2019 Research Forum

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Leila Moosavi MD R3, Jonathan Bowen MS IV, Carlos D'Asumpcao MD R1, Jeffrey Coleman MD R2, Arash Heidari MD, Everardo Cobos MD A CASE OF AML AND TRISOMY 8 WITH CONCOMITANT FACTOR VII DEFICIENCY

Department of Medicine Kern Medical

B)NormalFemaleKaryotype46XX,approx..8months postpresentation

Introduction

Cytogenetics & Cytopathology Initial Bone Marrow Biopsy (BMB) showed a cellularity consisting of approximately 70% immature myeloid blasts( Figure C ), the phenotype of the neoplastic cells showed blasts with strong expression CD 117+ , and dim HLA-DR and on the extended flow panel CD38+,HLA-B27, and negative for lymphoid markers Bone marrow cytogenetic analysis revealed mosaic trisomy 8 with translocation of chromosome X and 8 (See Figure 4A ) Furthermore, Molecular Biology workup detected gene mutations: CEBPA, IDH1, JAK2 V617F, and U2AF1 which confirmed the presence of abnormal neoplastic cells consistent with AML. Repeat bone marrow Biopsy on day 15 of hospital stay showed persistent blasts, but decreased in number from prior biopsy. (Figure D) However, further chemotherapy treatments were temporarily postponed as patient developed gram negative bacteremia, pancytopenia, and ANC of 0. After completing two inductions of chemotherapy, repeat bone marrow aspiration showed no residual blasts. In addition repeat molecular biology and flow cytometry were significant as they revealed patient’s trisomy 8 and previous molecular abnormalities all have cleared. (Figure B, E)

Discussion

Factor VII has a short half life and needs vitamin K for carboxylation of glutamic acid residue. NQO1 catalyzes the reduction of various quinones including vitamin K.

We report a 41 year-old Hispanic female with Acute Myeloid Leukemia(AML) associated with trisomy 8 and factor VII deficiency which is believed both to be acquired and cleared after induction chemotherapy. There are only two prior reported cases of acquired Factor 7 deficiency described in the literature, both associated with aspergillus infections[2]. We report the third case of acquired factor 7 deficiency and the second one with an associated Trisomy 8 cytogenetic abnormality. Acute Myeloid Leukemia (AML) is a heterogenous disorder that results from a block in the differentiation of hematopoietic progenitor cells along with uncontrolled proliferation. Trisomy 8 (+8) is the most common numerical chromosome abnormalities seen in acute myeloid leukemia (AML), occurring in 9% of adult patients, these patients are mostly classified as having an intermediate prognosis [1]. Acquired Factor VII deficiency has been reported in 31 cases and has been described with malignancy, sepsis, postoperatively, aplastic anemia, and during bone marrow transplantation. A 41-year-old Hispanic female with no past medical history presented with fever, severe headache, fatigue, bleeding gums, menorrhagia, and severe pancytopenia. Physical exam was significant for bilateral upper extremity spontaneous ecchymoses, pale conjunctivae and mucosal pallor, and diffuse petechiae over entire body. Initial labs revealed pancytopenia with severe neutropenia with 1% blast (Table 1). Coagulation panel was significant for elevated Prothrombin Time (PT) while International Normalized ratio (INR) and Partial Thromboplastin Time (PTT) were within normal limits (Table 4). Computed Tomography (CT) was negative for any hepatomegaly, splenomegaly, and cranial imaging was negative for any intracranial bleeding or abnormality. Blasts found in the peripheral blood smear guided our suspicion of an underlying hematological abnormality. Case Presentation

