Hematology Commons^™

Α-Synuclein Is The Major Platelet Isoform But Is Dispensable For Activation, Secretion, And Thrombosis, Alexis N. Smith, Smita Joshi, Harry Chanzu, Hammodah Rawhi Hammodah Alfar, Kanakanagavalli Shravani Prakhya, Sidney W. Whiteheart

Saha Cardiovascular Research Center Faculty Publications

Platelets play many roles in the vasculature ensuring proper hemostasis and maintaining integrity. These roles are facilitated, in part, by cargo molecules released from platelet granules via Soluble NSF Attachment Protein Receptor (SNARE) mediated membrane fusion, which is controlled by several protein-protein interactions. Chaperones have been characterized for t-SNAREs (i.e. Munc18b for Syntaxin-11), but none have been clearly identified for v-SNAREs. α- Synuclein has been proposed as a v-SNARE chaperone which may affect SNARE-complex assembly, fusion pore opening, and thus secretion. Despite its abundance and that it is the only isoform present, α-synuclein’s role in platelet secretion is uncharacterized. In …

Hypofibrinogenemia Following Injury In 186 Children And Adolescents: Identification Of The Phenotype, Current Outcomes, And Potential For Intervention, Justin Gerard, Jan-Michael Van Gent, Jessica Cardenas, Christian Gage, David E Meyer, Charles Cox, Charles E Wade, Bryan A Cotton

Faculty, Staff and Student Publications

OBJECTIVES: Recent studies evaluating fibrinogen replacement in trauma, along with newly available fibrinogen-based products, has led to an increase in debate on where products such as cryoprecipitate belong in our resuscitation strategies. We set out to define the phenotype and outcomes of those with hypofibrinogenemia and evaluate whether fibrinogen replacement should have a role in the initial administration of massive transfusion.

METHODS: All patients/17-4/21 were reviewed. We then evaluated all patients who received emergency-release and massive transfusion protocol (MTP) products. Patients were defined as hypofibrinogenemic (HYPOFIB) if admission fibrinogen(r-TEG) angleHYPOFIB, the impact on outcomes, and whether early replacement improved mortality. …

Design And Development Of A Clot Burst Pressure Device To Investigate Resuscitation Strategies, Atharwa R Mankame, Jacob B Schriner, Max A Skibber, Mitchell J George, Jessica C Cardenas, Charles S Cox, Brijesh S Gill

Faculty, Staff and Student Publications

Introduction: A reduction in clot strength is a hallmark feature of trauma-induced coagulopathy. A better understanding of clot integrity can optimize resuscitation strategies. We designed a device to gauge clot strength by pressurizing fluids over a formed clot and measuring the pressure needed to dislodge the clot. We hypothesized that this device could distinguish between clots formed in hypocoagulable and hypercoagulable states by observing differences in the clot burst pressure.

Methods: Whole blood from healthy volunteers was collected into sodium citrate tubes and was treated with heparin or fibrinogen to generate clots in a hypocoagulable or hypercoagulable state, respectively. Small …

Automated Large Vessel Occlusion Detection Software And Thrombectomy Treatment Times: A Cluster Randomized Clinical Trial, Juan Carlos Martinez-Gutierrez, Youngran Kim, Sergio Salazar-Marioni, Muhammad Bilal Tariq, Rania Abdelkhaleq, Arash Niktabe, Anjan N Ballekere, Ananya S Iyyangar, Mai Le, Hussain Azeem, Charles C Miller, Jon E Tyson, Sandi Shaw, Peri Smith, Mallory Cowan, Isabel Gonzales, Louise D Mccullough, Andrew D Barreto, Luca Giancardo, Sunil A Sheth

Faculty, Staff and Student Publications

Importance

The benefit of endovascular stroke therapy (EVT) in large vessel occlusion (LVO) ischemic stroke is highly time dependent. Process improvements to accelerate in-hospital workflows are critical.

Objective

To determine whether automated computed tomography (CT) angiogram interpretation coupled with secure group messaging can improve in-hospital EVT workflows.

