Evaluation and Management of Surgical Patients with Complicating Hematologic Conditions

•

Evaluation and Management of Surgical Patients with Complicating Hematologic Conditions ROBERT C. NEERHOUT, M.D.*

The traditions of good medical practice dictate that all patients being considered for a surgical procedure have, as part of their evaluation, a screening blood count and complete medical history. Frequently these turn up an unexpected anemia or bleeding history at the "eleventh hour" which requires immediate evaluation prior to surgery. If surgery is elective and if the abnormal findings are not readily explained, it is advisable to defer surgery until complete hematologic evaluation can be obtained. The purpose of this paper will be to outline an approach to such patients which will allow a reasonable assessment of their hematologic status in a short period of time.

BLEEDING TENDENCY The best form of screening test for a possible hemorrhagic disorder is a carefully taken history. Patients with a clear-cut history of such conditions as surgical bleeding, hemarthroses, bleeding with dental extraction, and multiple large hematomas should have a complete coagulation work-up to carefully pinpoint the mechanisms involved. Surgery should be postponed if at all possible until this has been completed. The more perplexing problem is that of the suggestive historythe child who bruises more than anticipated, the child with frequent nosebleeds, or the child who appears to bleed easily when cut. It is imperative that the physician judge, on the basis of the history, whether or not a bleeding disorder is a reasonable possibility. In patients whose history is considered positive, a complete screening evaluation is necessary. There is no one simple screening test for a bleeding disorder. *Associate Professor of Pediatrics, U.C.L.A. School of Medicine; Director, Pediatric Hematology Clinic, U.C.L.A. Center for the Health Sciences and Los Angeles County Harbor General Hospital, Los Angeles, California

Pediatric Clinics of North America- Vol. 16, No. 3, August, 1969

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In order to properly evaluate a bleeding history, several points should be stressed. The type of bleeding may be helpful. Petechial bleeding suggests a platelet or vascular problem and is generally not seen in defects of intrinsic coagulation. Purpuric lesions on the shins and forearms may be normal in active youngsters, whereas similar lesions on the trunk and thighs should be viewed with greater suspicion. Frequent nosebleeds that are easily controlled are rarely signs of a coagulation disorder unless associated with other more positive history. Schulman reported a negligible incidence of bleeding disorders in children evaluated solely on the basis of nosebleeds but an incidence of 94 per cent in children with nosebleeds plus a positive history of other bleeding manifestations in them or their families. 18 A previous exposure to surgical trauma, particularly in the form of dental extraction or tonsillectomy, that was not accompanied by undue bleeding would tend to rule out most congenital bleeding disorders. Although a history of bleeding at circumcision is an important fact in a male suspected of being a bleeder, the lack of such bleeding cannot be interpreted as strong evidence against such a disorder. Baehner and Strauss reported that most infants with hemophilias A and B undergoing circumcision had only mild bleeding or none at all (76 out of 107). 3 Of their patients with severe hemophilia A orB, more than half had no significant hemorrhage with circumcision. A family history of bleeding must be viewed in a similar light. A positive bleeding history in family members is quite important, particularly if it falls into the sex-linked recessive pattern associated with hemophilia A (factor VIII deficiency, or classic hemophilia) or hemophilia B (factor IX deficiency, or Christmas disease). Due to the high spontaneous mutation rate, however, no family history can be obtained in as high as 40 per cent of newly diagnosed hemophiliacs in some series. 21 A negative family history cannot be a deterrent to consideration of this diagnosis. A normal whole blood clotting time as a single screening test for a bleeding disorder is not only unreliable, but notoriously misleading. All but the most severe hemophilia A patients will have a normal clotting time. A factor VIII level of only 1 to 2 per cent of normal is sufficient to render the clotting time normal. When the test is prolonged, this generally signifies a significant hemostatic disorder. Patients with a congenital deficiency of factor XII (Hageman factor or glass activating factor) have prolonged clotting times in glass tubes similar to those seen in normal individuals when run in siliconized tubes. Despite this marked in vitro coagulation defect, these patients may have little or no bleeding problem and have withstood surgical procedures with little difficulty. The recalcification time of plasma deficient in Hageman factor can be easily corrected by performing the test in a tube on which Hageman factor has been absorbed by rinsing with normal serum. 15 Total inability to form a clot should raise the question of afibrinogenemia or a circulating anticoagulant. Once a clot has formed, it should be observed for several hours. Clot dissolution may be seen when activation of the fibrinolytic system is present. Failure of the clot to retract into a firm, rubbery mass is associated with low blood platelets or abnormal platelet

