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Case Report 15 Sandra Fátima Menosi Gualandro
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
2005-2007– Recurrent abdominal pain without diagnosis
Sep 2007 – Hemolytic crisis – Hereditary spherocytosis? Sent to HC-FMUSP
Sep 2007 – PNH diagnosed (typical features, PNH clone 78%) Prednisone and primary prophylaxis for thrombosis (warfarin INR 2-3)
Case Report: RGS, female, 23 y.o.
Case Report: RGS
Granulocytes
Erythrocytes
LDH = 6402 U/L D-dimer = 24 ng/ml
Abdominal MRI = normal
Jan 2008 - Nov 2008 –- Relief of abdominal pain, sporadic blood transfusion
Nov 2008 - Mar 2009 –- Symptomatic Cholelithiasis
Apr 2009 – Elective laparoscopic cholecystectomy. No immediate complications. Discharged 5 days later with enoxaparin.
Case Report: RGS
After 7days - admitted in another hospital Abdominal pain and anemia –– blood transfusion and antibiotics
After 20 days - admitted HC-FMUSP– abdominal pain, cough - fasting, antibiotics and blood transfusion. Discharged after 3 days
After 24 days - readmitted HCFMUSP – fever, abdominal distension and cough – no response to conservative measures – exploratory laparotomy – appendectomy – ICU 7th PO – Complications began...
Case Report: RGS
Central Venous Catheter: Right Internal Jugular Vein
21/05/2009 28/05/2009 02/06/2009 20/07/2009 07/08/2009 18/09/2009 15/03/2010
Cervical Hematoma With Mediastinal Involvement
21/05/2009 28/05/2009 02/06/2009 20/07/2009 07/08/2009 18/09/2009 15/03/2010
Deep Venous Thrombosis: Right Internal Jugular Vein
21/05/2009 28/05/2009 02/06/2009 20/07/2009 07/08/2009 18/09/2009 15/03/2010
DVT: Right Subclavian Vein
Left subclavian vein
21/05/2009 28/05/2009 02/06/2009 20/07/2009 07/08/2009 18/09/2009 15/03/2010
Massive swelling of the neck, thorax and right arm and severe tracheal compression causing respiratory failure
Superior vena cava
21/05/2009 28/05/2009 02/06/2009 20/07/2009 07/08/2009 18/09/2009 15/03/2010
before surgery (mar/2009) after surgery (09/jun/2009)
Small bowell wall
Abdominal Multislice Computed Tomography
Marked small bowel wall thickening and increased density of mesenteric fat (enteritis) Consider the possibility of thrombosis of the microvasculature
21/05/2009 28/05/2009 09/06/2009 20/07/2009 07/08/2009 18/09/2009 15/03/2010
DVT: Left Brachial Vein
21/05/2009 28/05/2009 02/06/2009 20/07/2009 07/08/2009 18/09/2009 15/03/2010
Chronic DVT: Right Internal Jugular, Right Subclavian, Right Axillary Vein
RIJV – no blood flow LIJV – normal blood flow
21/05/2009 28/05/2009 02/06/2009 20/07/2009 07/08/2009 18/09/2009 15/03/2010
DVT: Common Femoral Vein and Left Common Iliac Vein
Right Right Right
Left Left Left
Common iliac vein External iliac vein Common femoral vein
21/05/2009 28/05/2009 02/06/2009 20/07/2009 07/08/2009 18/09/2009 15/03/2010
Discussion
Definition
Acquired clonal disease Intravascular hemolysis Thrombosis
Bone Marrow failure
Paroxysmal Nocturnal Hemoglobinuria
Incidence 1:100 000 to 1:1000 000 All ages (mean = 30 yrs)
male = female
Schematic representation of the structure and mutations in the PIGA gene
Bessler M and Hiken J. Hematology Am Soc Hematol Educ Program. 2008:104-10
GPI-Anchor
Brodsky RA. Blood Reviews. 2008;22:65-70
GPI-anchored surface proteins on human hematopoietic cells
Bessler M and Hiken J. Hematology Am Soc Hematol Educ Program. 2008:104-10
Complement-mediated lysis in PNH
Parker C. Lancet 2009; 373:758-67
Brodsky RA. Hematology 2008; 111-115
Clonal expansion in PNH
International PNH Interest Group Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, Hillmen P, Luzzatto L, Young N, Kinoshita T, Rosse W e Socié G
Classification A. Classical PNH
B. PNH in other bone marrow diseases
C. Subclinical PNH with other bone marrow diseases
(eg, PNH/AA)
Paroxysmal Nocturnal Hemoglobinuria
Diagnosis Who should be tested for PNH and how often?
