Search

An evaluation of the comparative actions of Tromexan and dicumarol is herein reported. Five hundred fourteen patients were studied; a total experience of 6,642 days of Tromexan therapy and 5,006 days of dicumarol therapy were reviewed and analyzed. Previous reports of the more rapid initial prolongation of the prothrombin times and more rapid return to normal following cessation of therapy with Tromexan were confirmed. During adequate therapy the protection against thromboembolism was approximately equal for the two drugs. In other respects and with minor variations Tromexan and dicumarol were found to be quite comparable. The general advantages of anticoagulant therapy in the prevention of deaths and thromboembolic complications in myocardial infarction were comfirmed.

1.1. A study of the problem of specific hypersensitiveness of the skin to tobacco in 35 typical cases of thromboangiitis obliterans and 35 controls was made. 2.2. The patients with thromboangiitis obliterans did not show a higher evidence of positive skin reactions than the control group. 3.3. The high incidence of positive skin reactions to tobacco tests reported by other investigators and interpreted as allergic reactions is considered due to some of the many nonspecific reactions from chemical irritation. 4.4. Thrombo-angiitis obliterans is not caused by an allergic type of tobacco hypersensitiveness.

The use of heparin and dicumarol has provided important information regarding the effectiveness and the difficulties of anticoagulant therapy. Neither, however, is an ideal anticoagulant; therefore a search for new substances with advantages over them must be continued. Tromexan, which is administered orally, appears to have the advantages of more rapid utilization and more rapid cessation of action than dicumarol, although the mode of action is similar in that it produces a hypoprothrombinemia. It does require accurate prothrombin tests for satisfactory clinical use. It appears to be less prone to producing hemorrhagic complications. Animal and clinical experiences with Tromexan are herewith presented.

The case of a patient with thromboangiitis obliterans who had quadrilateral gangrene of the digits was reported in 1937. His disease became quiescent after cessation of smoking and intravenous typhoid vaccine. During the interim of 27 years, he has abstained from smoking, and there has been no reactivation of his disease. Clinically, there has been a regression of his vascular lesions during this time. He represents the ideal in terms of treatment and response. In 1937, as part of the preliminary examination, he received at least four intra-arterial injections of thorium dioxide sol for visualization studies, and in 1964, this material was visualized as deposited in the liver and spleen. There was, however, no evidence of liver or spleen dysfunction or disease. Our experience with this patient and many others leads us to the conclusion that thromboangiitis obliterans is a distinct disease, although it is sometimes wrongly diagnosed. The reasons for this conclusion and for the confusion of this disease with atherosclerosis obliterans have been discussed.

Coronary thrombosis with myocardial infarction is an extremely serious disease to the individual and to the nation. It kills at least 200,000 persons a year and cripples unknown numbers. The modern treatment is herein outlined. Established therapy is reviewed and evaluated. The use and technics for the control of anticoagulant therapy are discussed.

1.1. During the past decade the indications for anticoagulant therapy have been clarified. They are listed herein. 2.2. In view of the reduction in both death rate and in the incidence of thromboembolic complications following coronary thrombosis with myocardial infarction with the use of anticoagulants in mild and moderately severe cases, the position that their use should be reserved solely for those patients who are severely ill at onset does not appear justified. This because, despite apparent mildness during the first day or two of the disease, the future course is difficult or impossible to predict with certainty and because the first complication may produce death, more serious illness or permanent disability. 3.3. Recent evidence favors the increased use of anticoagulants during more severe periods o congestive heart failure. 4.4. Newer anticoagulants are now rapidly being developed which generally can be classified as acting similarly to heparin or to dicumarol. 5.5. The clinical facts regarding each of the better known anticoagulants, including their advantages and disadvantages, have been outlined. 6.6. More complete experimental studies should be carried out before crystalline trypsin should be released for general clinical use. 7.7. The final decision whether to use anticoagulants or not, and which ones to use in a specific patient, must rest with the physician responsible for his care. 8.8. Among the important factors to be considered in making this decision are: (1) The diagnosis and condition of the patient; (2) the presence of any coincidental problem requiring caution or contraindicating their use; (3) the sound evidence indicating anticoagulant therapy under these particular circumstances; (4) the qualities of the specific anticoagulants under consideration; (5) the availability of accurate prothrombin and coagulation time tests; (6) the availability of vitamin K and K 1 , and transfusions for emergency use; and, perhaps of greatest importance, (7) the conscientiousness, and skill in this particular field, of the physician who is responsible for their use.

