Brian Curtis, PhD, D(ABMLI), MT(ASCP) SBB

Transfusion Medicine

The focus of my lab’s research is on detection and characterization of platelet and neutrophil-reactive antibodies and antigens and studies of the glycoproteins that carry these antigens. The primary goal is to apply the results of this work to develop new and improved clinical tests for use by the Diagnostic Laboratories at Blood Center of Wisconsin. 

Drug-Dependent Platelet Antibodies

Some people develop antibodies against their platelets, red blood cells, or white blood cells following receipt of medications. Our Platelet & Neutrophil Immunology Reference Lab currently tests for drug-dependent platelet and white blood cell antibodies, and to date, we have identified drug-dependent antibodies in patients’ blood samples for over 60 drugs, including vancomycin, sulfa-drugs, beta-lactam antibiotics, and even over-the-counter medications like ibuprofen and Tylenol (view complete list). We currently have laboratory and clinical studies in progress, together with researchers at BRI, to better understand the formation of drug-dependent antibodies and their clinical significance. 

Studies of CD36 on Platelets

We showed that ~3% of African-Americans lack the protein CD36/glycoprotein IV on their platelets. CD36 is a receptor for malaria-infected red blood cells, and absence of the protein from platelets and monocytes may play a role in malaria infection. Studies are ongoing to identify the rate of alloimmunization to CD36 in patients with CD36 deficiency and the role of these antibodies in immune platelet disorders. 

Low Frequency Human Platelet Alloantigens (HPA)

The Platelet & Neutrophil Immunology Lab performs testing on over 400 samples each year to aid physicians in the clinical diagnosis of fetal & neonatal alloimmune thrombocytopenia (FNAIT). FNAIT is a disorder in pregnancy in which a mother makes antibodies against her baby’s platelets resulting in destruction of the baby’s platelets leading to severe bleeding into the baby’s brain (ICH) and even death. It is thus important that laboratory testing for FNAIT be thorough, including the ability to detect maternal antibodies reactive with low frequency or new HPA (view list Platelet Antigen Database). We are working with cutting-edge methods to detect and characterize newly discovered HPA.

Leukocyte Antibodies in TRALI

Transfusion-Related Acute Lung Injury (TRALI) is a severe reaction that some patients experience following transfusion of blood or plasma. TRALI is currently the number one cause of transfusion-related death reported to the Food and Drug Administration (FDA). In a significant number of TRALI cases, the plasma from donors of the implicated blood products contains leukocyte antibodies (HLA and neutrophil) that cause activation of the patient’s neutrophils, leading to TRALI. One of the antigens targeted by such antibodies is designated human neutrophil antigen (HNA)-3a, which has been implicated in numerous severe cases of TRALI, many of them fatal. We identified the protein carrier (CTL2) of HNA-3a and HNA-3b, alleles of gene SLC44A2. We are also investigating the use of tests that could be used to screen blood donors for antibodies against HNA-3 as a TRALI risk-reduction measure.

Versiti Moonshot Fund, "Designer Blood Cells Using CRISPR-Cas 9 Gene Editing," Role: PI (2019)

