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CARDIAC SURGERY IN PATIENTS WITH PLASMA THROMBOPLASTIN ANTECEDENT (P.T.A.) DEFICIENCY
CARDIAC SURGERY I N PATIENTS W I T H PLASMA THROMBOPLASTIN A N T E C E D E N T (P.T.A.) DEFICIENCY Margaret Hilgartner, M.D., Mary Allen Engle, M.D., and S. Frank Redo, M.D., New York, N. Y.
W
HEN a patient with heart disease gives a history of easy bruising or of unusual bleeding, his coagulation profile should be fully evaluated before the performance of specialized cardiac diagnostic studies involving cut-downs on veins or arteries and introduction of cardiac catheters. If the patient is then considered a suitable candidate for surgery, his safety during the operation and in the early postoperative period will require close teamwork of hematologist, cardiologist, and surgeon. The 2 patients to be presented illustrate this approach. One had congenital heart disease associated with an arteriovenous shunt of blood and no cyanosis; the other had a complicated malformation with cyanosis. Although the pre sumptive diagnosis in each case suggested that the patient could be benefited by surgery, it was deemed advisable to verify that diagnosis by catheterization and contrast visualization in advance of surgery rather than to risk a possible exploratory thoracotomy and chance of hemorrhage if the diagnosis proved to be erroneous. For the coagulation studies, specimens of venous blood were drawn with siliconized needle into a polyethylene syringe and transferred into a poly ethylene tube containing a balanced citrate solution (nine parts blood to one part anticoagulant). The plasma was separated in a refrigerated centrifuge at 4° C. and assayed immediately. Conventional methods were used for the coagula tion tests. 1-9 The method used for assay of P.T.A. (factor XI) was that of Horowitz and his co-workers with the use of a synthetic P.T.A. substrate. 10 Both patients were found to have deficiency of P.T.A. (factor X I ) . A sur prise bonus of the postoperative improvement in cardiac status of both children was the improvement of this deficiency. CASE REPORTS CASE 1.—E. O. was referred at the age of 9 years when a heart murmur was discovered. She had been healthy except for frequent nosebleeds, requiring packing and cauterization, From the Departments of Pediatrics and Surgery, The New York Hospital-Cornell Uni versity Medical Center, New York, N. Y, Presented at the XI International Congress of Hematology, Stockholm, Sweden, Sept. 1, 1964. Received for publication Jan. 4, 1965. 974
Vol. 49, No. 6
P.T.A. D E F I C I E N C Y
June, 1965
TABLE I. E. O.:
Clotting time Clot retraction P.T.A.
1
NORMAL
16 min. 63-136%
975
ABNORMAL COAGULATION FINDINGS |
PREOP.
14.5 min. Poor 54%
|
POSTOP. 3 MO.
13 min. Good 97%
from the age of 2 years. She was hospitalized in shock following one severe episode of epistaxis. She bled profusely after tonsillectomy and adenoidectomy at the age of 5 years. Physical examination revealed a noncyanotic child who had a continuous systolic and diastolic murmur localized to the second left intercostal space. The murmur was characteristic of patent ductus arteriosus. Electrocardiogram, cardiac fluoroscopy, and x-ray study were consistent with that diagnosis. Because of the history of bleeding, a comprehensive coagulation study was undertaken. This led to the discovery of mild P.T.A. deficiency (Table I ) . Her only living relative, the mother, was found to have neither the cardiac nor the hematologic abnormality. Although the most likely cardiac diagnosis was patent ductus arteriosus, it was con sidered advisable to seek confirmation by selective aortography. Accordingly, the child was given fresh frozen plasma, 10 e.c. per kilogram of body weight for a total of 500 c.c, be ginning half an hour before the percutaneous insertion of the cardiac catheter into the femoral artery and then into the descending arch of the aorta. Injection of contrast medium there was followed by immediate, dense opacification of the pulmonary arteries, thus proving that the arteriovenous communication was a patent ductus arteriosus (Fig. 1 ) . After with drawal of the catheter, pressure was maintained with a sandbag over the region of the
Fig-. 1.—Case 1, R. O. Selective aortogram in frontal (A.) and lateral (B) views shows catheter in descending aorta with tip in patent ductus arteriosus. Opacification of main pul monary artery and branches simultaneously with descending aorta confirms presence of a patent ductus.