* Initially once every 6 months; then annually
Bessler M and Hiken J. Hematology 2008; 104-110
Who should be tested for PNH?
n (%) Unexplained hemolytic anemia 59 (15.8) Cytopenia (s) 279 (74.8) Pancytopenia Anemia + thrombocytopenia Anemia + leucopenia Leucopenia + thrombocytopenia Thrombocytopenia Leucopenia
144 (38.6) 79 (21.2) 19 (5.0) 11 (3.0) 18 (4.8) 8 (2.2)
Thrombosis investigation 35 (9.4) Total 373 (100.0)
Hematology – HCFMUSP 1998 to 2009
89* patients with clone HPN (24%) 36/89 patients clone >50%
Hematology HC-FMUSP 1998 to 2009
40 (45%) Pancytopenia 24 (27%) Anemia + Thrombocytopenia 16 (18%) Anemia 2 (2%) Anemia + Leucopenia 3 (3%) Leucopenia + Thrombocytopenia 3 (3%) Thrombocytopenia 1 (1%) Normal CBC
Paroxysmal Nocturnal Hemoglobinuria
* 62 alive
Diagnosis Suportive laboratory tests
Reticulocytosis ↑ unconjugated bilirrubin ↑LDH Low haptoglobin Hemoglobinuria and Hemossiderinúria Erytroid hyperplasia in the bone marrow
Paroxysmal Nocturnal Hemoglobinuria
Diagnostic tests
• Ham test • Sucrose lysis test • Flow citometry
Paroxysmal Nocturnal Hemoglobinuria
Diagnosis Flow citometry analysis
• Preferred for the diagnosis of PNH
• Granulocytes / erythrocytes
• Determines the size of the clone (% of blood cells
deficient in the expression of GPI-anchored proteins)
• Useful to classify the PNH populations (I,II,III)
Paroxysmal Nocturnal Hemoglobinuria
Case Report: RGS
Granulocytes
Erythrocytes
LDH = 6402 U/L D-dimer = 24 ng/ml
Definition
Acquired clonal disease Intravascular hemolysis Thrombosis
Bone Marrow failure
Paroxysmal Nocturnal Hemoglobinuria
PNH and thrombosis
Development of life-threatening venous thrombosis particularly in veins: Cerebral Hepatic Portal Mesenteric Splenic Renal
40% thromboses during the course of the disease
Venous thrombosis is the major cause of death
Intravascular Hemolysis ↓ NO (scavenging through cell-free plasma Hb) Abdominal pain Erectil disfunction Endothelial disfunction Platelet activation
Thrombosis is related to the clone size Alterations of platelet and red cell membranes
including the formation of microparticules
Why do PNH patients have thrombosis? The pathophysiology of thrombosis in patients
with PNH is not fully understood
Hall C, Richards S, Hillmen P. Blood 2003; 102, 3587-3591
Why do PNH patients have thrombosis ?
Hugel B, Socié G, Vu T, Toti F, Gluckman E, Freyssinet JM, Scrobohaci ML Blood,1999,93:3451-56
Why do PNH patients have thrombosis?
Treatment - Thrombosis Acute phase → Heparin
Eculizumab
Avoid oral contraceptives Avoid pregnancy Bone marrow transplantation Secundary profilaxis
Paroxysmal Nocturnal Hemoglobinuria
Analysis of thrombosis before and during eculizumab therapy
Hilmen P. Hematology 2008;116-123
39 events
3 events
0 5
10 15 20 25 30 35 40 45
Pre-Eculizumab therapy
During Eculizumab therapy
Thro
mbo
sis
even
t rat
e
(TE
per 1
00 p
t-yea
rs)
P=0.0001
N=195
Why do PNH patients have thrombosis ?
Treatment - Thrombosis
Primary Profilaxis (If eculizumab is not available)
• PNH clone > 50% • Platelets above 100.000/mm3 • No contra-indication for anticoagulation • INR between 2-3
Paroxysmal Nocturnal Hemoglobinuria
Treatment -Thrombosis Primary Profilaxis ?