Design, Setting, and Participants

This cluster randomized stepped-wedge clinical trial took place from January 1, 2021, through February 27, 2022, at 4 comprehensive stroke centers (CSCs) in the greater Houston, Texas, area. All 443 participants with LVO stroke who presented through the emergency department were treated with EVT at the 4 CSCs. Exclusion …

Characteristics And Clinical Outcomes Of Patients With Myeloid Malignancies And Ddx41 Variants, Alex Bataller, Sanam Loghavi, Yoheved Gerstein, Alexandre Bazinet, Koji Sasaki, Kelly S Chien, Danielle Hammond, Guillermo Montalban-Bravo, Gautam Borthakur, Nicholas Short, Ghayas C Issa, Tapan M Kadia, Naval Daver, Guilin Tang, Andres Quesada, Keyur P Patel, Farhad Ravandi, Warren Fiskus, Cristopher P Mill, Hagop M Kantarjian, Kapil Bhalla, Guillermo Garcia-Manero, Betul Oran, Courtney D Dinardo

Faculty, Staff and Student Publications

DDX41 is the most frequently mutated gene in myeloid neoplasms associated with germline predisposition including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We analyzed 3795 patients with myeloid neoplasms and identified 151 (4%) with DDX41 variants and a diagnosis of AML (n = 96), MDS (n = 52), and chronic myelomonocytic leukemia (n = 3). The most frequent DDX41 variants were the somatic variant p.R525H, followed by the germline variants p.M1I and p.D140fs. Most neoplasms had a normal karyotype (59%) and the most frequent co-mutations were TP53 (16%) and ASXL1 (15%). 30% of patients had no concomitant mutations besides …

Geographic Disparity Of Outcome In Patients With Cancer Over Decades: The Surveillance, Epidemiology, And End Results, Koji Sasaki, Kiyomi Morita, Hagop Kantarjian, Guillermo Garcia-Manero, Elias Jabbour, Farhad Ravandi, Marina Konopleva, Gautam Borthakur, William Wierda, Naval Daver, Koichi Takahashi, Courtney Dinardo, Guillermo Montalban Bravo, Ghayas C Issa, Sherry A Pierce, Kelly A Soltysiak, Martha S Tingen, Jorge E Cortes

Faculty, Staff and Student Publications

Background: Improvements in prevention, early detection, and effective cancer therapy have decreased cancer-related mortality; however, significant health disparities exist. Therefore, we investigated the impact of these disparities on survival.

Methods: In the Surveillance, Epidemiology, and End Results, we identified 784,341 patients with cancer between 1990 and 2016 in Georgia, 68,493 between 1990 and 1999; 371,353 between 2000 and 2009; and 322,932 between 2010 and 2016. We assessed the overall survival (OS) of patients with all cancers, chronic myeloid leukemia (CML), and lung cancer, given the dramatic improvement in outcomes in patients with CML since 2000 compared to the generally considerably …

Tak1 And Tbk1 Are Differentially Required By Gmp- And Lmpp-Like Leukemia Stem Cells, Austin P. Runde, Joseph Michael Cannova, Ryan Mack, Kanak Joshi, Mark Sellin, Allan Youmaran, Mattias Lenz, Rohit Thalla, Wei Wei, Peter Breslin S.J., Jiwang Zhang

School of Medicine

Acute myeloid leukemia (AML) encompasses a diverse group of cancers that originate in the blood-forming tissues of the bone marrow. Aside from the M3 subtype (PML-RARA⁺), AML carries a 5-year survival rate of 28% for patients 20+ years of age. AML is the most common cancer of the hematopoietic system and is slightly more common in biological males; the average age at diagnosis is 68 years. Standard frontline treatment for AML is a 2-phase regimen of intensive chemotherapy (CTx) employing daunorubicin and cytarabine. Despite 60-70% of patients achieving complete remission (CR), at least half of CR-achieving patients …

A Phase I Trial Of Sirolimus With "7&3" Induction Chemotherapy In Patients With Newly Diagnosed Acute Myeloid Leukemia, Neil Palmisiano, Grace Jeschke, Lindsay Wilde, Onder Alpdogan, Matthew Carabasi, Joanne Filicko-O'Hara, Dolores Grosso, Thomas Klumpp, Ubaldo Martinez, John L Wagner, Martin Carroll, Alexander Perl, Margaret Kasner

Department of Medicine Faculty Papers

Chemotherapy remains a primary treatment for younger AML patients, though many relapse. Data from our group have shown that highly phosphorylated S6 in blasts may predict response to sirolimus given with chemotherapy. We report the results of a phase I study of this combination in newly diagnosed AML and the pharmacodynamic analysis of pS6 before and after treatment. Subjects received sirolimus (12 mg on day 1, 4 mg daily, days 2-10), then idarubicin and cytarabine (days 4-10). Response was assessed at hematologic recovery or by day 42 using a modified IWG criteria. Fifty-five patients received sirolimus. Toxicity was similar to …

