Bleeding Problems in the Surgical Patient

PROBLEMS OF PHYSIOLOGICAL IMPORTANCE

Bleeding Problems in the Surgical Patient

J. L. KOPPEL, PH.D.* JOHN H. OLWIN, M.D., F.A.C.S.**

To THE surgeon, excessive bleeding has always been an important problem and a major limiting factor in his work. With the advance in knowledge concerning blood groupings and the widespread establishment of blood banks, the fear of voluminous bleeding and/or hemorrhage has diminished and the margin of safety in the field of surgery thereby materially widened. The improvements in surgical techniques and the development of more radical procedures have themselves, however, necessitated the use of larger amounts of blood. These have been associated with the development of induced bleeding tendencies in surgical patients over and above the many already existing and confusing hemorrhagic diseases. It is the purpose of this paper to outline the problems of bleeding which may confront the surgeon, to suggest methods for identifying hemostatic abnormalities present in the patient prior to as well as those developing unexpectedly during surgery, and to outline methods of treatment for the various deficiencies. THE HEMOSTATIC MECHANISM

The Coagulation Mechanism. According to present day concepts, the coagulation of blood occurs in three distinct, although interrelated

* Research Associate in Surgery, University of Illinois College of Medicine, Chicago. ** Clinical Associa,te Professor of Surgery (Rush), University of Illinois College of Medicine, Chicago. 3

J. L. Koppel, John H. Olwin stages. In the first of these plasma thromboplastin is formed as the result of interactions between platelet substances and certain plasma proteins (Antihemophilic Globulin, AHG, Plasma Thromboplastin Component, PTC, and Plasma Thromboplastin Antecedent, PTA.) During the second stage thromboplastin interacts with prothrombin, various accelerators (Factors V and VII) and calcium to form thrombin. This, in turn, is followed by the conversion of fibrinogen to fibrin (the clot) through the enzymatic action of thrombin and, finally, the retraction of the clot and fibrinolysis. The V ascular Mechanism. The mechanism controlling the vascular response to trauma is highly important in the control of spontaneous hleeding. Even though platelets and the coagulation mechanism itself appear normal, hemorrhages may be caused by extreme vascular fragility, a condition often associated with a deficient intake of ascorbic acid and/or bioflavonoids. On the other hand, syndromes characterized by the inability of the vessels to contract following trauma appear to be caused by a qualitative deficiency of platelets. DIAGNOSIS OF HEMORRHAGIC DISORDERS

A differential diagnosis of the particular disorder involved may enable the surgeon to prevent the occurrence of avoidable bleeding episodes, and to use a precise and effective therapeutic approach if excessive hleeding does occur. Except in the very young, a patient with a hemorrhagic disorder will usually have had signs of it at some period in his life. A carefully taken history is therefore of primary importance. It is desirable that the surgeon have at hand a group of tests which will enable him to discover a hidden bleeding tendency preoperatively. The following laboratory procedures will in most instances provide such information: bleeding time, clotting time, prothrombin time, prothrombin consumption test, platelet count, fibrinogen assay, protamine titration, capillary fragility test and the inspection of the clot for retraction and lysis. If normal results are obtained with all these tests the existence of a coagulation defect or vascular abnormality is most unlikely. Should some of these tests provide abnormal results, their interpretation may be aided by the following brief discussion of individual disorders. ThrOlnbocytopenic States

The thrombocytopenic states include a variety of conditions in which there is a marked reduction of circulating platelets. The clinical picture found is much the same in all types, multiple petechiae, ecchymoses and bleeding gums often being observed. The bleeding and clotting times are prolonged and the prothrombin consumption and capillary fragility tests are abnormal. When a splenectomy is to be carried out on a patient with chronic idiopathic thrombocytopenic purpura, the preoperative administration of steroids, fresh blood (collected in siliconized bottles or plastic

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bags) and/or platelet concentrates is essential. The improved bleeding time and prothrombin consumption tests serve as an index of the effectiveness of these procedures and the relative margin of safety at any given time. Thrombasthenic States