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function. The capillary clotting time is an unreliable test because of the variable amount of tissue thromboplastins which may be introduced. The bleeding time is primarily a measure of platelet and vascular function and is routinely normal in bleeding problems involving other factors. Even patients with the more severe forms of hemophilia will have normal bleeding times. The detection of a prolonged bleeding time in conjunction with low levels of antihemophilic globulin (factor VIII) should suggest the presence of von Willebrand's disease."3 The performance of bleeding times has generally suffered by a lack of procedural standardization among various institutions. We prefer the forearm (Ivy) method to the ear lobe (Duke) method for children because of the greater ease in controlling any excess bleeding. The simplest generally available method is the use of a No. 11 Bard-Parker blade held in a hemostat with 5 mm. of the blade exposed. The skin can be quickly pierced and the depth accurately controlled. A blood pressure cuff inflated to 40 mm. Hg is applied and the drop of blood removed every 30 seconds by touching it with a piece of filter paper. Although bleeding times in excess of 8 minutes are occasionally seen by this method in normal individuals, they should be viewed with suspicion and indicate the necessity of further evaluation. Recent emphasis has been placed on the effect of aspirin ingestion on the bleeding time. The bleeding time may be almost doubled in normal individuals 2 hours after ingesting 1 gm. of acetylsalicylic acid. 10 This prolongation may be even greater in patients who have defects of the intrinsic coagulation system. Although proposed as a screening test for patients with the Minot-von Willebrand disease,t 7 marked prolongation of bleeding time has also been described in patients with hemophilias A and B following aspirin ingestion. 10 Because of this, it would appear appropriate to avoid the use of aspirin in all patients with known coagulation disorders.

Platelets Platelet numbers may be adequately evaluated by scanning a wellprepared blood smear. If there is any question of reduced numbers, a formal platelet count should be obtained. Where the history and clinical evaluation strongly suggest a platelet problem (e.g., petechial bleeding, positive capillary fragility by tourniquet test, prolonged bleeding time, and poor clot retraction), more formal testing of platelet function should be obtained despite a normal count. A simplified in vivo estimation of platelet adhesiveness can be made by comparing the capillary platelet count with the venous platelet count. The capillary platelet count is normally one-half to two-thirds the venous count, but this differential is not seen in conditions with poor platelet adhesiveness. 4 Evaluation of such phenomena as platelet factor 3 release, platelet adhesiveness, and platelet aggregation will help to further define platelet function. Clinically significant bleeding is rarely seen with platelet counts above 50,000 if the platelets are qualitatively normal.

Prothrombin Time The standard one-stage prothrombin time test available in most hospital laboratories is an assay of the competence of the extrinsic

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coagulation system (Fig. 1). It is a measure of the recalcification time of citrated plasma where clotting has been initiated by addition of a complete tissue thromboplastic substance (usually brain thromboplastin). The test is not specific for prothrombin, and deficiencies of any of the factors involved in the extrinsic pathway (factors V, VII, X, prothrombin, and fibrinogen) will cause prolongation. Since the curve relating prothrombin time to activity is hyperbolic, variations of between 50 and 100 per cent of normal control activity reflect little difference in actual prothrombin time, and any values in this range should be considered normal. Conversely, in values at the other end of the scale (below 30 per cent of normal control activity), small variations in per cent of normal activity denote large alterations in actual prothrombin time. It would appear that much confusion could be avoided by routinely reporting the patient and control prothrombin times in seconds and ignoring the per cent of normal activity. It should be emphasized at this point that, of the standard coagulation tests discussed (history, bleeding time, clotting time, platelet count, and prothrombin time), only the history would be expected to be positive in the usual patient with classical hemophilia.

