|
Alan E. Mast, MD, PhDInvestigator Blood Research Institute
BloodCenter of Wisconsin Associate Medical Director, Medical Services BloodCenter of Wisconsin Associate Professor Department of Pathology Medical College of Wisconsin Associate Professor Department of Cell Biology, Neurobiology and Anatomy Medical College of Wisconsin Education and training Doctoral TrainingM.D., Ph.D., Duke University, 1991 Contact Information Phone: (414) 937-6310 Fax: (414) 937-6284 E-mail: alan.mast@bcw.edu |
Thrombosis, Hemostasis and Vascular Biology
Our laboratory has two distinct research focuses:
- Basic science studies of hemostasis and vascular biology with a focus on the physiological function of Tissue Factor Pathway Inhibitor (TFPI)
- Clinical and translational research studies of iron metabolism in blood donors
1. Basic Science Studies:
The blood vessel contains several anticoagulant proteins that prevent the formation of blood clots. The work in our laboratory is focused on one of these proteins called TFPI. TFPI inhibits proteases in the very early stages of blood coagulation. Humans without TFPI have not been identified and genetically altered mice that do not make TFPI die during embryonic development demonstrating that TFPI has critically important physiological functions. Our laboratory uses a wide variety of biochemical, cellular (tissue culture) and animal models to define and characterize the physiological functions of TFPI. These include studies of the biochemical mechanisms that allow TFPI to associate with the surface of blood vessels and platelets, characterization and functional assessment of different alternatively spliced forms of TFPI and the development of new mouse models to examine the function of TFPI in vivo. The results of these studies will shed new light on a wide range of human diseases that are associated or caused by intravascular blood clots. We have recently demonstrated in mouse models that TFPI produced by the endothelial cells lining blood vessels as well as by platelets is important for preventing blood clots from forming in the brain. We are optimistic that our continued investigation of the physiological mechanisms underlying how TFPI functions in brain tissue will lead to new understanding of the causes and risk factors for stroke as well as vascular dementia.
2. Clinical and Translational Studies:
a. Blood donation removes a large amount of iron from the blood donor. This results in a large number of donors becoming iron deficient and developing iron deficiency anemia. However, some donors can donate blood repeatedly over many years and not develop iron deficiency anemia. We have performed studies of these donors to define their behavioral, biochemical and genetic characteristics that allow them to donate so frequently.
a. Blood donation removes a large amount of iron from the blood donor. This results in a large number of donors becoming iron deficient and developing iron deficiency anemia. However, some donors can donate blood repeatedly over many years and not develop iron deficiency anemia. We have performed studies of these donors to define their behavioral, biochemical and genetic characteristics that allow them to donate so frequently.
b. Our laboratory is leading a large epidemiological study performed in collaboration with other scientists in the National Heart Lung and Blood Institute’s Retroviral Epidemiology Donor Study II (REDSII) group. This study investigates low hematocrit deferral in over 700,000 blood donors from across the country in order to define demographic features of blood donors that increase or decrease their risk for having low hematocrit deferral. These studies are important because approximately 10% of people attempting to donate blood can not donate because they have low hematocrit. Identification of new strategies to decrease these deferrals could have a significant impact on the national blood supply.
c. As mentioned above, many people who attempt to donate blood are found to have anemia. There are many causes for anemia including nutritional deficiency, repeated blood donation, arthritis and diabetes. However, of particular concern in blood donors who represent a generally healthy segment of the population are “invisible” causes of anemia such as pre-malignant or malignant lesions within the gastrointestinal tract. In collaboration with scientists at the Medical College of Wisconsin and the National Anemia Action Council we have developed a new informational pamphlet based on the recommendations from two focus groups consisting of a total of 25 donors that had been deferred for low hematocrit. We are currently testing the ability of this pamphlet to influence the correct donors (i.e. those with high risk for a medically treatable cause for anemia) to seek medical care in a randomized study. We feel that the development of effective educational programs for blood donors with anemia represents a highly efficient and heretofore overlooked use of blood/plasma centers to significantly improve public health in the United States.