Somatic Mutational Landscape Of Hereditary Hematopoietic Malignancies Caused By Germline Variants In Runx1, Gata2, And Ddx41, Claire C Homan, Michael W Drazer, Kai Yu, David M Lawrence, Jinghua Feng, Luis Arriola-Martinez, Matthew J Pozsgai, Kelsey E Mcneely, Thuong Ha, Parvathy Venugopal, Peer Arts, Sarah L King-Smith, Jesse Cheah, Mark Armstrong, Paul Wang, Csaba Bödör, Alan B Cantor, Mario Cazzola, Erin Degelman, Courtney D Dinardo, Nicolas Duployez, Remi Favier, Stefan Fröhling, Ana Rio-Machin, Jeffery M Klco, Alwin Krämer, Mineo Kurokawa, Joanne Lee, Luca Malcovati, Neil V Morgan, Georges Natsoulis, Carolyn Owen, Keyur P Patel, Claude Preudhomme, Hana Raslova, Hugh Rienhoff, Tim Ripperger, Rachael Schulte, Kiran Tawana, Elvira Velloso, Benedict Yan, Erika Kim, Raman Sood, Amy P Hsu, Steven M Holland, Kerry Phillips, Nicola K Poplawski, Milena Babic, Andrew H Wei, Cecily Forsyth, Helen Mar Fan, Ian D Lewis, Julian Cooney, Rachel Susman, Lucy C Fox, Piers Blombery, Deepak Singhal, Devendra Hiwase, Belinda Phipson, Andreas W Schreiber, Christopher N Hahn, Hamish S Scott, Paul Liu, Lucy A Godley, Anna L Brown, Nisc Comparative Sequencing Program

Faculty, Staff and Student Publications

Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high …

Activation Of Coagulation And Proinflammatory Pathways In Thrombosis With Thrombocytopenia Syndrome And Following Covid-19 Vaccination, Malika Aid, Kathryn E. Stephenson, Ai-Ris Y. Collier, Joseph P. Nkolola, James V. Michael, Steven E. Mckenzie, Dan H. Barouch

Cardeza Foundation for Hematologic Research

Thrombosis with thrombocytopenia syndrome (TTS) is a rare but potentially severe adverse event following immunization with adenovirus vector-based COVID-19 vaccines such as Ad26.COV2.S (Janssen) and ChAdOx1 (AstraZeneca). However, no case of TTS has been reported in over 1.5 million individuals who received a second immunization with Ad26.COV2.S in the United States. Here we utilize transcriptomic and proteomic profiling to compare individuals who receive two doses of Ad26.COV2.S with those vaccinated with BNT162b2 or mRNA-1273. Initial Ad26.COV2.S vaccination induces transient activation of platelet and coagulation and innate immune pathways that resolve by day 7; by contrast, patients with TTS show robust …

Impairment Of Serine Transport Across The Blood-Brain Barrier By Deletion Of Slc38a5 Causes Developmental Delay And Motor Dysfunction, Inna Radzishevsky, Maali Odeh, Oded Bodner, Salman Zubedat, Lihi Shaulov, Maxim Litvak, Kayoko Esaki, Takeo Yoshikawa, Bella Agranovich, Wen-Hong Li, Alex Radzishevsky, Eyal Gottlieb, Avi Avital, Herman Wolosker

Faculty, Staff and Student Publications

Brain L-serine is critical for neurodevelopment and is thought to be synthesized solely from glucose. In contrast, we found that the influx of L-serine across the blood-brain barrier (BBB) is essential for brain development. We identified the endothelial Slc38a5, previously thought to be a glutamine transporter, as an L-serine transporter expressed at the BBB in early postnatal life. Young Slc38a5 knockout (KO) mice exhibit developmental alterations and a decrease in brain L-serine and D-serine, without changes in serum or liver amino acids. Slc38a5-KO brains exhibit accumulation of neurotoxic deoxysphingolipids, synaptic and mitochondrial abnormalities, and decreased neurogenesis at the dentate gyrus. …

Immune-Depleted Tumor Microenvironment Is Associated With Poor Outcomes And Btk Inhibitor Resistance In Mantle Cell Lymphoma, Preetesh Jain, Krystle Nomie, Nikita Kotlov, Vitaiy Segodin, Holly Hill, Chi Young Ok, Ahmed Fetooh, Rashmi Kanagal-Shamanna, Francisco Vega, Alexander Bagaev, Nathan Fowler, Christopher R Flowers, Michael Wang