Partial Thromboplastin Time (PTT) The partial thromboplastin time (PTT) test is an assay of the intrinsic coagulation system (Fig. 1). It is a measure of the recalcification time of citrated plasma where clotting has been initiated by the addition of a lipid partial thromboplastin, usually cephalin, as a platelet substitute. Kaolin particles are generally included in the system to provide optimal activation of Hageman factor (XII). As with all coagulation tests, normal control plasma is run also for time comparison. Since this test measures the entire intrinsic system (factors V, VIII, IX, X, XI, XII, prothrombin, and fibrinogen), significant deficiencies in any factor in the system will render the test abnormal. With the exception of factor VII and factor XIII (Fig. 1), all of the standard coagulation factors contribute to the PTT, making this test the single most inclusive screening test routinely available. When the prothrombin time and PTT are both performed, a reasonably accurate assessment of possible defects can be made. If both tests are abnormal, the deficiency should be a common factor-factors V, X, prothrombin, and fibrinogen. If the prothrombin time is abnormal while the PTT is normal, this implicates the one factor unique to the extrinsic system-factor VII. If the PTT is abnormal while the prothrombin time is normal, this implicates factors unique to the intrinsic system-factors VIII, IX, XI, XII. This latter combination would be seen, therefore, in hemophilia A (factor VIII, AHG), B (factor IX, PTC), or C (factor XI, PTA). The precise establishment of a specific factor deficiency again requires more sophisticated tests (e.g., thromboplastin generation test, cross-mixing tests with known deficient plasmas, and specific factor assay) than are generally available in routine hospital laboratories. Due to the marked lability of factors V and VIII at room temperature, it is imperative that test plasma be placed in an ice bath when drawn-particularly in hot weather.

685

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EXTRINSIC

INTRINSIC

________ ,

TISSUE THROMBOPLASTIN

PLATELET FACTOR

I I I

I

XII XI IX VIII

' '

XVII X

',

V PROTHROMBIN

1 I

'-,

PROTHROMBIN TIME

l....THROMBI~',,

PLASMINOGEN

+

PLASMIN

.----·---*---j',) XIII FIBRIN ~ SPLIT j FIBRINOGEN---.F'IBRIN · -;~!!!!....;.,..POLYMER~PRODUCTS ·-·-THROMBIN TIME-·-·_j

I

~-------------------J

Figure 1. Schematic representation of the coagulation mechanism as measured in vitro. Factors involved in the prothrombin time, partial thromboplastin time (PIT), and the thrombin time are noted.

Fibrinogen Determination In clinical situations where whole blood clots poorly or where both the prothrombin time and PTT are prolonged, it is important to obtain some quantitation of the fibrinogen level. The lack of visible turbidity in plasma that has been heated to 56° C. for 5 minutes denotes very low or absent fibrinogen. A simpler method is to add a small amount of commercially available powdered bovine thrombin to the plasma and look for a fibrin clot. This bypasses all early stages of coagulation and is the basis for the thrombin test (Fig. 1). When performed with serial dilutions of plasma and compared to normal controls, a reasonable quantitation of the fibrinogen level may be obtained. It is important to remember that fibrinogen determinations based on the thrombin time principle will be rendered totally unreliable once a patient is heparinized. We have seen a patient with presumed consumption coagulopathy in whom heparin dosage had been repeatedly increased because the fibrinogen level (assayed by a thrombin time method) continued to fall with therapy.

Preparation for Surgery Once the type of coagulation defect has been determined, appropriate replacement therapy may be given in preparation for surgery. The indications for surgery in patients with bleeding disorders should be quite clear cut and surgery deferred if at all possible. With the varied forms of replacement therapy available today, however, needed surgery can generally be performed without excessive risk to the carefully prepared patient. Platelets Since clinical bleeding is rare in patients with platelet counts over 50,000 per cu. mm., we have not attempted to treat such patients prior