Hall C, Richards S, Hillmen P. Blood 2003; 102, 3587-91
Paroxysmal Nocturnal Hemoglobinuria
39
Eculizumab Blocks Terminal Complement
C3 C3a
C3b
C5
Prox
imal
Te
rmin
al
Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3):359-395. Walport MJ. N Engl J Med. 2001;344(14):1058-66. SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. Rother RP et al. Nature Biotech. 2007;25(11):1256-64.
Eculizumab
• Proximal functions of complement remain intact
• Weak anaphylatoxin • Immune complex clearance • Microbial opsonization
• Terminal complement - C5a and C5b-9 activity blocked
• Eculizumab binds with high affinity to C5
Complement Cascade
C5a
C5b Membrane Attack
Complex Cause of Hemolysis
in PNH
Follow-up 04/09/09 – First administration of Eculizumab (compassionate basis)
05/09/09 – Discharged after losing 15 Kg
After beginning the treatment with Soliris the abdominal pain disappeared as well the fatigue. She put on 11 Kg
16/03/10 – After fever and flu-like symptoms – ↓ Hb and ↑ LDH – blood transfusion (2units)
•Adverse events – After 1st and 2nd doses: headache – After 3rd dose: evanescent cutaneous erythema – Transitory increase in GGT and AP – Nov 2009 - DAT-positive (C3d)
Transfusional Requirement
0
2
4
6
8
10
12
jan/
07
fev/
07
mar
/07
abr/0
7
mai
/07
jun/
07
jul/0
7
ago/
07
set/0
7
out/0
7
nov/
07
dez/
07
jan/
08
fev/
08
mar
/08
abr/0
8
mai
/08
jun/
08
jul/0
8
ago/
08
set/0
8
out/0
8
nov/
08
dez/
08
jan/
09
fev/
09
mar
/09
abr/0
9
mai
/09
jun/
09
jul/0
9
ago/
09
set/0
9
out/0
9
nov/
09
dez/
09
jan/
10
fev/
10
mar
/10
Laparoscopic cholecystectomy April 2, 2009
Exploratory Laparotomy and appendectomy
May 21, 2009 Eculizumab First administration Sept 4, 2009
PNH diagnosed Sept 19, 2007
Abdominal pain since 2005
D-Dimer (ng/ml)
Eculizumab 1st Infusion Sept 4, 2009
ULN:< 500 ng/mL
LDH (U/L)
Multiple transfusions of Red Blood Cells (32 U)
1st Infusion of Eculizumab
0 10 20 30 40 50 60 70 80 90
100
Set/2
009
Out
/200
9
Nov
/200
9
Dez
/200
9
Fev/
2010
Mar
/201
0
Abr/2
010
Mai
/201
0 Ju
n/20
10
Jul/2
010
Ago/
2010
Set/2
010
Out
/201
0
Hemoglobin (g/dl)
CD59 Negative Clone (%)
Patient suffered Viral Infection
Eculizumab First Infusion Sept 4, 2009
DAT positive C3d deposition
Nov 2009
Flu-like symptoms and fever
March 2010
Granulocytes
Erythrocytes
• The surgical procedure probably was the trigger for thromboses and abdominal features in this case
• Was the laparoscopic cholecystectomy the best choice?
• Consistent with international clinical trials, treatment with eculizumab in this patient has:
–Reduced thrombotic complications, transfusion requirements and D-Dimer levels
–Stabilized Hemoglobin levels
–Near-normalized LDH levels, which were maintained
through the entire time course
Conclusions
• Eculizumab is the only drug for the treatment of PNH.
• When to initiate therapy rather than what therapy to initiate is often the most important clinical question
• Eculizumab is expensive, does not eradicate the PNH clone, and must be given lifelong
• It is best reserved for the symptomatic patient with a large percentage of PNH cells or the PNH patient with thrombosis irrespective of the PNH clone size.
• Additional experience with eculizumab should clarify the indications for initiating therapy, whether or not prophylactic anticoagulation is necessary, and whether it is safe to use this drug during pregnancy.
Conclusions (Brodsky, RA. Blood 2009 113: 6522-6527)
Acknowledgments
Guilherme H. Hencklain Fonseca
Liliana M. Suganuma
Deyse M. T. Moromizato
Iara K. Yokomizo