Thrombasthenias are characterized by defects in one or more of the hemostatic functions associated with platelets, although there is a normal number of platelets. The platelets are often unable to correct the deficient clot retraction and prothrombin consumption of normal platelet-free plasma. The diagnosis is aided by the fact that there is usually a history of easy bruising and extensive bleeding as a result of trauma. A normal platelet count in conjunction with poor clot retraction, increased capilJary fragility and bleeding time tests and a diminished prothrombin consumption may be indications of a qualitative platelet deficiency. Transfusions of fresh, whole blood (collected in siliconized bottles or plastic bags) or platelet concentrates usually normalize the bleeding tendency of these patients within several days, thus making it possible to perform major surgery without undue risk. Hemophilia and Hemophilioid States

Classical hemophilia (Antihemophilic ·Globulin [AHG] Deficiency) will usually be known by the family history and by the occurrence of multiple bleeding episodes in the male patient. A prolonged clotting time and a poor prothrombin consumption will help to diagnose the defect. Since infused antihemophilic globulin disappears within 12 to 24 hours frequent and substantial blood or plasma transfusions are necessary to induce and maintain normal clotting. Following surgery this should be continued for a sufficiently long period of time to allow complete wound healing to take place. It should be emphasized that a hemophilic patient may become resistant to repeated transfusions of whole blood and plasma, a possibility which should always be considered when prophylactic therapy is contemplated. Plasma thromboplastin component (PTe) deficiency is generally a milder disorder in which the beneficial effects of transfusions last longer and in which transfusions with serum are effective. As in hemophilia, the clotting time and prothrombin consumption are abnormal. However, the two deficiencies can be distinguished by the ability of normal serum to correct the clotting time of a PTC-deficient plasma. Plasma thromboplastin antecedent (PTA) deficiency is a mild disease, affecting both sexes and giving rise to a slightly prolonged clotting time and poor prothrombin consumption. Whole blood or plasma transfusions can be used to alleviate this condition. The syndrome can be distinguished from AHG and PTC deficiencies by the fact that it can be corrected by serum which has been treated with adsorbents to remove PTC.

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J. L. Koppel, John H. Olwin

Hypoprothomhinemia

Hypoprothrombinemia is rarely of congenital OrIgm. Acquired deficiencies may occur in various types of biliary obstruction, liver disease, biliary or high intestinal fistulas, dysenteries of various types, preoperative sterilization of the colon by floracidal agents, hemorrhagic disease of the newborn and patients maintained on prothrombin-depressant anticoagulant therapy. The ingestion of an anticoagulant by error or on a malingering basis should not be overlooked. Excessive salicylate intake may occasionally be responsible for a depressed prothrombin. The history, physical findings and abnormal prothrombin time will usually assist in identifying the defect and its cause. Treatment is directed towards the elimination of the cause and the administration of vitamin K-active substances. In cases of severe liver deficiency prothrombin may remain depressed despite all efforts to raise it including energetic liver support. If surgery is necessary in such cases, fresh blood or plasma may give temporary, partial elevation of prothrombin. Factor V Deficiency

Although this abnormality is rarely hereditary it may be acquired as a result of liver disease, leukemia, malignancy or abruptio placentae. A transient decrease often occurs during the first week after surgery and is at its maximum at about the third postoperative day. A prolonged bleeding time and prothrombin time in conjunction with a normal prothrombin consumption will assist in diagnosing the defect. Because of its rapid disappearance in serum and oxalated whole blood or plasma, management of the deficiency is based on the use of fresh whole blood or plasma (collected in sodium citrate). Factor VII Deficiency .

The disease may be of congenital or acquired origin. It may be present in hepatic disorders, in the immediate neonatal period and as a result of the administration of prothrombin-depressant anticoagulant drugs. Laboratory findings include a prolonged prothrombin time and a normal prothrombin consumption. The acquired type of the deficiency usually responds to the administration of vitamin K-active substances. Whole blood, plasma or serum has to be used to alleviate the defect if it is of congenital origin. Fihrinogenopenic States

Fibrinogen deficiencies may be congenital or acquired. The congenital defect is rare and may exist without manifesting itself until trauma. Althol'lgh acquired fibrinogenopenia can be nonspecific in nature it is not infrequently associated with metastatic carcinoma or certain complications of pregnancy such as the presence of a dead fetus, ablatio placentae and amniotic embolism. Regardless of its specific cause,