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to surgery. The availability of platelets for transfusion if necessary should be established, however. Children who are thrombocytopenic secondary to idiopathic thrombocytopenic purpura rarely have significant bleeding at splenectomy, and it is generally not necessary to prepare them with platelet transfusions for this procedure. Patients whose thrombocytopenia is marked and associated with a systemic disease, aplastic anemia, or hypersplenism may benefit most from preoperative platelet transfusions. This is particularly true if they appear to be in an "active bleeding" state from their thrombocytopenia. When available, platelet concentrates are preferred to platelet-rich plasma because of the greater numbers of platelets per unit volume. The number of platelets required to attain a safe level will depend on many factors largely relating to the disease process. 7 Thrombocytopenia secondary to increased utilization or destruction of platelets may be extremely refractory to elevation of platelet count by transfusion, although some degree of hemostasis may still be attained. Thrombocytopenia secondary to decreased marrow production may respond well. Platelet concentrates are generally available in "unit" dosage. (One unit represents the platelets harvested from 1 unit of fresh whole blood by first separating platelet-rich plasma with low-speed centrifugation and then concentrating the platelets in 15 to 20 ml. of plasma by high-speed centrifugation.) Platelets should be obtained from donors compatible with the patient in the ABO and Rh blood groups. Administration of a dose of 1 unit of platelets per 10 pounds of body weight is a reasonable guideline. Administration should be within a few hours of surgery to provide maximal hemostatic effect. The need for subsequent platelet transfusions after surgery must be determined by the type of procedure, the degree of bleeding, and the subsequent rate of fall of the platelet count. Attempts to maintain platelet levels for prolonged periods when a patient is not bleeding are generally impractical because of the demands placed on the blood bank and the decreasing efficacy of platelet transfusions if isoimmunization develops. 20 Plasma Factors Plasma preparations and concentrates generally available today are shown in Table 1. Prior to the development of specific factor concentrates, it was not necessary to know the specific factor a patient lackedsome form of fresh plasma containing all coagulation factors could be used to treat all patients. The same principle still holds true in unexpected bleeding problems in which time or facilities preclude a complete identification of the factor involved. With the availability of concentrates, it is essential that the factor being replaced be specifically identified as the missing factor, since most concentrates contain only one or two factors in useful concentrations. The purified concentrates currently most available are fibrinogen and AHG (factor VIII). A concentrate containing clotting factors VII, IX, and X and prothrombin is now available and should prove useful in patients with liver disease or hemophilia B. 9 Pure fibrinogen deficiency is seen in pediatrics as a congenital disease. The tendency to spontaneous bleeding in these patients is not

T !

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COMPLICATING HEMATOLOGIC CONDITIONS

Table 1.

Preparations Available for Coagulation Factor Replacement':' WHOLE PLASMA PREPARATIONS

Fibrinogen Prothrombin Factor V Factor VII Factor VIII Factor IX Factor X Factor XI Factor VIII equivalent

CONCENTRATES

FRESH-

LYO-

GLYCINEt

PRO-

FRESH

FROZEN

PHIL I ZED

STORED

PRE-

PRE-

PLASMA

PLASMA

PLASMA

CIPITATE

CIPITATE

THROMBIN: COMPLEX

FIBRINOGEN§

PLASMA

+ + + + + + + +

+ + + + + + + +

+ + + + + + + +

+ +

0 0 0 0

0 0 0 0

0

+

0

+

+

0

+

+ + +

0 0 0

0 0 0

+ + 0

0 0 0

0.7

0.6

0

15-20

30-45

0

1.5-2.0

CRYO-

0

+

+ 0

+

WITH AHF

0 0 0

~'Factors present in clinically useful concentrations are shown with a+. The factor VIII equivalent gives a rough estimate of the volume of fresh normal plasma which would provide an amount of factor VIII equal to that contained in 1 ml. of the preparation. t Antihemophilic Factor (Human), Method Four (Hyland Laboratories). !Konyne (Cutter Laboratories). §Fibro-AHF (Merck, Sharp & Dohme).