To the ten published cases of surreptitious takers of oral anticoagulants, ten are added by this report. These patients were identified at Cornell Medical College or at the Mayo Clinic. They consisted of four men and six women. Five patients were nurses and two others had a medical background: a fraudulent physician attempting to escape military service and the mother of a veterinarian. All the others had a history of thromboembolism or previous anticoagulant treatment. The differential diagnosis of "Dicumarol-eaters" is that of a lengthened prothrombin time. It includes a congenital deficiency of factors I, II, V, VII or X, or acquired deficiencies of one or more of these factors based on a lack of vitamin K or on liver damage. The simple vitamin K deficiency states can be distinguished readily by the effect on the prothrombin time of the parenteral administration of a small dose of a water-soluble analog of menadione. Definitive diagnosis of this malingering syndrome requires identification of the oral anticoagulant in the blood.

The effectiveness of papaverine hydrochloride intravenously as a vasodilator was studied in a series of eighteen subjects, which included thirteen who suffered from thromboangiitis obliterans, three who had arteriosclerosis obliterans, and two normals. Four patients with Raynaud's syndrome were also observed, but are not included in the statistical analysis. Compared with the simple water immersion procedure for securing vasodilatation, papaverine hydrochloride is ineffective and uncertain in action.

(1) We have described an apparatus to measure claudication time. (2) Following one injection of deproteinated pancreatic extract, twenty-three of a series of twenty-seven patients with arteriosclerosis obliterans showed an improvement (prolongation) of their claudication time. This initial response was in most instances temporary. (3) Following ten or more injections of deproteinated pancreatic extract, nineteen patients showed improvement in their claudication time. (4) After a series of ten or more treatments, the claudication time was, in this series, prolonged to an average of more than three times that of the control tests. (5) Physiologic saline failed to produce an increase in claudication time under identical conditions (6) Further studies will be necessary to determine the extent to which improvement may be advanced, and the duration of the favorable effects after cessation of the treatment.

1. 1. The general reactions produced by large subcutaneous or oral doses of the more active choline compounds can be reproduced by iontophoresis, using the same drugs. In addition, there are certain local manifestations which appear at the site of application. 2. 2. On the basis of our experiments there is no consistent, marked change in the basal metabolic rate resulting from the use of the choline compounds in the dosages indicated. 3. 3. Although it is possible to produce a marked drop in blood pressure by the use of several of these compounds, this is a transient effect. We have not seen a single patient who has maintained a lowered blood pressure from the use of these drugs. 4. 4. Iontophoresis with mecholyl has proved to be a palliative method for the treatment of arthritis. 5. 5. In peripheral vascular disease, where organic occlusion has been the major factor, the choline compounds have not been of marked value. 6. 6. In vascular disease in which spasm is the major factor, the use of the choline compounds, as outlined, has proved helpful. 7. 7. A preliminary report on the successful treatment of long-standing chronic varicose ulcers in presented.

Evidence has been presented that pernio is a vascular disease, affecting the smaller vessels of the skin, causing anoxemia of the supplied tissue, and resulting in necrosis and ulceration. Later, a definite sclerodermic-like change in the skin may occur. It is precipitated by a downward change in temperature, not necessarily freezing, but by mere cooling. This may occur at a temperature which, under ordinary circumstances, would not cause an appreciable change in normal skin, but which causes definite changes in susceptible persons. Characteristically, exacerbations of this condition occur in the fall and winter, and regression in the summer. In long-standing cases, however, complete recovery may not occur in the summer. We believe that this is due to the extensive vascular changes in the tissues. We have been able to demonstrate giant cells in our sections, but we have found no evidence of tuberculosis. We have very carefully checked our patients clinically with this in mind, so that we can make the definite statement that our patients were free from clinical and roentgenologic evidence of active tuberculosis at the time their leg lesions were active. The following tentative criteria are suggested for the diagnosis of pernio. 1. 1. It may occur in both sexes, predominantly in females. 2. 2. It usually commences in adolescence or early adulthood. 3. 3. It is associated with cool or cold weather and may show spontaneous recovery in warm weather. 4. 4. The lesions have a predilection for exposed areas, particularly the lower third of the leg, around the internal malleolus and calf. They may extend down to the dorsum of the foot and toes, and up the legs to below the knees. 5. 5. The clinical course of these lesions may be characterized briefly as (a) the formation of a reddened area which later becomes elevated, hard, and very painful; (b) this becomes violaceous and fluctuating; (c) it opens, producing an ulcer; (d) this oozes, drains, and heals, becoming less painful; (e) a violaceous scar remains; and (f) the following winter ulceration tends to recur in the same area. 6. 6. There is a definite pathologic picture. Most characteristic is, first, an angiitis of the smaller vessels; secondly, necrosis of the fat; and, thirdly, the presence of giant cells. This pathologic picture, while characteristic of all our cases, must not be considered morphologically specific, for a number of other vascular conditions present similar histologic changes. They all represent a chronic irritative process in the subepidermal tissue. Wherther the irritative phenomenon is secondary or primary cannot be definitely stated. Treatment of this condition is not specific, but the best results in our hands have been achieved by triweekly treatments with acetyl-betamethylcholine chloride (mecholyl) by iontophoresis, and by protection of the legs with proper clothing from undue exposure. Living in a warm climate should minimize the occurrence of the lesions. Early recognition of this syndrome, and treatment as suggested, will help to prevent permanent disfigurement and long periods of incapacitation.

