Dr. Eberhard F. Mammen Remembered: A Great Clinician-Scientist, Mentor, and Friend

Although our great mentor and friend, Dr. Eberhard Mammen, passed away on July 1, 2008, he has left a legacy that will continue to impact the areas of hemostasis and thrombosis for years to come. He was truly an international teacher who laid the foundation of modern hemostasis and thrombosis. His teachings and educational pursuits have impacted all areas of hemostasis and thrombosis around the world. He was visionary, innovative, and an exemplary clinician-scientist who also laid the foundation of translational research, which is now considered an important focus in validating new medical concepts from bench to bedside.

Dr. Mammen received his initial training at the University of Marburg in Germany where he was trained by some of the pioneers in protein studies. In the late 1950s, Dr. Mammen joined Professor Walter Seegers at Wayne State University at a time when Detroit was the lead center for research training and drug development in hemostasis and thrombosis. There he worked with such leaders as Orhan Ulutin from Turkey in programs that were dedicated to understanding the role of plasma proteins in clotting and bleeding. Dr. Mammen was appointed a Fulbright scholar in the Departments of Physiology and Pharmacology in 1958 at Wayne State University. He continued his research work on plasma proteins, in particular prothrombin complexes, until 1960. At that time he returned to Marburg, Germany, to fulfill his clinical qualifications and to complete his internal medicine residency.

The strong interaction with Professor Seegers brought Dr. Mammen back to Wayne State University in 1962 as a faculty member in the Departments of Physiology and Pharmacology. At this stage of his career, he worked diligently as a clinician-scientist and progressed to the rank of full professor.

Long before the discipline of molecular biology evolved, Dr. Mammen described fibrinogen Detroit, a hallmark in the investigation of molecular defects in coagulation. The fibrinogen Detroit molecule was found to have an abnormal end terminal disulfide knot of the α chain and arginine at the 19th position that was replaced by serine. This led to allosteric conformational changes in fibrinogen that altered its ability to clot. In addition, his research contributions included the recognition of the calcium-binding anticoagulant protein, protein C, which has been the subject of extensive research for the past 30 years.

As a clinician, Dr. Mammen was very interested in the development of new drugs to manage thrombotic and bleeding disorders. He described the sticky platelet syndrome in diabetic and other pathological states. This visionary clinical observation led to the multidisciplinary investigation of the molecular processes involved in transforming normal platelets into activated platelets with strong adhesion to surfaces. Today this line of research is extended to the structure of adhesion molecules such as selectins and the intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), and endothelial-leukocyte adhesion molecule (ELAM).

Dr. Mammen was involved in the pharmaceutical development of antithrombin concentrates. It is because of his work that antithrombin concentrates were used for the management of disseminated intravascular coagulation, burns, and thrombophilia. Based on this work, the recombinant product was developed. Dr. Mammen was also a pioneer in the use of low-dose heparin for the management of venous thrombosis. As a result, low molecular weight heparins and heparinomimetic drugs such as the synthetic pentasaccharide were developed. Based on his work on thrombin, synthetic anti-thrombin agents were developed. He was a great friend of the late Professor Okamoto and interacted with him on the development of protease inhibitors, which eventually lead to the development of several therapeutic inhibitors. Professor Okamoto's team later introduced the first clinically used synthetic inhibitor of thrombin, argatroban. Today, anti-thrombin drugs such as argatroban are widely used for the anticoagulant management of heparin-compromised patients such as those suffering from heparin-induced thrombocytopenia. The future management of thrombotic disorders will be strongly influenced by some of the early concepts introduced by Professor Mammen and his colleagues.

In addition to his primary appointments, Dr. Mammen also contributed significantly to the research and teaching programs in the Departments of Pathology and Obstetrics-Gynecology. His administrative skills and his ability to develop biomedical faculty eventually led to his appointment as dean of the School of Pharmacy and Allied Health Professionals in 1974, a position that he held until 1982. He was instrumental in the development of clinical pharmacy and medical technology (clinical laboratory scientist) programs that impacted the development of these disciplines across North America. Dr. Mammen and his faculty were pioneers in design and implementation of innovative curricula in basic medical sciences and clinical medicine. Today the clinical pharmacist and the clinical laboratory scientist play very important roles in overall patient care due, at least in part, to the impact of the curricular advancements developed by Dr. Mammen and his team.

After completing his tenure as dean of the School of Pharmacy and Allied Health Professionals, Dr. Mammen continued his research work and clinical practice by joining the Detroit Medical Center where he became the technical director. He simultaneously directed the Wayne State University Coagulation Research at the Mott Center. While actively working in both the basic and clinical arenas, Dr. Mammen directed and supervised several research programs in North America, Europe, and Japan. His expertise and advice was sought by all of us who worked in hemostasis and thrombosis regardless of academic, industrial, or hospital affiliation. Such drugs as low molecular weight heparins, therapeutic proteins such as antithrombin III, protein C, activated prothrombin complexes, and the foundations of recombinant antithrombotic agents are a result of his contributions.

Dr. Mammen had a great interest in the laboratory investigation of hemostatic disorders, which resulted in the development of several novel tests and instrumentation. He was a pioneer in introducing automation to coagulation testing. Even after retiring from the Detroit Medical Center, Dr. Mammen continued to work with clinical laboratories in area hospitals along with his global network of experts, most of whom had been his trainees in clinical hemostasis and fundamental research areas.

Dr. Mammen also had a profound impact in the area of hemostasis and thrombosis through his impeccable writing and editing expertise. For many years he was the chief editor of the legendary Seminars in Hemostasis and Thrombosis, a journal that made the concepts of this discipline accessible to all in the field. He served in several editorial capacities with the American Journal of Hematology, Biomedical Progress, Clinical Trends in Coagulation and Fibrinolysis, and Clinical/Applied Thrombosis and Hemostasis. He was an author and coauthor of more than 500 publications, several books, and position statements. Various professional organizations and regulatory agencies consulted him on important issues related to the diagnosis and management of thrombotic and bleeding disorders.

Dr. Mammen was truly a mentor who trained so many of us. He played a key role in fostering international collaborations and was instrumental in several societies and expert groups such as the International Society on Thrombosis and Haemostasis, International Society of Hematology, World Federation of Hemophilia, and various societies for laboratory medicine. He organized several scientific symposia and congresses on dedicated topics. He always remained a strong advocate of educating all levels of health-care professionals and increasing the public awareness of thrombosis.

Dr. Mammen was a generous friend to all of us. He was always ready to help and direct us in achieving our goals and objectives. He was an approachable and a caring person. In addition to his role as a great mentor and teacher, he was instrumental in the professional development of many of us. In recognition of his contributions, Dr. Mammen was honored by several organizations and received numerous awards throughout his life from his peers all over the world. The hemostasis and thrombosis community will remember him as one of the pioneers whose teachings will have a far-reaching impact in years to come.