great, but surgery would best be covered with fibrinogen infusions. A dose of 100 mg. of fibrinogen per kg. of body weight should give an effective plasma level in excess of 80 mg. per 100 ml.' 9 Decay should then be monitored and further infusions given to retain a concentration in excess of 80 mg. per 100 ml. In evaluating patients with afibrinogenemia, it is imperative that patients with fibrinolytic processes and consumption coagulopathy be identified, as replacement therapy may be of little benefit and may actually be harmful. Congenital afibrinogenemia should give a prolonged history, while the processes mentioned above are associated with an acute, acquired bleeding diathesis. Patients with hemophilia A (factor VIII, AHG) present the most common surgical problem. Prior to the availability of concentrates, surgical preparation was generally achieved by giving 15 to 20 ml. of type-specific fresh or fresh-frozen plasma per kg. of body weight immediately before the procedure, followed by infusions of 5 to 10 ml. per kg. every 4-6 hours. The use of large quantities of lyophilized pooled plasma in patients of blood type A, B, or AB may cause a hemolytic anemia because of the isohemagglutinin content. The actual preparation depends to some degree on the type of surgery involved, and in some instances exchange transfusion with fresh blood has been utilized to attain high levels. The limiting factors in plasma therapy are over-all volume utilized and total protein content, making hypervolemia a constant danger. The use of cryoprecipitate or glycine preparation has helped greatly in alleviating these problems. The result with either of these concentrates appears good-the former is the less expensive, while the latter is somewhat more predictable. 6 The cryoprecipitate is dispensed in "units" that represent approximately 70 per cent of the factor VIII activity of a 500 ml. whole blood donation concentrated to 10 to 20 ml. Because of the wide variation in normal factor VIII levels (normal assay range is 50 to 200 per cent of the mean), the actual factor

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VIII assay per unit may be quite variable. The glycine preparations are all assayed so that the fresh plasma equivalent of each vial is known (one factor VIII unit equals the amount of factor VIII in 1 ml. of normal plasma). Various dosages are available, the most concentrated being a 10-ml. vial containing 450 units (i.e., 10 ml. of concentrate has a factor VIII content equivalent to 450 ml. of fresh plasma). With either preparation, it is thus possible to calculate with reasonable accuracy the quantity to be administered to achieve a desired plasma level. A factor VIII level of 50 per cent should provide adequate hemostatic levels for most surgical procedures, although we have preferred to aim for 80 to 100 per cent levels for major operations. (With the glycine preparation, a 100 per cent level is attained by administering a number of units of factor VIII equal to the calculated plasma volume; lower levels can be judged accordingly). One must be prepared to continue maintenance therapy for periods of 2 or 3 weeks in major surgical procedures. The interval between infusions may be roughly calculated assuming a half-life of 12 hours. 6 Monitoring the actual factor VIII level of the patient is helpful if the test is available. Use of the standard PTT as described above will provide reasonable guidelines, since a normal PTT denotes a factor VIII level usually in excess of 30 to 40 per cent. 8 Since some patients will have antibodies that inhibit the function of factor VIII, it is wise to ascertain that a hemostatic level has been reached prior to starting surgery and not rely purely on calculated doses. Inhibitors, if present, may be overcome by providing massive doses of factor VIII, but their ultimate efficacy then becomes rather limited. Specific Problems THE NEWBORN. The normal neonate may show significant alterations in the coagulation mechanism, although significant bleeding is not common. Over the first few days of life, these abnormalities may become intensified so that the child is more prone to bleeding on day 2 or 3 of life than he is at birth. 1 This "physiologic" defect lies primarily with factor XI (PTA) and the vitamin K dependent factors- prothrombin, factor VII, factor IX, and factor X. The labile factors-factor V and factor VIII (AHG)-are generally normal, as is fibrinogen. Levels of factor XII and XIII appear more variable. Thus the clotting time, the prothrombin time, and the PTT will show moderate abnormalities, while the thrombin time should be normal in normal neonates. Clinically significant bleeding in normal newboms is largely secondary to the further postnatal drop in the vitamin K dependent factors and can generally be prevented by the routine parenteral administration of 0.5 to 1 mg. of vitamin K1 to all newboms at birth. 1 If this is done routinely, further administration of vitamin K to infants undergoing surgery on the second or third day of life is unnecessary. If there is any question of the drug having been administered to the baby, particularly in infants transferred from other hospitals, it is reasonable and safe to administer another dose. It should be remembered that breast-fed infants or infants in whom cow's milk formula feedings are withheld represent a group uniquely susceptible to vitamin K deficient hemorrhagic disease of the newbom. 22