This report summarizes the results obtained by a preliminary statistical analysis of the first 800 cases studied by the Committee for the Evaluation of Anticoagulants in the Treatment of Coronary Thrombosis With Myocardial Infarction. In the analysis the incidence of deaths and of both thromboembolic and hemorrhagic complications has been compared in a “control” series of patients treated by conventional methods alone and in a series of “treated” patients who received anticoagulants (Dicumarol, heparin, or both) in addition to conventional therapy. The composition of the two groups was found to be essentially the same. The rates of deaths and the number of thromboembolic complications per 100 cases have been calculated for the control and treated groups as a whole, by week of illness, by age of patient, and by type and location of the specific thromboembolic complication. The percentage of patients developing one or more complications has also been analyzed. The results in every category studied indicate that the use of anticoagulants improves strikingly the outlook of the patient suffering a coronary occlusion with myocardial infarction. The incidence of hemorrhagic manifestations was also analyzed. It was found that about six minor or moderate hemorrhagic manifestations per 100 cases occur in patients not receiving anticoagulants. This incidence is about six per 100 higher in patients receiving anticoagulants.

The present knowledge regarding the pathogenesis of thrombosis is reviewed. New conceptions and technics involving physical principles are outlined. Hitherto unemphasized aspects of thrombosis are discussed. The present status of anticoagulant therapy is summarized. The effects of other factors on the action of anticoagulants are considered.

Great interest continues in the treatment of cerebrovascular vascular accidents with anticoagulant agents. This paper presents a preliminary report of a cooperative study of this subject and indicates the methodology and protocol of the study, problems inherent in it, and preliminary findings of the first two years, without drawing definite conclusions.

The importance and frequency of pulmonary embolism has been discussed. The diagnosis and treatment have been presented. Important strides have been made in the treatment of this condition during the past twelve years since the advent of anticoagulant drugs. While death and recurrent emboli may occur during such therapy, the incidence of both has been strikingly reduced by the use of heparin and coumarin derivatives. Greater awareness of the possibility of thrombosis and pulmonary embolism will result in earlier diagnosis and treatment and further reduction in mortality from these conditions.

The symptomatology of carotid artery occlusive disease has always been of great interest to clinicians and has been well described in the past. 1-5 It has been emphasized that the patterns and potential course of the disease are numerous and complex. Since the development of therapeutic measures which have been advocated for this condition, it has become essential to study carefully a group of patients with documented carotid occlusive disease. This is particularly so in view of the need for early diagnosis, for the earlier a therapeutic measure is applied the less certain can one be of its effect on the future course of the syndrome. Transient ischemic attacks can occur for a year or more without any residual neurologic deficit being found. In addition, a single stroke may completely resolve without any treatment, and there may be no further difficulty for a few years. The clinical picture in 57

MANIFESTATIONS of pulmonary disease in patients with systemic lupus erythematosus reflect a spectrum of etiologic processes ranging from collagen vascular pneumonitis to bacterial, tuberculous, and fungal pneumonitis. 1-3 The use of chronic adrenocorticoid therapy predisposes to uncommon infectious pneumonitides which are difficult to distinguish clinically from the primary pulmonary disease of lupus. This case report illustrates the association of systemic lupus erythematosus with an infrequently encountered pathogen, Nocardia asteroides . Previous reports have noted this association on only three occasions. 4-6 Report of Case A 27-year-old man entering the New York Hospital on Sept 16, 1965, had a nine-year history of Raynaud's phenomenon, and a persistent malar erythematous rash for five years. In July 1965, he developed malaise, generalized lymphadenopathy, anemia, and albuminuria. No diagnosis was ascertained during hospitalization elsewhere. One week after discharge on July 2, 1965, a high fever and pleuritic pain in the right side of the