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fibrinogenopenia results in a prolonged clotting time and in increasingly abnormal prothrombin times as the plasma fibrinogen level falls below 100 mg./100 ml. It is important to have a quantitative fibrinogen determination on such patients. If excessive fibrinolysin activity is present the clot will lyse rapidly, under extreme conditions in one hour or less. The fibrinogen deficiency may be corrected by the administration of human fibrinogen. Excessive fibrinolytic activity, on the other hand, may be neutralized by the administration of protamine sulfate. Early recognition of this condition is highly important, since fatal hemorrhage may occur rapidly. If the defect is acute the administration of plasma or blood is inadequate and 2.5 to 10 grams of fibrinogen should be given in a short period of time (one-half to one hour). Calculated replacement based on quantitative fibrinogen data is desirable. Hyperheparinoid States

Conditions in which there is an increased heparin or heparin-like activity in the blood are poorly understood. They are frequently associated with anaphylactic states, particularly those brought on by transfusion of improperly matched blood which mayor may not be due to technical error. They may also occur in response to chemical or physical agents such as the administration of nitrogen mustards or the treatment with ionizing radiations of various types. The condition can be recognized by an abnormal prothrombin consumption and increased protamine titration. It can usually be corrected by the administration of protamine sulfate. Presence of Other Circulating Anticoagulants

N onheparin-like circulating anticoagulants may act by preventing the formation of thromboplastin, a mechanism apparently operating in some hemophiliacs after repeated transfusions, or by inhibiting the activity of formed blood thromboplastin as observed in some patients with lupus erythematosus. The abnormality is characterized by a prolonged clotting time which is not corrected by the addition of normal blood or plasma. Prothrombin consumption is decreased to a variable extent depending on whether the anticoagulant prevents thromboplastin formation or inhibits thromboplastin activity. There is, at present, no rational management for syndromes of this type although the administration of ACTH or cortisone may improve the hemorrhagic manifestations nonspecifically. MANAGEMENT OF EXCESSIVE BLEEDING DEVELOPING DURING OR FOLLOWING OPERATION

The foregoing types of hemorrhagic states are usually detectable before the patient reaches the operating room. With the deficiency precisely diagnosed, all available corrective measures must be used to alle-

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J. L. Koppel, John H. Olivin

viate or normalize it. The responsibility for this preoperative study and preparation of the patient may be shared with the internist or hematologist. Of particular concern to the surgeon is the unexpecteJ onset during operation of a continuous brisk oozing from the tiny vessels and capillaries which normally seal themselves within four to ten minutes after injury. The replacement of blood lost and the administration of vitamin K-active substances often have no effect and may seem only to aggravate the condition. In order to institute effective therapy it is essential that the specific defect involved be identified as rapidly as possible. On an emergency basis and before any treatment is begun the technician should be called to the operating room and blood should be drawn for the following tests: clotting time, prothrombin time, prothrombin consumption, protamine titration, platelet count, fibrinogen assay and the determination of fibrinolysin activity. Furthermore, an extra 9.0 ml. volume of blood should be added to 1 ml. of 3.2 per cent sodium citrate for possible additional tests at a later time. Immediately after the blood has been withdrawn and before the results of the tests are available, the administration of 100 mg. of protamine sulfate should be started. This should be placed into two different flasks in order to infuse it into the patient as rapidly as possible. Too heavy a concentration at any given site may result in thrombosis of the vein at that point. In addition, vitamin Kl (50 mg. of Mephyton) shaken to a fine emulsion in saline or glucose should also be given. If blood loss does not appear to be too critical it is well to stop the infusion of blood, as it may be the cause of the bleeding. As soon as the results of the tests become available, the specific type of therapy indicated should be initiated. If, because of the time of day or other reasons, laboratory tests cannot be carried out immediately, 20 ml. of blood should be drawn, citrated and stored at 40 C. until laboratory processing is available. Although the results of some of the tests carried out at a later time are less accurate than those obtained with freshly drawn blood and some cannot be done except immediately on collection of blood, they may still be of value in suggesting suitable postoperative therapy. Since bleeding, even though temporarily controlled, may recur at a later time, it is important to follow the patient carefully by daily assays of the factors responsible for his deficiency. CONCLUDING STATEMENTS