.. COMPLICATING HEMATOLOGIC CONDITIONS

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Premature infants and severely ill term infants show a much broader range of coagulation defects which may involve capillary-platelet function, fibrinogen, and factor V, as well as the vitamin K dependent factors. 1 In this group, the response of the vitamin K dependent factors to the administration of vitamin K is unpredictable and unreliable. Although vitamin K should be administered to such infants, correction of the complex coagulation disorder is most likely to be attained only by the judicious use of fresh whole blood, fresh plasma, and platelets. Appropriate treatment of any underlying condition is imperative. LIVER DISEASE. Hemorrhagic manifestations secondary to hepatobiliary disease have several etiologies. Intestinal absorption of vitamin K is dependent on normal bile flow. Conditions associated with obstruction to bile flow (e.g., biliary atresia and choledochal cyst) may be reflected in secondary malabsorption of vitamin K. Similar alterations may be seen in intestinal disorders associated with steatorrhea. This defect may be circumvented by the oral administration of water-soluble vitamin K preparations, although parenteral administration is probably justified in preparation for surgery. Patients with severe primary hepatic disease secondary to biliary obstruction demonstrate reduced levels of the vitamin K dependent factors (prothrombin, and factors VII, IX, and X), as well as factor V. 11 These defects cannot be corrected with parenteral vitamin K and must be replaced by plasma transfusion or suitable prothrombin complex concentrate (Table 1). Because of the lability of factor V, fresh plasma should be used. The lowered levels of factor V and the inability to respond to parenteral vitamin K may occasionally prove helpful in differentiating hepatocellular jaundice from obstructive jaundice. UREMIA. Uremic states are frequently associated with a bleeding tendency. Although coagulation factor deficiency, particularly factor VII, may be involved, the defect ,more typically lies in platelet-capillary function." A thrombopathic state frequently exists where the platelets, though not necessarily reduced in numbers, have an abnormal thromboplastic function and diminished adhesive qualities. These abnormalities appear secondary to the uremic plasma environment, making administration of fresh normal platelets of transient and questionable value. Control of the uremic state by means of dialysis has been the most effective method of handling this problem in our experience. Once the uremia is controlled, replacement of plasma factors or platelets may be of value, depending on the specific deficiencies remaining. ANTICOAGULANTS. Circulating anticoagulants may be seen in patients with congenital coagulation disorders who have received numerous plasma infusions. In the pediatric population, they are also found in patients with systemic diseases, particularly lupus erythematosus and lymphomas. Occasionally, an acquired anticoagulant is found without any obviou~ underlying or antecedent disease. The anticoagulants may be directed against a specific factor (e.g., anti-factor VIII antibodies) or against a specific intermediary stage (e.g., antithrombin). 12 When present, they generally have a profound effect on tests aimed at evaluating the specific phase of coagulation i_nvolved. Since most coagulation factors are effective in vitro at 50 per cent concentration, the

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performing of coagulation tests with a mixture of one-half patient plasma and one-half normal plasma should render the test normal if the patient has a specific factor deficiency. If an anticoagulant is present, the test will remain abnormal and may require dilution of the patient's plasma several hundred times with normal plasma before the effect of the anticoagulant is overcome. Treatment of anticoagulants must be individualized to the type involved. Antibodies against factor VIII may be overcome by large doses of concentrated factor VIII. Heparin-like substances may respond to the use of protamine sulfate. Adrenocorticosteroids may be of benefit in certain cases. Control of the underlying disease process is often necessary before the anticoagulant can be suppressed. FIBRINOLYSIS. The normal process of blood coagulation in vivo includes a step for clot dissolution through the activation of plasminogen to the fibrinolytic substance plasmin (Fig. 1). Excess activation of this pathway can lead to rapid clot lysis and defibrination. 16 The presence of increased fibrinolytic activity can be suspected if there is dissolution of a whole blood clot when the clot is incubated at 37o C. for several hours. More rapid and sensitive tests for activator, such as the euglobulin lysis time and thromboelastography, are unfortunately less readily available. Although pure fibrinolytic states have been implicated in children, they appear to be uncommon in this age group. If hyperfibrinolysis is detected, it is imperative to determine if it is a primary process or, more typically, secondary to a diffuse coagulation process. Epsilon aminocaproic acid blocks the activation of plasminogen to plasmin and may be quite beneficial in primary hyperfibrinolysis. Its use may be contraindicated in the secondary form. INTRAVASCULAR COAGULATION. Abnormal activation of the coagulation mechanism in vivo leads to diffuse intravascular coagulation. The clinical syndromes produced by this process include multiple organ dysfunction from small vessel thrombi and a bleeding diathesis from utilization of several coagulation factors. 2 Normal serum differs from plasma in the lack of fibrinogen, prothrombin, factor V, factor VIII, and platelets, which are consumed in the coagulation process in the test tube. With diffuse coagulation in vivo, the plasma takes on the characteristics of serum, as the same factors are consumed. Clear-cut intravascular coagulation is therefore characterized by a prolonged clotting time, reduced platelets, reduced fibrinogen, prolonged prothrombin time, prolonged PTT, and prolonged thrombin time. Secondary activation of the fibrinolytic system is associated with the appearance of fibrin split products, although methods for their detection are not generally available. Trauma to circulating erythrocytes during passage through involved vessels leads to fragmentation and hemolysis in some cases. Examination of a blood smear for fragmented erythrocytes may then be helpful diagnostically. Intravascular coagulation may be initiated by a variety of thromboplastic and endotoxic substances, as well as processes which cause widespread endothelial damage. Severe trauma, hemolytic transfusion reactions, sepsis, shock, and burns are some surgical situations in which intravascular coagulation has been impli-