One hundred fifty individuals of different ages without evidence of peripheral vascular impairment (100 normal persons and 50 patients with history of cerebral vascular disease) were examined with the Allen test; the radial and ulnar arteries were examined in both hands. A false-positive test could easily be obtained spontaneously or be provoked by intentional hyperextension of the hand more than 20° beyond the straight position. In the straight position of the hand, the time for appearance of rubor after opening of the hand exceeded 5 seconds in 34% of the normal persons. When a relaxed slight flexion at the wrist joint was used, the flush after opening the hand appeared at an average of 3 seconds for the ulnar artery and 2.75 for the radial artery. In 50 normal individuals examined with optimal technique described, no individual artery required more than 6 seconds for the flush to appear after opening of the hand. The authors recommend that the Allen test be performed with the patient's hand slightly flexed and relaxed.

Pulmonary embolism is a serious and highly lethal disorder which is greatly underdiagnosed and undertreated. In elderly patients it is a common and often fatal complication of thrombotic disease. It is not described in the ancient literature, nor thereafter until the chair became universally used in our civilization. Present habits of prolonged sitting, as during travel, entertainment, study, and certain forms of work, contribute to venous stasis and secondary pulmonary embolism. Etiologic factors are reviewed and new iatrogenic factors discussed. Modern techniques increase the accuracy of diagnosis, but a strong index of suspicion on the part of the physician and a careful history still play a major role. Prophylactic and treatment measures are highly effective if used early and adequately. The prevention of venous stasis is important in prophylaxis. Anticoagulant drugs, notably heparin and the coumarin compounds, are the most effective weapons in the majority of cases.

Interest has recently been revived concerning the efficacy and safety of crystalline trypsin (Enzar) administered intravenously in the treatment of intravascular thrombosis. This has followed reports by Innerfield, Schwartz, and Angrist 1 stating that trypsin intravenously induces lytic effects upon artificially formed intravascular thrombi in rabbits and dogs. They also claim that with certain amounts of trypsin "complete dissolution" of such clots may be obtained "with restoration of circulatory integrity." These observations have led them to administer trypsin intravenously to patients with what they claim to have been gratifying results. 2 As the attempted dissolution of an intravascular protein thrombus with a proteolytic enzyme would appear to be an empiric but rational procedure, further consideration and investigation seemed mandatory. The concomitant possibility that it might activate the profibrinolysin system of the plasma had also to be considered. Reference to the literature, however, revealed that in certain amounts trypsin will, in

Thromboembolic complications frequently occur following myocardial infarction. Following the general acceptance of anticoagulant therapy for the treatment of myocardial infarction, there have been some authors who have recommended that this therapy be withheld from "mild cases," unless they develop thromboembolic complications. It is the belief of the present authors that this is not justified unless there are contraindications for anticoagulant treatment, provided that proper facilities are available. Summaries of experience with 14 so-called "good risk" cases of myocardial infarction who developed a total of 18 certain and 4 probable thromboembolic complications are presented. As a result, there were 4 major amputations in 3 patients, 1 of whom died. Other complications are discussed in detail.

The nitroglycerin-flicker test, as suggested and modified by Krasno and Ivy, has been used to test normal individuals and patients with a variety of cardiovascular diseases. The hypothesis that this test would serve as an index of the presence of vascular disease or spasm elsewhere in the body than the retina was explored. These studies have failed to justify the drawing of conclusions based on the results of this test regarding the presence or absence of generalized vascular disease or of localized vascular disease or spasm elsewhere than the retinal vessels. It is concluded that the use of this test in mass surveys to detect cardiovascular disease is not justified.

Recent investigations of the value of anticoagulants in myocardial infarction have indicated the need for a critical analysis of the blood-clotting mechanism in this disease. 1 Observations have been reported 2 which suggest that there is an increased tendency toward a coagulation associated with coronary thrombosis. Certain studies have yielded evidence that "hyperprothrombinemia" (in reality a summation of factors producing a shortening of the prothrombin time) is one of the factors responsible for the increased clotting tendency. 3 The importance of careful inquiry into whether such a state actually exists in patients with coronary thrombosis becomes obvious when the use of the anticoagulant drugs for both treatment and prophylaxis is being considered. Opportunity to observe daily prothrombin times in patients in whom coronary occlusion with myocardial infarction developed was afforded us during studies of the use of bishydroxycoumarin (dicumarol®) in this syndrome. The data obtained from observations of a group