Whole blood and plasma (and, in certain instances, serum) represent the main source of coagulation factors for the treatment of various hemorrhagic diseases. From the available information concerning the survival of transfused clotting factors in vivo and their preservation and stability in vitro the following conclusions can be drawn: 1. Fresh plasma or whole blood, within 12 hours of collection in citrate,

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is the preferred treatment in cases of cla88ical hemophilia and those with factor V deficiency. 2. Bank blood or plasma, preferably within 20 to 30 days of collection, can be used in patients with hypoprothrombinemia, deficiencie8 of factor8 VII, PTC and PTA and those with fibrinogenopenia. 3. Fresh or stored serum is effective in the treatment of factor VII and PTC deficiencie8. Table 1 SUMMARY OF LABORATORY FINDINGS AND TREATMENT OF BLEEDING TENDENCIES

FACTOR

Deficiency of: Platelets

Antihemophilic Globulin Plasma Thromboplastin Component Plasma Thromboplastin Antecedent Prothrombin Factor V

Factor VII Fibrinogen Excess of: Fibrinolysin

LABORATORY FINDINGS

TREATMENT

Prolonged bleeding time, poor prothrombin consumption, increased vascular fragility, poor clot retraction Prolonged clotting time, poor prothrombin consumption; corrected by fresh, normal plasma but not by serum Prolonged clotting time, poor prothrombin consumption; corrected by normal plasma and serum Slightly prolonged clotting time, poor prothrombin consumption; corrected by normal plasma and serum; partially corrected by BaS04 adsorbed serum Prolonged prothrombin time not corrected by normal serum; corrected by oxalated aged plasma Prolonged bleeding time, prolonged prothrombin time, poor prothrombin consumption; corrected by fresh normal plasma; not corrected by normal serum or oxalated aged plasma Prolonged clotting time, prolonged prothrombin time; corrected by normal plasma and serum Prolonged clotting time, prolonged prothrombin time, low plasma fibrinogen concentration

Steroids; fresh, whole blood; platelet concentrates

Abnormally rapid clot lysis

Whole blood; plasma

Whole blood; plasma; serum Whole blood; plasma

Whole blood; plasma; vitamin K - active substances Fresh, whole blood; plasma

Whole blood; plasma; serum Whole blood; plasma; human fibrinogen

Whole blood; plasma; fibrinogen; protamine sulfate Heparin or Hep- Prolonged clotting time, prolonged Protamine sulfate arinoid Subprothrombin time; abnormal prostances tamine titration Other: Circulating Prolonged clotting time not corrected Steroids (?) Anticoagulants by small amount of normal blood or plasma; often poor prothrombin consumption

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J. L. Koppel, John H. Olwin

4. Whole blood should be used only where necessary to correct anemia due to severe loss of blood or where such loss can be definitely anticipated. 5. The indiscriminate use of blood or plasma transfusions in patients with bleeding tendencies should be discouraged, particularly when it is intended to prevent rather than arrest hemorrhage. The potential danger of transmitting homologous serum hepatitis should always be considered, as should be the possibility of sensitization of the patient against the very coagulation factor he does not possess. This phenomenon is known to occur in certain patients with classical hemophilia as well as others with thrombocytopenia where repeated transfusion of platelets may result in the formation of platelet antibodies. Table 1 may be of aid in diagnosis and treatment of bleeding tendencies. For additional detailed information on hemorrhage and hemorrhagic disorders the following publications are suggested: Alexander, Benjamin: Coagulation, Hemorrhage and Thrombosis. New England J. ~ed.252:432-442,484-494, 526-535,1955. Biggs, Rosemary and ~acFarlane, R. G.: Human Blood Coagulation and Its Disorders, 2nd Ed. Oxford, Blackwell Scientific Publications, 1957. De Nicola, Pietro: The Laboratory Diagnosis of Coagulation Defects. Springfield, Ill., Charles C Thomas, 1956. Owen, C. A. Jr., ~ann, F. D., Hurn, ~. ~. and Stickney, J. ~.: Evaluation of Disorders of Blood Coagulation in the Clinical Laboratory. Am. J. Clin. Path. 25: 1417-1426, 1955. Stefanini, ~ario and Daneshek, William: The Hemorrhagic Disorders. New York, GrUlle & Stratton, 1955. Tocantins, L. ~.: The Coagulation of Blood. New York, Grune & Stratton, 1955. 1753 W. Congress Street Chicago 12, Illinois