US3457347A - Method for controlling the coagulation of blood by administering epsilon amino caproic acid and heparin - Google Patents

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3,457,347 Patented July 22, 1969 ice METHOD FOR CONTROLLING THE COAGULA- TION OF BLOOD BY ADMINISTERING EPSILON AMINO CAPROIC ACID AND HEPARIN Jeanette L. Rubricius, Jamaica, N.Y., assignor to Harry H. Le Veen, Jamaica, N.Y. No Drawing. Filed Nov. 22, 1965, Ser. No. 509,211 Int. Cl. A61k 17/18 US. Cl. 424-183 6 Claims ABSTRACT OF THE DISCLOSURE The administration of heparin is improved by simultaneously administering epsilon aminocaproic acid.

This invention relates to methods and materials for controlling clotting characteristics of blood. More particularly, this invention relates to methods and materials useful in safely preventing extension of internal clotting while simultaneously preventing the breaking loose or general dissolution of clots once formed.

Anticoagulants, such as dicoumarol and heparin, constitute a well known class of medical agents, which delay clotting time by inhibiting the lay-down of fibrin. These materials, such as heparin and discoumarol, are routinely used under certain circumstances. However, certain undesirable complications may arise due to the use of anticoagulants.

Of the commonly used anticoagulants, heparin is generally considered the most useful and practical. Heparin therapy has been limited in its utility by a number of heretofore unsolved complications associated with its application. These complications are of such a frequent and serious nature that a number of medical experts in many instances have advised against heparin treatment. Examples of such complications are wound infections, severe hemorrhaging and embolization.

It is therefore one object of this invention to provide methods and materials which will obviate the problems associated with the use of anticoagulant therapy. Another object is to provide a method which will render anticoagulants safer for postoperative therapy. A further object is to provide a composition which, when administered to patients, will have the beneficial effects associated with anticoagulants without the corresponding detrimental efiects. Another object is to provide such a composition which can be safely administered to patients having a history of thrombophlebitis or varicose veins. A still further object shall be to provide a method of utilizing an agent which can be administered separately from but simultaneously with an anticoagulant and which will obviate or alleviate problems associated with the use of the anticoagulant.

These and other objects which shall become apparent from the following description are accomplished by the use of an epsilon aminocaproic acid.

Epsilon amino-n-caproic acid is known to be useful in cases of hyperfibrinolysis to inhibit plasmin and to inhibit activation of plasmin from US. Patent No. 2,939,- 817. Lysine, or alpha, epsilon diaminocaproic acid behaves similarly.

Plasmin, or fibrinolysin, has been recommended as an alternative to heparin for preventing intravascular thrombosis. In fact, fibrinolysin is considered by some as superior to heparin for this purpose and still others have suggested the use of both heparin and fibrinolysin in treating intravascular thrombosis. In accordance with the present invention, however, it has been found that the use of an epsilon aminocaproic acid which was a known inhibitor of fibrinolysin, in combination with anticoagulants such as heparin results in the elimination of the problems heretofore associated with the use of anticoagulants.

It has been discovered that embolization which may result with the use of an anticoagulant is avoided by the simultaneous administration of the aminocaproic acid. The expression simultaneous administration as referred to herein and in the appended claims describes an administration such that the effects of the anticoagulant and the amino caproic acid occur within the host simultaneously. Generally, according to the present invention, the anticoagulant is administered parenterally while the epsilon aminocaproic acid can be administered in combination with the heparin or in a separate injection or separately by oral administration, for example in tablet or syrup.

Although in the broader aspects of the invention epsilon aminocaproic acids such as lysine may be utilized, in a particularly useful embodiment of the invention epsilonamino-n-caproic acid is the additive which renders anticoagulants such as heparin safe therapeutic agents in situations where anticoagulant therapy otherwise would be dangerous because of the aforementioned complications. The effectiveness of epsilon-amino-n-caproic acid (EACA) in heparin therapy is indeed surprising since EACA is known as a blood coagulant or clotting promoter and would be expected to negate the known anticoagulant properties of heparin. With respect to the use of EACA, it is to be noted that, heretofore, the acid is useful only in cases of hyperfibrinolysis. In accordance with the present invention, however, plasmin content of the blood treated is usually quite normal. Accordingly, it is considered part of the present invention to utilize EACA for patients having normal or even sub-normal plasmin activity.