The need for continuous administration of anticoagulants became apparent early in the clinical use of these drugs.* As a result of experience gained in the treatment of patients with rheumatic heart disease and recurrent embolization, we suggested in 1946 that these patients be maintained on anticoagulants. In 1949 our group reported on the management of 19 patients with long-term therapy. 3 Additional reports by Nichol and Fassett, 4 Cosgriff, 5 Askey and Cherry, 6 Bay and co-workers, 7 and Tulloch and Wright 8 have confirmed the favorable impression reported earlier, and the technique of long-term anticoagulant therapy is being increasingly employed. At the International Conference on Thrombosis and Embolism, at Basle, Switzerland, July, 1954, Catherine C. Burt, of Edinburgh; P. A. Owren, of Oslo; J. Dedichen, of Oslo; J. Beaumont, of Paris, and others reported similar results. CLINICAL MATERIAL AND DOSAGE The total number of patients we have followed on

In summary, the total world evidence suggests that in the absence of compelling contraindications and with the availability of satisfactory laboratory and clinical facilities, patients suffering with acute myocardial infarction should receive adequate anticoagulant therapy during the first month, and that the risk of reinfarction and death is reduced if this is continued for 1 to 2 years after the first month. More long-term studies should be conducted to evaluate this treatment for succeeding years. This form of therapy presents certain difficulties that must be weighed against the possible gains in deciding whether or not to continue it.

Excerpt Reversal of the vertebral artery blood flow associated with occlusion of the proximal portion of the subclavian artery was first reported in 1960 (1). Toole (2) and others (3, 4) described ...

In the course of a physical examination one is often confronted with the question whether the inability to palpate a pulse in a usual location is the result of arterial spasm, occlusive arterial disease, or an aberrant location of the artery. Evidence is presented that the sublingual administration of glyceryl trinitrate (nitroglycerin) will frequently solve this problem. If the absent or markedly diminished pulse becomes bounding and objective tests confirm this, it can be concluded that the reduced pulsation was due to spasm of the artery under study. This is a simple test readily applied in clinical practice.

Excerpt Four years ago I presented before the Annual Session of the College a brief analysis of the state of knowledge concerning certain major aspects of the problem of strokes.1Emphasis was place...

As early as 1943, E. V. Allen and N. W. Barker 1 suggested that anticoagulants might be of value in the treatment of thrombosis of the cerebral arteries. In 1946, one of us (I. S. W.) 2 reported experiences with anticoagulants in patients with cerebral emboli from myocardial infarction. In 1947, at the meeting of this same section of the A. M. A. convention, 4 we reported on cases of cerebral emboli from rheumatic hearts which were so treated. Four years later, in 1950, 3 a small series of cases was described in Medical Clinics of North America . Since then, many more patients have been treated and reported in the medical literature.* Before the advent of successful therapy, either medical or surgical, the exact diagnosis of cerebral vascular lesions was purely academic. However, in the past two decades, surgery has shown great advances. Hematomas, both epidural and subdural, are now

The hyperabduction syndrome was described in 1945. This report includes information and experience gained from the study of 52 patients suffering from its consequences and of many others in whom the diagnosis was necessarily considered. The signs and symptoms and age and sex incidence are summarized. Among the most striking findings was the fact that Raynaud's syndrome occurred in 20 of the 52 patients, an incidence far greater than anticipated in the general population. In some patients elimination of the hyperabduction position abolished Raynaud's syndrome. So far as we can determine this relationship has not been previously reported.

Among a group of 303 patients having signs and symptoms of cerebral vascular disease 4 were later found to have pathological lesions of other than vascular origin. The histories of these four patients and two others, not of this group but exhibiting a similar situation, are here reviewed. The lesions discovered were subdural hematoma, cerebral abcess, two metastatic brain tumors, and two primary brain neoplasms. To limit errors of diagnosis and to obtain best results from therapeutic measures such as anticoagulation, the author advises that any patient with a stroke should have a complete and careful evaluation. When the medical history is inadequate, when atypical features are noted, or when the patient is younger than the age group in which cerebral thrombosis is usually encountered, both arteriography and pneumoencephalography should be seriously considered.

The possibility of preventing the extension of coronary thromboses and the development of mural thrombi in the presence of myocardial infarction by the use of anticoagulants was suggested by Solandt, Nassim and Best 1 in 1938. These investigators were able to prevent the development of both coronary thrombi and of intracardiac mural thrombi under conditions in which such thrombi are usually produced experimentally in animals, by the use of the anticoagulant, heparin. Their observations were not applied to human beings on any significant scale because of the difficulties and the risk felt to be inherent in the use of heparin clinically. In the years 1945 and 1946, Wright, 2 Nichol and Page 3 and Peters, Guyther and Brambel 4 reported encouraging results following the use of the anticoagulant "dicumarol" in the treatment of coronary thrombosis with myocardial infarction in human beings. These reports were preliminary in nature, since only small