Faculty, Staff and Student Publications

Mantle cell lymphoma (MCL) is a generally aggressive B cell non-Hodgkin lymphoma (B-NHL). Outcomes of patients have improved in the era of Bruton’s tyrosine kinase inhibitors (BTKi). However, MCL patients can develop resistance to BTKi over time and can progress [1]. Ibrutinib resistance in MCL is correlated with an overexpression of OXPHOS, MYC and PI3K/AKT/m-TOR pathways. Somatic mutations in TP53, KMT2D, NSD2, SMARCA4, CCND1, TRAF2, NFKBIE genes are reported with ibrutinib resistance [2]. A few reports have also demonstrated that a decrease in T cell numbers [3, 4] or a downregulation of effector/cytotoxic …

Sickle Cell Anemia In Hispanic-Americans In South Texas: Two Case Reports, Ashika A. Chacko, Shadi Jafari-Esfahani, Nevin A. Varghese

Research Colloquium

Introduction: Sickle cell anemia and traits are well described in the African-American population. Hispanic Americans are an underappreciated community affected by Sickle cell disease, where it affects about every 1 in 16300 live births compared to 1 in every 365 African-American births.Hence, it is essential to acknowledge the incidence in Latin American origin people to provide competent and specific care to these populations.

Case Description: Case 1: A 28-year-old Latin-American lady with sickle cell anemia, multiple transfusions, and exchange transfusion in the past presented with complaints of lower back and lower extremity pain. The patient got admitted with acute sickle …

Covid-19 As A Second Hit For Anti-Phospholipid Syndrome, Himabindu Kolli, Pooja Maknoor, Celin Rajan, Nevin Varghese

Research Colloquium

Background: Anti-phospholipid syndrome (APS) is an autoimmune disorder characterized by venous and arterial thrombosis, usually in setting of underlying autoimmune disorders. Here, we present a case of anti-phospholipid syndrome post covid infection.

Case Presentation: 41-year-old lady presented to the ER with complaints of left sided facial droop for 3-day duration. On further evaluation, she was found to have subacute ischemic stroke and was managed with anticoagulation and supportive treatment. Past medical history is significant for a recent diagnosis of Covid infection and for subsequent development of lower extremity deep vein thrombosis (DVT). She was started on anticoagulation with rivaroxaban for …

Activated Protein C, Protein S, And Tissue Factor Pathway Inhibitor Cooperate To Inhibit Thrombin Activation, Xian Li, Xiaohong Song, Dlovan F. D. Mahmood, Martha M. S. Sim, Sara J. Bidarian, Jeremy P. Wood

Saha Cardiovascular Research Center Faculty Publications

Introduction: Thrombin, the enzyme which converts fibrinogen into a fibrin clot, is produced by the prothrombinase complex, composed of factor Xa (FXa) and factor Va (FVa). Down-regulation of this process is critical, as excess thrombin can lead to life-threatening thrombotic events. FXa and FVa are inhibited by the anticoagulants tissue factor pathway inhibitor alpha (TFPIα) and activated protein C (APC), respectively, and their common cofactor protein S (PS). However, prothrombinase is resistant to either of these inhibitory systems in isolation. Materials and methods: We hypothesized that these anticoagulants function best together, and tested this hypothesis using purified proteins and plasma-based …

Renal Cell Carcinoma Of Variant Histology: Biology And Therapies, Pavlos Msaouel, Giannicola Genovese, Nizar M Tannir

Faculty, Staff and Student Publications

The term variant histology renal cell carcinomas (vhRCCs), also known as non-clear cell RCCs, refers to a diverse group of malignancies with distinct biologic and therapeutic considerations. The management of vhRCC subtypes is often based on extrapolating results from the more common clear cell RCC studies or basket trials that are not specific to each histology. The unique management of each vhRCC subtype necessitates accurate pathologic diagnosis and dedicated research efforts. Herein, we discuss tailored recommendations for each vhRCC histology informed by ongoing research and clinical experience.