The following examples, although not intended to in any way limit the scope of the invention, will serve to illustrate the beneficial results obtained by the invention. In each of the Examples I through IV below, the therapy has been utilized with more than 50 human beings.

Example I In thrombophlebitis, it is desirable to prevent propagation of thrombosis. Heparin is the usual form of therapy. There is, however, a danger in using heparin where thrombi are already present because of the embolism known to occur with heparin therapy. According to this invention, epsilon amino n caproic acid has been found to be compatible with heparin and can either be given together with heparin in the same solution or independently. Both techniques have been used. When the compounds were mixed, 500 mgm. of EACA were mixed with 50 mgm. of heparin. The usual dosage intravenously was 50 mgm. of heparin every 4 hours and 500 mgm. of EACA every 4 hours. EACA was administered by mouth. Where the heparin was given separately in dosage of 50 mgm. every 4 hours either intravenously or subcutaneously, the EACA was given 500 mgm. every 4 hours by mouth.

The present composition and method was applied to over 50 human clinical cases of thrombophlebitis. The EACA-heparin combination prevented the unwanted embolism often associated with normal heparin therapy and prevented extension and complication of the thrombophlebitis.

Example II During vascular surgery, cross clamping of the aorta or large vessels is often required. When this is done, there is a hazard of thrombi forming beneath the clamp in the occluded vessel. For that reason, it is standard practice to administer 50 mgm. of heparin intravenously at the time the aorta is cross clamped. This, however, increases the risk of embolization and wound hemorrhage and infection due to clot dissolution. Therefore, according to 3 this invention, EACA in dose of 500 mgm. was administered for every 50 mgm. of heparin given intravenously. This treatment precluded clot formation beneath the clamp and, although post-surgical bleeding time was slightly prolonged, clots once formed were not susceptible to dissolution.

Example III Following vascular surgery, heparin is frequently used to prevent thrombosis in the recently operated vessels. There is, however, increased hemorrhage into the wound which causes hematoma and wound infection, therefore often requiring discontinuance of heparin therapy. This was obviated by the administration of EACA concomitant with heparin. The dosage used was 50 mgm. of heparin intravenously every 4 hours together with 500 mgm. of EACA.

Example IV Patients who have had pulmonary emboli either postoperatively or spontaneously without evidence of thrombophlebitis are often treated with heparin or vena cava ligation or both. These, however, increase the probability of other thrombi breaking loose. To obviate this problem, the following regime was employed: Vena cava ligation was done immediately after the embolization occurred. Heparin, 50 mgm. every 4 hours, together with EACA, 500 mgm. every 4 hours, was administered intravenously in the post-operative period for approximately 2 or 3 weeks after surgery. The dosage scale employed was approximately 10 parts by weight EACA to one part heparin. This dosage scale may be somewhat high, and it was found that doses as low as 250 mgm. of EACA for every 50 mgm. of heparin would give satisfactory results. In other words, the dosage schedule varies somewhat between 5 and parts EACA to 1 part heparin. The treatment obviated any complications due to further embolization.

Example V To investigate the cause of bleeding following heparin therapy, an experiment was performed on 25 rabbits. A longitudinal incision was made into the vena cava to produce what would be a fatal hemorrhage. This hemorrhage was controlled by the application of gelatin foam with pressure to obturate the bleeding site. After 5 minutes a fibrin clot was formed in the gelatin foam and the bleeding was controlled. The fibrin seal was sufiicient to prevent further bleeding. The animals were thereafter placed on heparin therapy. Fourteen of the twenty-five animals succumbed to fatal hemorrhage. The fibrin network which had held the gelatin foam to the opening in the venacava had undergone lysis.

Example VI The same procedure as in Example V was followed except that the animals were given epsilon-amino-n-caproic acid along with the heparin therapy. Fatal hemorrhage occurred in only three animals. This figure compared favorably to a control group of animals of which neither heparin nor epsilon-amino-n-caproic acid were administered.

Example VII The same procedure as in Example V was followed except that the animals were given lysine along with the heparin therapy. Only three animals succumbed to fatal hemmorrhage.