Allison Ujcich
Director, Diagnostic Hematology

Mia Sullivan 
Technical Specialist

• Curtis BR, Edwards JT, Hessner MJ, Klein JP, Aster RH. Blood group A and B antigens are strongly expressed on platelets of some individuals. Blood 2000;96:1574-1581.
• Aitman TJ, Cooper LD, Norsworthy JP, Wahid FN, Gray JK, Curtis BR, McKeigue PM, Kwiatkowski D, Greenwood BM, Snow RW, Hill AV, Scott J. Malaria susceptibility and CD36 mutation. Nature 2000;405:1015-1016.
• Curtis BR, Bussel JB, Manco-Johnson M, Aster RH, McFarland JG. Fetal and neonatal alloimmune thrombocytopenia in pregnancies involving in vitro fertilization: a report of four cases. Am J Obstet and Gynecol 2005;192:543-547.
• Silliman CC, Curtis BR, Kopko P, Khan SY, Kelher M, Shuler R, Sannoh B, Ambruso DR. Donor antibodies to HNA-3a implicated in TRALI reactions prime neutrophils and cause PMN-mediated damage to human pulmonary microvascular endothelial cells in a two-event in vitro model. Blood 2007;109:1752-1755.
• Von Drygalski A, Curtis BR, Bougie DW, McFarland JG, Ahl S, Limbu I, Baker KR, Aster RH. Vancomycin-induced immune thrombocytopenia. N Engl J Med 2007;356:904-910.
• Podrez EA, Byzova TV, Febbraio M, Salomon RG, Ma Y, Valiyaveettil M, Poliakov E, Sun M, Finton PJ, Curtis BR, Chen J, Zhang R, Silverstein RL, Hazen SL. Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. Nature Medicine 2007;13:1086-1095.
• Curtis BR, Fick A, Lochowicz, McFarland JG, A, Ball RH, Peterson, JA, Aster RH. Neonatal alloimmune thrombocytopenia (NATP) associated with maternal fetal incompatibility for blood group B. Transfusion 2008;48:358-364.
• Curtis BR, Cox NJ, Sullivan MJ, Konkashbaev A, Bowens K, Hansen K, Aster RH. The neutrophil alloantigen HNA-3a (5b) is located on choline transporter- like protein 2 (CTL2) and appears to be encoded by an R>Q154 amino acid substitution. Blood 2010;115:2073-2076.
• Reese JA, Li X, Hauben M, Aster RH, Bougie DW, Curtis BR, George JN, Vesely SK. Identifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods. Blood 2010;116(12):2127-2133.
• Curtis BR, Sullivan MJ, Holyst T, Szabo A, Bougie, DW, Aster RH. A 36-mer peptide from CTL2 containing arginine 154 is recognized by a subset of HNA-3a alloantibodies implicated in TRALI. Transfusion 2011; ;51:2168-2174.
• Adam Kanack, Julie A Peterson, Mia Sullivan, Daniel W Bougie, Brian R Curtis, Richard H Aster. Full-length recombinant choline transporter-like protein 2 containing arginine 154 reconstitutes the epitope recognized by HNA-3a antibodies. Transfusion 2012;52(5):1112-6.
• Roos Achterbergh, Eric Vermeer, Brian Curtis, Leendert Porcelijn, Richard H Aster, Wendy Deenik, Karin Daemen-Gubbels. Thrombocytopenia in a nutshell. Lancet 2012;379:776.
• Krista Bowens, Mia Sullivan, Brian R. Curtis. Determination of neutrophil alloantigen HNA-3a and HNA-3b genotype frequencies in six racial groups by high-throughput 5’ exonuclease assay. Transfusion 2012 Nov; 52(11):2368-2374. 
• GM Thomas, C Carbo, BR Curtis, K Martinod, IB Mazo, D Schatzberg, SM Cifuni, TA Fuchs, UH von Andrian, JH Hartwig, RH Aster, DD Wagner. Extracellular DNA traps are associated with pathogenesis of TRALI in humans and mice. Blood 2012; 119:6335-6343. 
• JG McFarland, AJ Lochowicz, RH Aster, BT Chappell, BR Curtis. Improving the specificity of the PF4 ELISA in diagnosing heparin-induced thrombocytopenia. Am J Hematol 2012;87:776–781.
• Curtis BR, McFarland JG.  Human platelet antigens - 2013.  Vox Sang 2014; 106:93-102.
• Brian R. Curtis. Drug-induced immune thrombocytopenia: incidence, clinical features, laboratory testing, and pathogenic mechanisms. Immunohematology 2014;30(2):55-65.
• Anand Padmanabhan, Curtis G. Jones, Daniel W. Bougie, Brian R. Curtis, Janice G. McFarland, Demin Wang and Richard H. Aster. Heparin-independent, PF4-dependent binding of HIT antibodies to platelets: implications for HIT pathogenesis. Blood 2015;125:155-161.
• Mia J. Sullivan, Julie Peterson, Janice G. McFarland, Daniel Bougie, Richard H. Aster, Brian R. Curtis. A new low frequency alloantigen (Khab) located on platelet glycoprotein IIIa as a cause of maternal sensitization leading to neonatal alloimmune thrombocytopenia. Transfusion 2015;55:1584-1585.
• DM Arnold, BR Curtis, T Bakchoul. Recommendations for standardization of laboratory testing for drug-induced thrombocytopenia. J Thromb Haemost 2015; Apr;13(4):676-678.