976
HILGARTNEK, ENGLE, KEDO
J. Thoracic and Cardiovas. Surg.
Fig. 2.—Case 2, A. S. Roentgenogram of chest shows apex of heart in right chest. Pulmonary vascularity is decreased. Stomach is on the left. femoral artery, and she was given an additional infusion of 5 e.c. per kilogram of body weight of fresh frozen plasma. Although blood was in the room for use if needed, bleeding did not occur. When the pressure dressing was removed 24 hours later, there was no more than the usual amount of ecchymosis in the area. The pulses in the leg were normal. The next day the patient was operated upon. Administration of fresh frozen plasma was begun 30 minutes before induction of anesthesia and continued throughout the operation for a total of 750 c.c. Measured blood loss was 375 e.c. Bleeding caused no problem and, though blood was available in the operating room, transfusion was not needed. The patent ductus, 6 mm. long and 5 mm. wide, was multiply ligated and sutured. Postoperatively the patient received two more infusions of fresh frozen plasma in a dosage of 5 mg. per kilogram of body weight at 8 hour intervals. Drainage through the chest tube was only 150 c.c. that day and had ceased by the third postoperative day, when the tube was removed. Her convalescence was uneventful, and she was discharged on the ninth day following surgery. The continuous murmur was heard no more. Remarkably, the mild P.T.A. deficiency also improved postoperatively (Table I ) . Epistaxes have not recurred. CASE 2.—-A. S. was also 9 years of age when she was referred to have the decision made as to whether heart surgery might help her. She had been cyanotie from birth and could walk only 4 blocks before becoming short of breath and tired. For the past year she had complained of headaches and occasional chest pain. Tonsillectomy and adenoidectomy at the age of 7 had been associated with bleeding that was excessive but had not required trans fusion. Easy bruising was acknowledged on questioning. She showed marked cyanosis, clubbing of fingers and toes, and suffusion of mucus membranes. The apex impulse was in the right chest. A loud, ejection-type systolic murmur, indicative of pulmonic stenosis, was heard. Only the aortic component of the second heart sound was audible. Cardiac fluoroscopy and roentgenograms with barium swallow showed an average-sized heart with the apex in the right chest ( M g . 2 ) . The pulmonary artery segment was not seen, and the pulmonary arterial markings were decreased. There was a left aortic arch and de scending aorta. The liver and stomach were normally situated. Electrocardiogram indicated that the heart was dextro-rotated, rather than being a mirror-image dextroeardia. There was a bizarre intraventricular conduction disturbance. The patient was polycythemic. The hemoglobin was 24.5 Gm. per cent, and the hematocrit was 74 per cent (Table I I ) . Because of the polycythemia and the suggestive history
P.T.A. D E F I C I E N C Y
Vol. 49, No. 6 June, 1965
TABLE I I . A. S.: NORMAL
Hematocrit ( % ) Hemoglobin (Gm. % ) Platelets (mm.3)
|
Quick Prothrombin Factor V Factor V I I Fibrinogen (plasma)
A. S.:
BLOOD COUNT PREOP.
POSTOP. 15 MO.
47 14.5 320,000
74 24.5 190,000
40 12.0 180-400,000
TABLE I I I .
977
ABNORMAL COAGULATION FINDINGS
NORMAL
12.0 sec. 70-120% 70-120% 70-120% 180-400 mg. %
|
PREOP.
13/12 sec. 42% 72% 30% 135%
|
POSTOP. 15 MO.