Basic Science Grant Support:
- Novo Nordisk Research Grant 12/2009-12/2011
- National Heart Lung and Blood Institute R01 Award 8/2002-12/2012
Clinical and Translational Studies Grant Support
- National Heart Lung and Blood Institute Retroviral Epidemiology Donor Study (REDS-III) 3/2011-2/2018
- National Heart Lung and Blood Institute R01 Award 1/2011-12/2014
Susan Maroney, DVM, PhD
Research Scientist II
Paul Ellery, PhD
Postdoctoral Fellow
Jeremy Wood, PhD
Postdoctoral Fellow
Karen Hansen
Predoctoral Fellow
Walter Bialkowski
Research Coordinator
Nicholas Martinez
Asst. Research Technologist
Shanita Thomas
Asst. Research Coordinator
Zoya Udee
Asst. Research Coordinator
Selected basic science publications:
- Lockett JM, Mast AE: The contribution of the region between Gly-160 and the end of the third Kunitz domain to the anticoagulant activity of tissue factor pathway inhibitor. Biochemistry 2002, 41:4989-4997
- Cunningham AC, Hasty KA, Enghild JJ, Mast AE: Structural and functional characterization of tissue factor pathway inhibitor following degradation by matrix metalloproteinase-8. Biochem J 2002, 367:451-458
- Mast AE, Acharya N, Malecha MJ, Hall CL, Dietzen DJ: Characterization of the association of tissue factor pathway inhibitor with human placenta. Arter. Thromb. and Vasc. Biol. 2002, 2099-2104
- Maroney SA, Cunningham AC, Ferrel J, Hu R, Haberichter S, Mansbach CM, Brodsky RA, Dietzen DJ, Mast AE: A GPI-anchored co-receptor for tissue factor pathway inhibitor controls its intracellular trafficking and cell surface expression. J Thromb Hemost 2006, 4:1114-1124
- Donahue BS, Gailani D, Mast AE: Disposition of tissue factor pathway inhibitor during cardiopulmonary bypass. J Thromb Hemost 2006, 4:1011-1016
- Maroney SA, Haberichter SL, Friese P, Collins ML, Ferrel JP, Dale GL, Mast AE: Active tissue factor pathway inhibitor is expressed on the surface of coated platelets. Blood 2007, 109:1931-1937
- Timmer JC, Enoksson M, Wildfang E, Zhu W, Igarashi Y, Denault JB, Ma Y, Dummitt B, Chang YH, Mast AE, Eroshkin A, Smith J, Tao WA, Salvesen GS: Profiling constitutive proteolytic events in vivo. Biochem J 2007, 407:41-48
- Maroney SA, Cooley BC, Sood R, Weiler H, Mast AE: Combined tissue factor pathway inhibitor and thrombomodulin deficiency produces an augmented hypercoagulable state with tissue specific fibrin deposition. J Thromb Hemost, 2008, 6:111-117
- Maroney SA, Ferrel JP, Collins ML, Mast AE: TFPIγ is an active alternatively spliced form of TFPI present in mice but not humans. J Thromb Hemost, 2008, 6:1344-1351
- Maroney SA, Ferrel JP, Pan S, White TA, Simari RD, McVey JH, Mast AE: Temporal expression of alternatively spliced forms of tissue factor pathway inhibitor in mice. J Thromb Hemost, 2009, 7:1106-1113
- White TA, Johnson T, Zarzhevsky N, Tom C, Delacroix S, Holroyd EW, Maroney SA, Singh R, Pan S, Fay WP, van Deursen J, Mast AE, Sandhu GS, Simari RD: Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis. Blood, 2010, 116:1787-1794
- Zaman FS, Mast AE, Hall CL: Evaluating surface bound rTFPI through an in vitro model of vessel wall injury. Thrombosis Research, 2011, 127:149-153
- Maroney SA, Mast AE: Tissue factor pathway inhibitor and bacterial infection. J Thromb Haemost, 2011, 9:119-121
- Maroney SA, Cooley BC, Ferrel JP, Bonesho CE, Mast AE: Murine Hematopoietic Cell Tissue Factor Pathway Inhibitor Limits Thrombus Growth. Arterioscler Thromb Vasc Biol, 2011, In Press
- Maroney SA and Mast AE: Tissue factor pathway inhibitor and bacterial infection. Commentary. J. Thromb Hemost, 2011, 9:119-121
- Gilbert GE, Mast AE: Curbing an inhibitor of hemostasis. Commentary. Blood, 2011, 117:5277-5278
- Maroney SA, Ellery PE, Wood JP, Ferrel JP, Bonesho CE, Mast AE: Caveolae optimize tissue factor-factor VIIa activity of cell surface associated tissue factor pathway inhibitor. Biochem J, 2012, 443:259-263
- Maroney SA, Cooley BC, Ferrel JP, Bonesho CE, Nielsen LV, Johansen PB, Hermit MB, Petersen LC, Mast AE: Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia. Proc Natl Acad Sci USA, 2012, In Press.
Selected clinical and translational studies publications:
- Mast AE, Blinder MA, Gronowski A, Chumley C, Scott MG: The clinical utility of the serum transferrin receptor level in the evaluation of iron deficiency anemia. Clin Chem 1998; 44:45-51
- Mast AE, Stadanlick JE, Lockett JM, Dietzen DJ: Solvent/detergent treated plasma has decreased antitrypsin activity and absent antiplasmin activity. Blood 1999; 94:3922-3927
- Mast AE, Blinder MA, Lu Q, Flax S, Dietzen DJ: The clinical utility of the reticulocyte hemoglobin content in the diagnosis of iron deficiency. Blood 2002, 99:1489-1491
- Mast AE, Blinder MA, Dietzen DJ: Test of the Month: Reticulocyte Hemoglobin Content. Am. J. Hematology 2008, 83:307-310
- Mast AE, Foster T, Pinder HL, Beczkiewicz CA, Bellissimo DB, Murphy AT, Kovacevic S, Wroblewski VJ, Withcher DR: Behavioral, biochemical and genetic analysis of iron metabolism in high intensity blood donors. Transfusion, 2008, 45:2197-2204
- Young S, Fink A, Geiger S, Marabella A, Mast AE, Schellhase KS: Community blood donors knowledge of anemia and design of a literacy appropriate educational intervention. Transfusion, 2010, 50:75-79
- Mast AE, Schlumpf KS, Wright DJ, Custer B, Spencer B, Murphy EL, Simon TL: Demographic correlates of low hemoglobin deferral among prospective whole blood donors. Transfusion, 2010, 50:1794-1802
- Scott EA, Schlumpf KS, Mathew SM, Mast AE, Busch MP, Gottschall JL: Biospecimen repositories: are blood donors willing to participate? Transfusion, 2010, 50:1943-1950
Information currently unavailable.
