Eugene E. Cliffton

Fibrinolytic (Plasmin) Therapy of Experimental Coronary Thrombi with Alteration of the Evolution of Myocardial Infarction

To explore the possibilities of fibrinclytic therapy of coronary thrombosis, experimental studies were carried out to document lysis of coronary thrombi and to investigate the effect of fibrinolytic blood upon myocardial infarction. Serum-induced coronary thrombi were produced by a new technic and were followed by serial coronary arteriography. Control animals were compared to animals in which significant fibrinolytic activity had been induced by systemic infusions of plasmin. Tissue studies suggest that plasmin may change the evolution of early infarction. Whether these changes will ultimately result in salvage of ischemic tissue will be determined by studies now in progress.

Salvage of heart muscle by fibrinolytic therapy after experimental coronary occlusion

Abstract 1. 1. The extent of experimental canine myocardial infarction was markedly diminished by fibrinolytic therapy. 2. 2. This effect appeared to be the result of maintaining the patency of the microcirculation of the heart, with the salvage of ischemic marginal areas after coronary occlusion. 3. 3. Fibrinolytic therapy extends the duration of viability of large areas of the myocardium after ischemic injury. 4. 4. Intense fibrinolytic activity was induced to the extent of producing hemorrhagic complications in some of the animals. 5. 5. The implications of this therapy in human myocardial infarction are discussed.

Early experience with fibrinolysin.

* From the Enzyme Research Section of the Division of Experimental Surgery of the SloanKettering Institute for Cancer Research, the Memorial Center for Cancer and Allied Diseases, and the Department of Surgery, Cornell University School of Medicine, all in New York, New York. † Associate Professor of Clinical Surgery, Cornell University School of Medicine; Associate, Sloan-Kettering Institute. t The fibrinolysin used in this study was supplied as Actase Fibrinolysin (Human) by the Ortho Pharmaceutical Corporation, Raritan, New Jersey. The rapid dissolution of intravascular clots or thrombi by fibrinolytic activity is an accomplished fact. The lysis of artificially produced intravascular thrombi in animals by human fibrinolysin (plasmin) t was first reported in 1954.1, 2 Subsequently we have shown by indirect evidence that spontaneous thromboses in man can be eradicated by this same material.3-1 These observations have been confirmed by other investigators, including Mouser,6 and Johnson and associates’ have reported,lysis of induced thrombi in patients with streptokinase. The advances in this field have been rapid, but unfortunately results and ideas have been clouded by semantics, differences in terminology, and variations in techniques and substrates for testing fibrinolytic and proteolytic activity. So many different preparations have been available in such small quantities that comparable studies could not be made by several qualified observers. V’e hope that prejudice for a given product will not be permitted to cloud our perspective. First the semantics involved in these studies

Effect of prolonged coumadin treatment on the production of pulmonary metastases in the rat

To evaluate the effect of prolonged anticoagulant treatment using Coumadin (warfarin sodium) on the production of pulmonary metastases, 455 rats with Walker 256 carcinosarcoma were given either water or Coumadin solution ab lib in addition to their chow. Administration of Coumadin for 10 days resulted in a significant decrease in metastases from 85.8% of the control group to 9.8% of the Coumadin‐treated animals (P < 0.001). The survival of these animals also was increased from 3.8% to 42.6% at 9 weeks. No excessive bleeding occurred in any of these animals though the prothrombin time was prolonged more than twice the average value observed in the normal rat.

Factors affecting the formation and dissolution of experimental thrombi

Abstract The use of the serum-induced clot as a standard experimental model has been found to be highly satisfactory. In twenty-two dogs the effectiveness of fibrinolytic therapy of fresh clots was studied. Systemic fibrinolysin therapy was found to be effective in dissolving such clots, although local administration of fibrinolysin to the clot was found to result in even more rapid lysis. No difference was found in the susceptibility of fresh arterial and venous clots to treatment. In twenty-one dogs the effect of the age of the clot in relation to treatment with fibrinolysin was studied. Clots treated within four days of formation were susceptible to partial or total dissolution. The effect of hyperfibrinogenemia on clot dissolution was studied in ten dogs. Clots formed in the hyperfibrinogenemic state were significantly more resistant to fibrinolytic therapy.