COMPLICATING HEMATOLOGIC CONDITIONS

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cated. This process should be considered in any seriously ill person who develops an acute bleeding diathesis. The current method of choice for treatment is to break the vicious cycle of coagulation by heparinizing the patient. Various schedules for heparinization are available, but we have generally started with 1 mg. per kg. every 4 hours and then titrated the dose to maintain a clotting time in the range of 20 to 25 minutes. It should again be pointed out that, once a patient is heparinized, routine coagulation tests requiring the fibrinogen to fibrin conversion as an endpoint will all be rendered unreliable. This is particularly true of methods which quantitate fibrinogen by a modification of the thrombin time. When coagulation has been interrupted, levels of clotting factors and platelets will generally return to normal. Judicious use of specific replacement therapy after heparinization is indicated in. selected cases, but the use of epsilon aminocaproic acid to block fibrinolysis may prove harmful.

ANEMIA A detailed review of the multiple causes of anemia in children is beyond the scope of this article. When an unsuspected anemia is discovered as part of a preoperative evaluation, two basic questions must be answered: (1) Is this a type of anemia that would be expected to respond to specific therapy, and (2) how urgent is it that surgery be performed? If the anemia is one that can be treated and a return to normal levels can be anticipated in a short period of time (i.e., the usual iron-deficiency anemia), then all but the most urgent surgical procedures should be postponed and the child appropriately treated. To transfuse a child with iron-deficiency anemia in order to perform elective surgery should not be condoned. Patients with chronic forms of anemia (e.g., sickle-cell anemia and thalassemia major) would not be expected to attain normal levels of hemoglobin at any time except by transfusion. Individual attention must be paid to anemia secondary to chronic illness or malignancy, as a return to normal may be anticipated in some cases where the underlying condition can be successfully treated. In anemia not secondary to acute blood loss, transfusion with packed red cells rather than whole blood remains the treatment of choice. Plasma volumes are generally normal or. increased, making further administration of plasma unnecessary and potentially dangerous. In severely anemic children, initial transfusion volumes should be smalla reasonable guideline is the volume of packed cells per pound of body weight = the hemoglobin level. Thus, the lower the hemoglobin, the smaller the initial transfusion. Such caution appears particularly indicated in patients with anemia secondary to chronic renal disease, as they are often quite sensitive to volume overload. Whole blood should be used when transfusing for acute blood loss to maintain plasma volume as well as red cell mass. Volumes employed must be tailored to estimates of blood loss as well as physiologic parameters of pulse and blood pressure. The use of central venous catheters to monitor venous pressure has proven qu~te helpful during massive bleeding episodes. 23 Bank blood contains very low levels of factors V and

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VIII and platelets, so freshly drawn blood units should be obtained if volumes approaching total blood volume replacement are required. The anticoagulant effect of citrate in donor blood can be overcome by the administration of intravenous calcium gluconate, although the rapid mobilization of calcium by the body makes this problem one of more theoretical interest. 14 In our experience, platelet depletion leads to more bleeding problems from massive transfusions than does hypocalcemia. The low pH of stored citrated whole blood is potentially harmful, and correction of arterial blood pH in patients receiving massive transfusions may be indicated. 14

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