10.4/11 sec. 100% 95% 90% 230%
of hemorrhagic diathesis, comprehensive coagulation studies were undertaken. Along with the polycythemia and relatively decreased plasma volume and platelets, these studies revealed hypoprothrombinemia, low factor V I I , and hypoflbrinoginemia (Table I I I ) . I n addition, she had severe P.T.A. deficiency. The mother and father were found to have mild deficiencies of factor X I . A complicated cardiac defect is likely when the patient has cyanosis and the heart lies in the right chest. Additional cardiac diagnostic studies were therefore undertaken to evaluate the venous return to the heart and the intracardiac anatomy. Fresh frozen plasma, 10 c.c. per kilogram of body weight, was used for protection against bleeding. Selective angiocardiography was performed, first, through an incision in the groin with the catheter introduced through the saphenous vein. I t was found that she had no inferior vena cava but that the inf radiaphragmatic venous return was through the azygos system into the superior vena cava (Fig. 3, A). I n the next study, the catheter was inserted through a cut-down in the right antecubital fossa and thus into the heart (Fig. 3, B). Injection of contrast medium disclosed a right-to-left shunt at the atrial level. Only one ventricle was identified. This supplied the aorta as the anterior and lateral vessel and the pulmonary artery as the posterior and medial vessel. There was evidence of infundibular and valvular pulmonic stenosis (Fig. 4 ) . I t was evident that the complex cardiac malformation rendered her unsuitable for open-heart surgery, but, with evidence of a right-to-left shunt and pulmonic stenosis, she might be benefited by an anastomosis between the subelavian and pulmonary arteries. I n preparation for operation, phlebotomies were undertaken in an attempt, first, to decrease the red cell mass to gain some correction of the coagulation abnormalities asso ciated with polycythemia, and, second, to obtain a larger plasma volume for control of the P.T.A. deficiency. The patient was hospitalized and kept at bed rest to minimize any worsening of symptoms, such as sometimes occurs with blood loss in a cyanotic patient. Removal of 800 c.c. of blood in the 3 days prior to surgery produced a drop in hemoglobin from 24.5 to 18.9 Gm. and a decrease in hematocrit from 74 to 62 per cent. Although the polycythemia was lessened by phlebotomy, there were no other changes in the coagulation studies. Fresh frozen plasma, 10 c.c. per kilogram of body weight, beginning half an hour before the procedure was used throughout the operation under hypothermia the next day. An artificial ductus arteriosus was created by an anastomosis between the right subelavian artery and the side of the right pulmonary artery. I t was necessary to insert a graft of Teflon to bridge the gap between the two arteries. The surgeon noted continuous oozing of blood which did not clot, but a t no time was bleeding out of control. Measured blood loss of 1,100 c.c, about twice the expected amount for this operation, was covered by administration in the operating room and recovery room of 500 c.c. of whole blood and 1,250 c.c. of fresh
978
HILGAKTNEE, ENGLE, REDO
J. Thoracic and Cardiovas. Surg.
F i g . 3.—Case 2, A. S. Selective a n g i o c a r d i o g r a m . A, C a t h e t e r i n s e r t e d from t h e gToin ; tip in a z y g o s vein (AZ) w h i c h d r a i n s into s u p e r i o r v e n a c a v a . I n f e r i o r v e n a c a v a is a b s e n t B C a t h e t e r t i p is i n t r o d u c e d t h r o u g h s u p e r i o r v e n a c a v a into v e n o u s a t r i u m o n t h e r i g h t (RAJ C o n t r a s t m e d i u m injected t h e r e p a s s e s t o a r t e r i a l a t r i u m on lower left c a r d i a c b o r d e r (LA) a n d t h e n into a v e n t r i c l e (V) on r i g h t lower c a r d i a c b o r d e r , from w h i c h b o t h g r e a t vessels a r i s e . T h e e n l a r g e d a o r t a (AO) f o r m s t h e u p p e r left c a r d i a c b o r d e r ; t h e p u l m o n a r y a r t e r y (PA) is m e d i a l to t h e a o r t a .
P i g . 4.—Case 2, A. S. T h e a o r t a (AO) is a n t e r i o r to t h e p u l m o n a r y a r t e r y (PA). d i c a t e t h e n a r r o w e d region of p u l m o n a r y s t e n o s i s .
A r r o w s in
P.T.A. D E F I C I E N C Y
Vol. 49, No. 6 June, 1965
979
TABLE I V . A. S.: ABNORMAL COAGULATION FINDINGS
Clot retraction Partial thromboplastin time
1
NORMAL
|
|
POSTOP. 15 MO.