Example VIII Vena caval thrombosis was produced by chemical means in fourteen healthy mongrel dogs. After production of the thrombus, i.e. about live days after the operation, seven animals were treated with heparin while the other seven were treated with heparin in conjunction with E-amino-n-caproic acid. In those animals receiving only heparin, the thrombus became free floating and eventually embolized. In the remaining seven, no free floating thrombi developed and no embolism occurred. In each case the heparin was administered by intravascular in admixture with the heparin solution and orally by addition to the drinking Water.

Microscopic studies confirmed that in the animals treated with heparin alone each clot lacked cellularity and organization, while in the EACA-heparin treated animals each clot was highly cellular and organized.

As indicated above, this invention provides efficacious results in combating a number of specific problems associated with heparin therapy. The dosages of the epsilon amino caproic acid to be administered depend on the specific problem to be avoided as well as the size etc. of the individual to be treated. Generally the EACA to heparin ratio should be controlled at about 5-30 parts EACA to 1 part heparin (parts herein refer to parts by Weight), whereas a particularly effective range appears to be 5-10 parts EACA to one part heparin.

Although the maximum dosage of EACA can be as high as 30 gm. per day, generally the dosage is not over 15 grams and the particularly useful dosage for this invention does not exceed about 3-4 gm. in 24 hours of about 500 milligrams every four hours. Indications are that as little as 250 mg. of EACA will give beneficial results during heparin therapy. The heparin dosage does not generally exceed 450 milligrams per day, but the dosage is again determined by the particular problem and patient being treated and as little as 50 milligram dosage has been shown to be effective.

The administration of the heparin can be carried out in generally accepted methods usually involving intravenous injections of a glucose and/or saline solution of a suitable pharmaceutical carrier containing about 50-150 mgm. of heparin per liter of solution. The EACA can be added directly to the heparin solution, injected separately by solution of a suitable pharmaceutical carrier in a concentration of about 250 mg./cc., or, as previously mentioned, administered orally in the form of tablets, syrup etc. The administration is often initiated by a priming dosage of heparin and EACA followed by smaller doses at periodic intervals. Again, the rate of such doses are dependant upon the particular circumstances involved, but a particularly useful rate involves a primwing dosage of l50 mgm. of heparin followed by 50 mgm. every four hours; the EACA being simultaneously added in the ratio of 5-10 parts EACA to one part heparin. The dosage can, however, also be by a gradual administration over a period of time, eg by instillation.

The solutions of this invention for injection or syrups etc. for oral administration can contain additional quantities of other normally accepted therapeutic agents, e.g. sedatives, anesthetics, etc., even in somewhat large quantities, the prime limitation being the compatibility of the additive with heparin and/or the epsilon amino caproic acid.

What is claimed is:

1. A method of avoiding wound hemorrhage or embolization during heparin therapy in patients having normal or sub-normal plasmin activity which comprises the simultaneous administration of epsilon aminocaproic acid and heparin wherein the heparin is administered parenternally and the epsilon aminocaproic acid is simultaneously administered either parenternally or orally in an amount of from 250 mg. to 30 grams per day and wherein said epsilon aminocaproic acid is administered in an amount of from 5 to 30 parts by weight of heparin.

2. A method according to claim 1 wherein said heparin and epsilon aminocaproic acid are administered together as a mixture.

3. A method according to claim 1 wherein said heparin and epsilon aminocaproic acid are administered separately.

4. A method according to claim 1 wherein said amount is from 5 to 10 parts by weight per part by weight of heparin.

5. A method according to claim 1 wherein the acid is epsilon arnino-n-caproic acid.

6. A method according to claim 1 wherein the acid is alpha, epsilon diaminocaproic acid.

References Cited UNITED STATES PATENTS 6/1960 Nagasawa et a1 167-65 OTHER REFERENCES Lederle, Amicar, March 1964. The Journal of Biochemistry, The Inhibition of Plas- 6 min by Some Amino Acid Derivatives, Nagamatsu, A. et a1. vol. 54, pp. 491-496, 1963.

Acta Physiologica Scandinavia, The Effect of Heparin and e-Aminocaproic Acid, etc., Johansson, B. et al., pp. 267-77; March 1964.

ALBERT T. MEYERS, Primary Examiner HOWARD M. ELLIS, Assistant Examiner Us. 01. X.R.