Decrease of metastases of carcinosarcoma Walker 256 with irradiation and heparin or fibrinolytic agents.

Cancer cells in the circulating blood of patients with malignant tumors were first demonstrated by Ashworth (4) almost one hundred years ago (1869). Pool and Dunlop (19) in 1934 observed unusual cells in the peripheral blood in cases of advanced malignant disease, and in 1955 Engell (12) reported the presence of cancer cells in the peripheral blood of patients with resectable and unresectable neoplasms. There have been many more recent reports. With this evidence and the observation that venous invasion frequently is dcmonstrated in microscopic sections of malignant tumors (5, 11), it has been presumed that cancer cells may be spilled from the primary lesion into the circulating blood. An increase in the number of cancer cells in the venous blood draining the tumor may be noted (6, 22) at the time of examination (17), at biopsy (23), and during surgical procedures (10). Not all of these cancer cells become metastases. Some may lie dormant in the tissues for years (13), while others are destroyed in the ci...

Studies on the Production of Intravascular Thrombi and Their Treatment with Fibrinolysin

In 22 dogs, the effect of fibrinolysin therapy of fresh intravascular clots was evaluated by serial angiograms and autopsies. The average time required for dissolution of such clots, when treated by systemic plasmin, was 4 hours and 45 minutes, while the average time necessary for lysis with local fibrinolytic therapy was 2 hours 10 minutes. Treatment of fresh venous and arterial clots did not disclose any significant difference in susceptibility to lysis. In 21 dogs, the effect of age of the clot on the effectiveness of plasmin therapy was studied in clots formed with serum and morrhuate. Clots treated within 4 days of formation were susceptible to dissolution, although clots treated after 3 days did not uniformly undergo complete lysis. The serum-induced clots were more amenable to fibrinolytic therapy than were those formed with morrhuate.

Experiences with clot-lysing agents in coronary thrombosis☆

Abstract Thrombolysin was administered to forty-five patients with acute myocardial infarction. Anticoagulants were not administered during thrombolysin therapy but were begun in most patients a few hours after administration of thrombolysin was stopped. There were thirty male and fifteen female patients. Of this group, six died and thirty-nine survived. Those who died were admitted to the hospital either in shock and/or congestive heart failure. Significant side reactions were noted in four patients. In view of the results in experimental animals and the results obtained in our series, early institution of thrombolysin therapy is imperative for optimum results. This is a preliminary report. The patients who survived are being re-evaluated and comparisons are being made with a control group on a long term basis in the follow-up clinic.

Pancreatic dornase aerosol in postoperative atelectasis.

Abstract 1. 1. One hundred twelve patients with atelectasis or other serious pulmonary complicaplications of surgery were treated with pancreatic dornase aerosol. 2. 2. No toxic or allergic reactions or undesirable side effects were noted. 3. 3. Resolution of the atelectasis or other complication resulted in 91 per cent of patients. Improvement can be expected in a few hours and relief is usually complete within one to three days of treatment.

Irradiation and Anticoagulant Therapy to Prevent Pulmonary Metastases of the V2 Carcinoma in Rabbits

Dissemination of cancer may occur by way of the lymphatics and by the venous blood. Spread by the blood stream is the more serious and is the method about which the least is known. It is presumed that the cancer cells enter the blood stream by invasion of blood vessels and circulate in the blood until they are destroyed or caught in the small vessels. When the cells become fixed, they may pass through the vessel walls and begin to grow (24, 25), or may become fixed by fibrous tissue and be destroyed. It is possible that the majority of the malignant cells released into the circulation are destroyed by lytic properties of the blood (5) or continue to circulate until they are no longer viable. Others may lodge and remain dormant for years (12), and still others will produce obvious early metastatic cancer (6). It has long been known that cancer cells may be found in the circulating blood of patients with cancer (4, 8, 11, 18, 19). During operative manipulation both in man (22) and in laboratory animals (6) ...