Variant Of Fii Gene Plays A Critical Role In Coagulation Potential In Mexican-Americans, Hoang Anh T. Nguyen, Shuchita Vijay Jhaveri, Marcio A. Almeida, Vincent P. Diego, Satish Kumar, Juan M. Peralta, Joanne E. Curran, Bernadette W. Luu, Donna M. Lehman, Ralph A. Defronzo, Laura Almasy, Sarah Williams-Blangero, Ravi Duggirala, John Blangero, Tom Howard

Research Symposium

Background: Disruption in the balance between coagulation and bleeding can result in varying phenotypes such as hypercoagulability and can lead to the development of cardiovascular disease. In our study utilizing extended families of Mexican-Americans from South Texas, we performed a search for protein-altering variants influencing coagulation potential.

Methods: Mexican-Americans in the study were genotyped using Illumina-(human)-exome-24 chip to screen for protein-altering variants. Variants were analyzed for their association with FII activity, aPTT, and PT. Linear-mixed-model analysis was performed to estimate trait heritabilities and to interrogate single nucleotide variations (SNV) for evidence of genetic association. To control for multiple testing, associations …

A Whole Clotta Pain: A Case Of Ivc Thrombosis Presenting As Severe Abdominal Pain In A Patient With Anti-Phospholipid Syndrome, Mery Bartl, Christine E. Loftis, Josenny Rodriguez-Paez, Emilia C. Dulgheru

Research Symposium

Background: Anti-phospholipid syndrome (APS) is an immune-mediated condition characterized by the presence of antiphospholipid antibodies in the setting of venous and arterial thrombosis and or pregnancy loss [1]. APS can be a primary syndrome or can be associated with connective tissue diseases such as systemic lupus erythematosus. The goal of treatment in patients with APS is to decrease the risk of thromboembolic events and the standard of care is warfarin therapy. We describe a case of a 42-year-old gentleman with a history of APS on anticoagulation with apixaban who presented to the hospital with severe abdominal pain secondary to infrarenal …

Pet Imaging Of Microglia Using Pbr28suv Determines Therapeutic Efficacy Of Autologous Bone Marrow Mononuclear Cells Therapy In Traumatic Brain Injury, Supinder S Bedi, Michael C Scott, Max A Skibber, Akshita Kumar, Henry W Caplan, Hasen Xue, David Sequeira, Alison L Speer, Fanni Cardenas, Franciska Gudenkauf, Karen Uray, Amit K. Srivastava, Alan R Prossin, Charles S Cox

Cardeza Foundation for Hematologic Research

Traumatic brain injury (TBI) results in activated microglia. Activated microglia can be measured in vivo by using positron emission topography (PET) ligand peripheral benzodiazepine receptor standardized uptake values (PBR28suv). Cell based therapies have utilized autologous bone marrow mononuclear cells (BMMNCs) to attenuate activated microglia after TBI. This study aims to utilize in vivo PBR28suv to assess the efficacy of BMMNCs therapy after TBI. Seventy-two hours after CCI injury, BMMNCs were harvested from the tibia and injected via tail-vein at 74 h after injury at a concentration of 2 million cells per kilogram of body weight. There were three groups of …

Epichaperome Inhibition Targets Tp53-Mutant Aml And Aml Stem/Progenitor Cells, Bing Z Carter, Po Yee Mak, Muharrem Muftuoglu, Wenjing Tao, Baozhen Ke, Jingqi Pei, Andrea D Bedoy, Lauren B Ostermann, Yuki Nishida, Sevinj Isgandarova, Mary Sobieski, Nghi Nguyen, Reid T Powell, Margarita Martinez-Moczygemba, Clifford Stephan, Mahesh Basyal, Naveen Pemmaraju, Steffen Boettcher, Benjamin L Ebert, Elizabeth J Shpall, Barbara Wallner, Robert A Morgan, Georgios I Karras, Ute M Moll, Michael Andreeff

Faculty, Staff and Student Publications

TP 53-mutant acute myeloid leukemia (AML) remains the ultimate therapeutic challenge. Epichaperomes, formed in malignant cells, consist of heat shock protein 90 (HSP90) and associated proteins that support the maturation, activity, and stability of oncogenic kinases and transcription factors including mutant p53. High-throughput drug screening identified HSP90 inhibitors as top hits in isogenic TP53-wild-type (WT) and -mutant AML cells. We detected epichaperomes in AML cells and stem/progenitor cells with TP53 mutations but not in healthy bone marrow (BM) cells. Hence, we investigated the therapeutic potential of specifically targeting epichaperomes with PU-H71 in TP53-mutant AML based on its preferred binding to …