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Clinical Pathological Conference Elizabeth Ross, M.D. Chief Resident Department of Medicine October 12th, 2007 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 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 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 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 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 0 104 10 M1 M2 M2 0 101 102 103 104 10 CD16- FITC 101 102 103 CD55 PE M2 104 100 101 M1 102 103 CD59 PE 104 RBC PNH 06-1 13.0 01 R2 75% 88% M2 0 20 0 40 0 60 0 80 0 10 00 Fo rwa rd Scatte r M1 100 101 102 103 104 CD55 PE 100 101 102 CD59 PE CD 59 103 104 M1 M2 100 101 102 103 104 Glyco phori n 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 High rates of thrombosis reported in the United States, Europe and India 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 Hillmen et al, NEJM, 1995 PNH 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, 2006) 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 Follow-up 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 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 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