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Conclusions It’s not entirely clear why trisomy 8 leads to abnormalities of Factor VII However, since factor VII is a vitamin K dependent factor, one possibility is the association of Trisomy 8 with the NAD(P)H:Quinone pathway (NQO1)A high frequency of NAD(P)H:quinone oxidoreductase 1 (NQO1) C(609)T germline polymorphism in MDS/AML with trisomy 8 has been reported While trisomy 8 is the most common trisomy in AML, this is the first reported case to the best of our knowledge of t(8,X) translocation resulting in AML, as well as an incidental finding of factor VII deficiency we believe to have been induced and resolved with chemotherapy. Most commonly, factor VII deficiency is congenital but it may be possible to acquired inhibitors of coagulation There appears to be a link between trisomy 8 cytogenetic aberrations and the level or function of Factor VII. Prior reports have highlighted the association of trisomy 8 and multiple hemorrhages and trisomy 8 controlling the expression of factor Vll [10]. References 1. H Becker, K Maharry, K Mrozek, S Volinia, A-K Eisfeld, M D Radmacher, K kohlschmidt, K H Metzeler, S Schwind, S P Whitman, J H Mendler, Y-Z Wu, D Nicolet, P Paschka, B L Powell, T H Carter, M Wetzler, J E Kolitz, A J Carrol, M R Baer, M A Caligiuri, R M Stone, G Marcucci; Prognostic gene mutations and distinct gene-and microRNA-expression signatures in acute myeloid leukemia with a sole trisomy 8, Leukemia. 2014 Aug;28(8):1754-1758 (2014) 2. Soumaya Anoun, Mouna Lamchahab, Bouchra Oukkache, Maryam Qachouh, Said Benchekroun and Asmaa Quessar; Acquired factor VII deficiency associated with acute myeloid leukemia: Blood Coagulation and fibrinolysis: April 2015,26:331-333 3. de Grouchy J, Dautzenberg MD, Turleau C, Beguin S, Chavin-Colin F. Regional mapping of clotting factors VII and X to 13q34. Expression of factor VII through chromosome 8 HumGenet. 1984;66(2-3):230-3 4. Soumaya Anoun, Mouna Lamchahab, Bouchra Oukkache, Maryam Qachouh, Said Benchekroun and Asmaa Quessar ; Acquired factor VII deficiency associated with acute myeloid leukemia: Blood Coagulation and fibrinolysis: April 2015,26:331-333 5. de Grouchy J, Dautzenberg MD, Turleau C, Beguin S, Chavin-Colin F. Regional Mapping Of Clotting Factors VII And X To 13q34. Expression Of Factor VII Through Chromosome 8. Hum Genet. 1984;66(2-3):230-3 6. Zachaki S, Stavropoulou C, Koromila T, Manola KN, Kalomoiraki M, Daraki A, Koumbi D, Athanasiadou A, Kanavakis E, Kollia P, Sambani C. High frequency of NAD(P)H:quinone oxidoreductase 1 (NQO1) C(609)T germline polymorphism in MDS/AML with trisomy 8. Leuk Res. 2013 Jul;37(7):742-6. doi: 10.1016/j.leukres.2013.04.015. Epub 2013 May 1. 7. Caramazza D, Lasho TL, Finke CM, Gangat N, Dingli D, Knudson RA, Siragusa S, Hanson CA, Pardanani A, Ketterling RP, Tefferi A . IDH mutations and trisomy 8 in myelodysplastic syndromes and acute myeloid leukemia. Leukemia. 2010 Dec;24(12):2120-2. doi: 10.1038/leu.2010.213. Epub 2010 Sep 23. 8. White B, Martin M, Kelleher S, Browne P, McCann SR, Smith OP. Successful use of recombinant FVIIa (Novoseven) in the management of pulmonary haemorrhage secondary to Aspergillus infection in a patient with leukaemia and acquired FVII deficiency. Br J Haematol. 1999 Jul;106(1):254-5. 9. Lazjuk GI, Lurie IW, Usova YI, Gurevich DB, Nedzved MK. Trisomy 8p due to the 3:1 segregation of the balanced translocation t(8;15)mat. Hum Genet. 1979 Feb 15;46(3):335- 9 10.Fagan K, Wilkinson I, Allen M, Brownlea S.The coagulation factor VII regulator is located on 8p23.1. Hum Genet. 1988 Aug;79(4):365-7. It would be of interest for future studies to prospectively evaluate coagulation and to specifically investigate factor VII levels, factor VII inhibitor assays, vitamin K level and document any associated fungal infections, and assess for NQO1 germline polymorphism in trisomy 8 related MDS/AML patients.

