Arnold Meshkov MD. is a cardiologist, heart health expert, and was a Professor of Medicine at Temple University School of Medicine until 2015 when he returned to private practice. He is Board Certified in Internal Medicine, Cardiology, and Echocardiography and has lectured on a broad range of topics in cardiology and bioethics. Dr. Meshkov served for many years as the Chairman of the Ethics Committee at Temple University Hospital and was the coordinator of Cardiology Grand Rounds, a weekly lecture series at Temple.
In this column, Arnold Meshkov, MD, explores the history of the "Thrombus Hypothesis" and his experiences with thrombus in myocardial infarction as a practicing clinician.
I knew he disliked all cardiologists, but I wasn’t sure why. He was an internationally known hematologist and the Chairman of Medicine at Temple University in Philadelphia when I was a resident there in the late 1970’s. He took Morning Report just about every day and when he was not interested, he would look down at the floor and we could see his bald tan head. And he was looking at the floor one morning as one of my resident colleagues was droning on and on about the so often futile treatment of cardiogenic shock after a large anterior wall myocardial infarction.
Sol Sherry, MD, has heard too many of those case presentations over the years, about pressors, diuretics, and Swan-Ganz catheters. He was bored, but suddenly in the middle of the resident’s talk, he raised his head and said: “You know, all of your guys who are going into cardiology, acute myocardial infarction is a hematologic disease.” And then he looked down at the floor again.
Sherry had been an almost lone voice in the academic world for over twenty years by then, a proponent of the “Thrombus Hypothesis,” convinced that thrombus formation on top of an atherosclerotic plaque was the final trigger for the large anterior wall myocardial infarctions related to the “Widowmaker” lesions of the left anterior descending coronary artery. We had all seen those infarctions, with their frightening EKG patterns of ST-segment elevation known by the malignant moniker of “tombstone sign.”
The controversy about the role of thrombus in the pathogenesis of myocardial infarction had raged for decades, with strong advocates claiming that thrombus was only a secondary finding due to the primary problem of reduced flow in an atherosclerotic artery. But Sherry was also convinced of something even more important—medication could improve the outcome of a disease with close to 50% mortality at the time.
Sherry had been working with a powerful intravenous medication since the early 1950’s. He began his academic career as a hematologist working with William Tillett MD at Washington University School of Medicine in St. Louis. Dr. Tillet was the discoverer of the C-reactive protein molecule so commonly used to detect inflammation. But he and Dr. Sherry were more fascinated by a very strange molecule secreted by the streptococcus bacteria – this substance magically broke up blood clots. In honor of its humble bacterial origin, they named their molecule “streptokinase.”
Sherry and Tillett thought that streptokinase might have clinical importance. After they purified the molecule, they used it to break up the viscous pleural effusions that sometimes occurred after lung trauma and surgery. But by the late 1950’s, Sherry had a revolutionary thought – he wanted to use streptokinase in the early hours after the onset of chest pain in patients with acute myocardial infarction.
The study was a small one, but the results were astounding for the times. Overall, 87% of the 24 patients survived their infarctions! In an era before CCUs this was miraculous, and one would have expected other researchers, especially cardiologists, would have latched on to Sherry’s findings and vigorously pursued more studies.
But cardiologists focused on the new tool of the CCU, and the treatment of arrhythmias and heart failure, noble endeavors but treatment after the damage to the myocardium was already complete. They were worried about streptokinase’s allergic reaction potential, and also the risk of cerebral hemorrhage from this potent thrombolytic agent. Unable to gain the cooperation of cardiologists, Dr. Sherry began trials of streptokinase in the treatment of acute pulmonary emboli, studies that confirmed the beneficial effects of thrombolysis for hemodynamically severe pulmonary emboli, treatment that has stood the test of time.
So, streptokinase and thrombolysis lurked in the background of the treatment of myocardial infarction for almost two decades, as cardiologists tried so many different drugs to try to allow the heart to heal and have the remaining slightly damaged and normal myocardial cells compensate for the slaughter of their neighbors. But the larger point was just missed—true improvement in both short and long-term prognosis depended on restoring blood flow to the myocardium, a principle that we now accept as obvious.
Within a year of my entering my cardiology fellowship in 1979, with the memory of Sherry’s admonition resonating every time I cared for an MI patient, two startling new research studies stunned the cardiology world. A group of cardiologists in Gottenberg Germany, led by K. Peter Rentrop MD, had a great idea. They would avoid the possible toxicities of systemic intravenous streptokinase by infusing much smaller doses of the “clot-buster” medication directly into an acutely occluded coronary artery in the cardiac cath lab. In 76% of their 29 patients, the intracoronary streptokinase opened up the clot completely within minutes, and only one of the 29 people died. The results were wonderful, proving after 20 years that lysing a clot in a coronary artery early on after symptom onset saved heart muscle and improved outcomes.
In the United States, for even a few years prior, Marcus Dewood MD, a cardiologist in Spokane, Washington was accumulating data to prove the “Thrombus Hypothesis” of acute myocardial infarction. Dewood also believed that prompt restoration of blood flow was the key to improving outcomes. But he was going use surgery to achieve his goal. He convinced his surgical colleagues to perform coronary artery bypass surgery within hours of his documenting the extent of coronary artery disease by cardiac catheterization done on patients taken straight from the emergency room.
Dewood found something unexpected; 87.3% of the patients who underwent catheterization within 2 hours after their symptoms began had complete occlusion of one of their major coronary arteries. To Dewood, this abrupt cutoff of blood supply meant only one thing – he was imaging a thrombus in a coronary artery. But the bold confirmation of Dewood’s suspicion came in the operating room – the surgeons were able “fish-out” fresh thrombus using a Fogerty catheter from the artery Dewood identified in the cath lab.
The findings of Rentrop and Dewood opened the door to the era of thrombolytic therapy for acute myocardial infarction, and the dogma that “Time is muscle.” Emergency rooms around the world were placed on urgent standby for MI patients, and the results were remarkable. Many more patients survived and the complications of malignant arrhythmias and acute heart failure dropped, as long as the patients were treated promptly.
The “Thrombosis Hypothesis” confirmation led to William O’Neill, MD, and Cindy Grimes, MD, of Beaumont Hospital in Michigan to organize trials of, by the 1990’s, the well-developed technique of Andreas Grüntzig, MD, angioplasty, and use this technique instead of thrombolytic drugs for acute myocardial infarction. The “standard of care” of acute angioplasty for ST-segment myocardial infarction has been consistent for over two decades now, and the prognosis for our patients treated quickly has improved dramatically.
But it took so long for the “Thrombus Hypothesis” to gain acceptance. There will never be a good explanation for why Sherry’s study was ignored for so many years. I can understand why he didn’t like cardiologists. We always need to keep our minds open to the ideas and work of our other colleagues pushing the boundaries of the science and art of medicine.