletion
H: Hot spot reported by Mortazavi et al 2003
Acquired Somatic Mutations in PIG-A (Xp22.1) in PNH patients
From Luzzatto & Nafa 2000
Marked Geographical Disparity
High rates of thrombosis reported in the High rates of thrombosis reported in the United States, Europe and India United States, Europe and India
Much lower rates in Mexico, Japan, Much lower rates in Mexico, Japan, China, and ThailandChina, and Thailand
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Years
Thr
ombo
sis-
Fre
eT
hrom
bosi
s-F
ree
AA/PNH
Classic PNH
Other patientsLatin-
American
African-American
A
B
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
5 10 15 20 25
Sur
viva
l
COtherPatients
Latin-American
African-American
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Years
Thr
ombo
sis-
Fre
eT
hrom
bosi
s-F
ree
AA/PNH
Classic PNH
Other patientsLatin-
American
African-American
A
B
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
5 10 15 20 25
Sur
viva
l
COtherPatients
Latin-American
African-American
Ethnicity as a Risk Factor for Thrombosis and Death
Araten et al 2005
Wrap-Up
Dr. Elizabeth RossDr. Elizabeth Ross
Final Diagnosis:
Paroxysmal Nocturnal HemoglobinuriaParoxysmal Nocturnal Hemoglobinuria
--with granulocyte and erythrocyte clone with granulocyte and erythrocyte clone size greater than 50% size greater than 50%
PNH An acquired hemolytic anemia An acquired hemolytic anemia somatic somatic
mutation of the PIG-A gene in a multipotent mutation of the PIG-A gene in a multipotent hematopoietic stem cellhematopoietic stem cell
This results in the impaired synthesis of the This results in the impaired synthesis of the GPI anchor so proteins (CD 55, 59) can’t GPI anchor so proteins (CD 55, 59) can’t link antigens to cell surfacelink antigens to cell surface
Used to be diagnosed with Ham’s test, Used to be diagnosed with Ham’s test, illustrating red cells’ susceptibility to lysis illustrating red cells’ susceptibility to lysis by complement, now flow cytometry is usedby complement, now flow cytometry is used
PNH See intravascular hemolysis, cytopenias and See intravascular hemolysis, cytopenias and
venous thrombosisvenous thrombosis Venous thrombosis occurs in ~50% of Venous thrombosis occurs in ~50% of
patients which is the most common cause of patients which is the most common cause of deathdeath
When granulocyte clone size is larger than When granulocyte clone size is larger than 50%, patients are at increased risk of 50%, patients are at increased risk of thrombosis thrombosis (Hall et al, Blood, 2003)(Hall et al, Blood, 2003)
PNH accounts for 15-25% of patients with PNH accounts for 15-25% of patients with hepatic venous thrombosishepatic venous thrombosis
Hillmen et al, NEJM, 1995
PNH Management: Management:
Note – 15% spontaneous remission Note – 15% spontaneous remission (Hillmen, 1995)(Hillmen, 1995)
Thrombolysis for hepatic vein thrombosis as soon Thrombolysis for hepatic vein thrombosis as soon as possible – case reports with TPA as possible – case reports with TPA (McMullin et al, Jrnl (McMullin et al, Jrnl of Int Med, 1994)of Int Med, 1994)
Warfarin should be used as primary prophylaxis in Warfarin should be used as primary prophylaxis in patients if platelets >100 patients if platelets >100 (Hall et al, Blood, 2003)(Hall et al, Blood, 2003)
Monoclonal Ab, Eculizumab – inhibit lytic effect Monoclonal Ab, Eculizumab – inhibit lytic effect of complement by binding to C5 of complement by binding to C5 (Hillmen et al, NEJM, (Hillmen et al, NEJM, 2006)2006)
Cure?: bone marrow transplant, gene therapyCure?: bone marrow transplant, gene therapy
Pathogenesis of Patient’s DiseaseAcquire PIG-A mutation Acquire PIG-A mutation Defect of GPI anchor on cell surface Defect of GPI anchor on cell surface GPI-linked proteins (CD 55, 59) can’t link antigens to cell surface GPI-linked proteins (CD 55, 59) can’t link antigens to cell surface Multipotent hematopoietic stem cells are susceptible to complementMultipotent hematopoietic stem cells are susceptible to complement
PlateletsPlatelets RBCs RBCs
Platelet activationPlatelet activation Intravascular hemolysisIntravascular hemolysis
AnemiaAnemia
ThrombosisThrombosis ThrombocytopeniaThrombocytopenia
Venous ThrombosisVenous Thrombosis Heparin gtt Heparin gtt HIT Ab HIT Ab
(Budd Chiari)(Budd Chiari)
Abdominal distention and ascitesAbdominal distention and ascites ProgressionProgression
Diffuse epigastric pain Diffuse epigastric pain of of thrombosisthrombosis
Elevated aminotransferases and INRElevated aminotransferases and INR
Follow-up The patient’s abdominal pain and distention The patient’s abdominal pain and distention
continued to cause her distress as an continued to cause her distress as an inpatientinpatient
She was evaluated by the transplant service She was evaluated by the transplant service for liver transplant and GI for a portocaval for liver transplant and GI for a portocaval shunt but given the presence of extrahepatic shunt but given the presence of extrahepatic thrombosis, neither was pursuedthrombosis, neither was pursued
Once the HIT Ab was found to be positive Once the HIT Ab was found to be positive she was taken off of heparin and transferred she was taken off of heparin and transferred to the MICU so that she could receive TPA to the MICU so that she could receive TPA based on hematology’s consultationbased on hematology’s consultation
Follow-up She received 6 cycles of tissue plasminogen She received 6 cycles of tissue plasminogen
activator (Alteplase) – which was stopped activator (Alteplase) – which was stopped secondary to a thigh hematoma and she was secondary to a thigh hematoma and she was started on lepirudin (Refludan) and started on started on lepirudin (Refludan) and started on warfarin with a goal INR 2.8-3.4warfarin with a goal INR 2.8-3.4
Abd/Pel CT and doppler ultrasound 2 weeks Abd/Pel CT and doppler ultrasound 2 weeks after admission (approximately 1 week after after admission (approximately 1 week after the TPA) revealed some flow through the the TPA) revealed some flow through the hepatic veinhepatic vein
Follow-up Once her ascites and epigastric pain improved, and Once her ascites and epigastric pain improved, and
her INR was at goal, she was dischargedher INR was at goal, she was discharged Approximately one year later she had an abd Approximately one year later she had an abd
ultrasound with doppler which revealed:ultrasound with doppler which revealed:
-patent main portal vein, collateral flow -patent main portal vein, collateral flow in the porta hepatis supplying the left portal in the porta hepatis supplying the left portal vein, patent hepatic and splenic vein, patent hepatic and splenic veins. No veins. No ascites.ascites.
Abd/pel CT showed: portal venous hypertensionAbd/pel CT showed: portal venous hypertension Her platelets remain near 90,000Her platelets remain near 90,000
Thank You
Martin Blaser, MDMartin Blaser, MD
Mitchell Charap, MDMitchell Charap, MD
David Araten, MDDavid Araten, MD
Kay Cho, MDKay Cho, MD
Josh Olstein, MDJosh Olstein, MD
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