• Jessica A. Reese, Daniel W. Bougie, Brian R. Curtis, Deirdra R.Terrell, Sara K. Vesely, Richard H. Aster, James N. George. Drug-induced thrombotic microangiopathy: Experience of the Oklahoma registry and the BloodCenter of Wisconsin. Am J Hematol 2015; 90(5):406-410.
• DM Arnold, BR Curtis, T Bakchoul. Recommendations for standardization of laboratory testing for drug-induced thrombocytopenia. J Thromb Haemost 2015;Apr;13(4):676-678.
• Jessica A. Reese, Daniel W. Bougie, Brian R. Curtis, Deirdra R.Terrell, Sara K. Vesely, Richard H. Aster, James N. George. Drug-induced thrombotic microangiopathy: Experience of the Oklahoma registry and the BloodCenter of Wisconsin. Am J Hematol 2015;90(5):406-410.
• Brian R. Curtis. Recent progress in understanding the pathogenesis of fetal and neonatal alloimmune thrombocytopenia. Br J Haematol 2015; 171, 671–682.
• Brian R Curtis, Ashley Roman, Mia Sullivan, Cindy Raven, Judy Larison, LeeAnn Weitekamp. Two Cases of Maternal Alloimmunization Against Human Neutrophil Alloantigen-4b, One Causing Severe Alloimmune Neonatal Neutropenia. Transfusion 2016;56:101–106.
• Anand Padmanabhan, Curtis G. Jones, Brian R. Curtis, Daniel W. Bougie, Mia J. Sullivan, Namrata Peswani, Jancie G. McFarland, Daniel Eastwood, Demin Wang, Richard H. Aster. A novel PF4-dependent platelet activation assay identifies patients likely to have heparin-induced thrombocytopenia/thrombosis (HIT). Chest 2016;150(3):506-15.
• Nanyan Zhang, Huiying Zhi, Brian R Curtis, Sridhar Rao, Chintan Jobaliya, Mortimer Poncz, Deborah L. French, Peter Newman. Designer Platelets:CRISPR/Cas9-mediated conversion of human platelet alloantigen allotypes. Blood 2016;127(6):675-680.
• Krista Metzner, Julie Bauer, Heather Ponzi, Allison Ujcich, Brian R. Curtis. Detection and identification of platelet antibodies using a sensitive multiplex assay system - Platelet Antibody Bead Array (PABA). Transfusion 2017;Jul;57(7):1724-1733.
• Mia J. Sullivan, Randy Kuhlmann, Julie Peterson, Brian R. Curtis.  A new low frequency alloantigen (Dom^b) located on platelet glycoprotein IIIa as a cause of maternal sensitization leading to neonatal alloimmune thrombocytopenia. Transfusion 2017;Jul;57(7):1847-1848.
• Curtis BR. Non-chemotherapy drug-induced neutropenia: key points to manage the challenges. Hematology Am Soc Hematol Educ Program. 2017 Dec 8;2017(1):187-193. doi: 10.1182/asheducation-2017.1.187.
• Curtis, BR, Hsu, Y-MS, Podoltsev N, Lacy J, Curtis S, DeSimone R, Samuel MS, Bougie DW, Aster RH. Patients treated with oxaliplatin are at risk for thrombocytopenia caused by multiple drug-dependent antibodies. Blood 2018;Mar 29;131(13):1486-1489. doi: 10.1182/blood-2017-10-812461
• Aye Myat Myat, Thinn, Zhengli Wang, Dongwen Zhou, Yan Zhao, Brian R. Curtis, Jieqing Zhu. A The autonomous conformational regulation of β₃ integrin and the conformation-dependent property of HPA-1a. alloantibodies. PNAS 2018; Sept. 25;115(39):E9105-E9114. doi: 10.1073/pnas.1806205115. PMID:30209215
• Huiying Zhi, Maria Therese Ahlen, Aye Myat Thinn, Panida Lertkiatmongkol,  Hartmut Weiler, Brian Curtis, Bjørn Skogen, Jieqing Zhu, and Peter J. Newman. High-resolution mapping of the polyclonal immune response to the human platelet alloantigen HPA-1a (Pl_A1). Blood Advances 2018; Nov 13;2(21):3001-3011. doi: 10.1182/bloodadvances.2018023341.
• Rachel Petermann, Tamam Bakchoul, Brian Curtis, Francois Mullier, Shigeki Miyata, Donald M. Arnold. Investigations for Fetal and Neonatal Alloimmune Thrombocytopenia (FNAIT): Recommendations from the Platelet Immunology Scientific Subcommittee. J Thromb Haemost 2018; Dec;16(12):2526-2529. doi: 10.1111/jth.14294.
• Alekhya Mitta, Brian R. Curtis, Jessica A. Reese, James N. George. Drug‐Induced Thrombocytopenia: 2018 Update of Clinical and Laboratory Data. Am J Hemtol 2019;Mar;94(3):E76-E78.
• Amir H. Ameri, Brian R. Curtis, and David B. Sykes. Immune neutropenia mediated by micafungin. Am J Hematol 2019;Apr 3. doi: 10.1002/ajh.25483. [Epub ahead of print]

Patents:

• 1996    U.S. Serial No. 5,585,243. Inventors - RH Aster and BR Curtis. METHOD OF DETECTING CYTOPENIA THAT IS MEDIATED BY DRUG-DEPENDENT ANTIBODY BINDING TO BLOOD CELLS
• 2015    U.S. Serial No. 9,017,958 B2. Inventor – Brian R. Curtis. METHOD OF SIMULTANEOUS DETECTION OF HEPARIN-INDUCE IMMUNOGLOBULINS TYPES G, A, AND M.