Figure A. Abnormal Karyotype: 47,X,t(X;8)(q13:q24.1),+8[6]/46,XX[14] obtained one day after presentation and

Figure B) Normal Female Karyotype 46XX,[20] . After Two inductions of Chemotherapy.

C

D

E

Complete Blood Count WBC (4.0-11.0x10^3/uL) RBC (3.8-5.3x10^6/ uL)

Day 1 1.2 L 1.22 L

←

Hemoglobin (Hgb) (11.5-15.3 gm/dL)

4.6 L

Hematocrit (Hct) (34.0-45.0%)

13.4 L

MCV (80-100)

110.3 H

Platelets (155-400x10^3 /uL) Neutrophil No. (1.6-7.7x10^3/uL) Lymphocyte No. (1.0-4.5 x10^3/uL) Monocyte No. (0.1-1.0 x10^3/uL)

13 L 0.3 L 0.9 L 0.0 L

Table 1: Complete Blood Count (CBC) on day 1

Figure E : 40x magnification. s/p 2 cycles of chemotherapy Sections of the core show unremarkable bone trabeculae and a marrow cellularity of approximately 50%. Erythroid and myeloid elements are evenly distributed and scattered megakaryocytes are present . There is no evidence of lymphoid aggregates or metastatic malignancy.

Figure D : 20x magnification. s/p one cycle of chemotherapy day 15.Sections of the core show marrow cellularity of approximately 30%, with a background of degenerating cells and serous atrophy . No megakaryocytes or erythroid colonies are noted . Scattered cells appear to be degenerating immature cells and some plasma cells, predominantly.

Basic Metabolic Panel

Day 1

Figure C : 40x magnification. Day 2 Sections of the core show cellularity of approximately 70%. Erythroid elements and megakaryocytes are decreased, and the main population appears to be immature cells with slightly enlarged round to oval nuclei and clear cytoplasm .

Sodium (Na) (136-145 mEq/L) Potassium (K) (3.5-5.1mEq/L) Chloride (Cl) (98-107 mEq/L) Bicarbonate(HCO3-) (21-32 mEq/L)

136

3.4L

106

24

Chemotherapy Acquired Factor 7 Deficiency

Glucose (74-100 mg/dL)

113H

BUN (7-18 mg/dL)

6L

Creatinine, blood (0.60-1.10 mg/dL) Calcium (Ca2+) (8.5-10.1 gm/dL)

0.49L

8.2L

CoagulationPanel*

Day1 *

Day 3 Day10 ‡ Day23 Day 52

Albumin (3.4-5.0 gm/dL)

3.7 8.2

Initial chemotherapy induction of Cytarabine(Ara-C) and Daunarubicin 7+3 infusion was begun four days after initial presentation on the basis of AML. Additionally, patient had consistently isolated elevated PT without bleeding events due to factor VII level deficiency which was confirmed by correction of PT on mixing study. Also Shown is resolution of factor VII deficiency post chemotherapy

Total Protein, blood (6.4-8.2 gm/dL)

Prothrombin Time (12.5-14.2s)

15.2H 16.5H 14.6 H 18.7 H 12.9

Table 2: Basic Metabolic Panel Day 1

International normalized ratio (0.9-1.1)

1.22 H 1.36H 1.16 1.61H 0.98

LIVER FUNCTION TESTS

Day 1

Partial Thromboplastin time (25.4-37.6s) 25.2 L 28.8 21.6L 37.3 n/a

AST (15-37 U/L) ALT (30-65 U/L)

9 L

110

Factor VII (factor 7) (60-150)%

49 L

18 L

Alkaline Phosphatase (ALP)(45-117 U/L)

77

Table 4. Coagulation Panel and Factor 7 deficiency and resolution post chemotherapy

Total Bilirubin (0.0-1.0 mg/dL)

0.5

*days since presentation ‡ completed 6/7 days of first cycle of chemotherapy

Table 3 : Liver Function Tests day 1

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