Poor
142 sec.
80 sec.
Abnormal
Improved
22%
40%
45-83 see.
Thromboplastin generation test (inosithin) Factor X I
PREOP.
Very poor
63-136%
TABLE V. F A M I L Y OP A.
S.
P. T. A. LEVELS
Normal Mother Father Sister L. Sister S.
63-130% 38% 45% 120% 120%
Bleeding with tonsil and adenoid surgery Bleeding with surgery 0 0
frozen plasma. Five cubic centimeters of plasma per kilogram of body weight was given every 12 hours during the first 5 days postoperatively and 5 c.c. per kilogram of body weight for 2 additional days for a total of 7 days. Chest drainage tubes were left in place longer than usual, 1 for 3 days and the other for 5 days. There was no further bleeding. Immediately after the anastomosis was established, a continuous murmur gave auscultatory evidence of a functioning shunt. The patient's color improved, so that there was no visible cyanosis at rest, and, with exercise, only mild cyanosis appeared. Marked improvement in exercise tolerance and in color has been sustained. As anticipated with lessening of cyanosis, there has been a decrease in polycythemia postoperatively. Fifteen months after operation, the hemoglobin was 14.5 Gm. and the hematocrit 47 per cent (Table I I ) . From being relatively thrombopenie preoperatively, the patient has regained a normal platelet count. A comprehensive coagulation survey was repeated (Tables I I I and I V ) . This showed that the Quick prothrombin time, the prothrombin activity, factors V and V I I , and plasma fibrinogen were now normal. I n addition to these changes, there was the surprise finding of improvement in P.T.A. deficiency, which was now mild and comparable to that of her parents. DISCUSSION
Alterations in the coagulation mechanism have been found in patients of all ages with congenital heart disease. Many workers in this field, such as FavreGilly, Hartmann, van Creveld, and Jackson,11"14 have documented the changes in patients with cyanotic heart disease. These include polycythemia, thrombocytopenia, hypoprothrombinemia, low factor V, hypofibrinogenemia, and poor clot retraction. In addition to these problems in the cyanotic patients, Alagille 15 reported hypoeoagulability due to some of the aforementioned protein deficits in 13 of 30 acyanotie patients. He also noted a qualitative platelet abnormality in children with both cyanotic and acyanotie heart disease. These patients had an increased bleeding time in the absence of thrombocytopenia.
980
HILGARTNER, ENGLE, REDO
J. Thoracic and Cardiovas. Surg.
Paul, 16 working in Schulman's laboratory, found that thrombocytopenia in children was rare unless the hematocrit was greater than 65 per cent and/or oxygen saturation was less than 70 per cent. In addition, he stressed the in fluence of age on the incidence of thrombocytopenia. Only 10 per cent of his patients under 1 year of age had thrombocytopenia, whereas the incidence in those who were older approached 60 per cent. Even though the degree of thrombocytopenia was similar, only patients over the age of 6 years had sig nificant operative hemorrhage. Hartmann 12 reported fatal hemorrhage following cardiac surgery in 7 per cent of adults and adolescents, presumably due to their hemorrhagic diathesis, but only 0.7 per cent in children under 14 years of age. Jackson 14 proposed phlebotomy for these patients who had polycythemia, throm bocytopenia, impaired clot retraction, low blood fibrinogen, and the formation of soft friable clots, and reported that this procedure was beneficial in selected adults and adolescents. Such benefits were not observed, however, in the cyanotic patient (A. S.) whose case is presented here. Furthermore, phlebotomy is haz ardous in such patients; several of ours have noted an increase in symptoms of fatigue and shortness of breath, and one adult with a tetralogy of Fallot ex perienced severe syncope for the first time after phlebotomy. In him, the benefits of increased platelets and an improved clot retraction were minimal. The experience in this clinic with cyanotic patients in the pediatrie age group reveals a mild thrombocytopenia below 180,000/mm.3 in relatively few patients with polycythemia. These patients exhibited petechiae with coughing and/or bruising following minor trauma. None who have come to surgery have had significant bleeding. Only 1 patient has had a platelet count less than 100,000/mm.3; this rose to normal levels following steroid therapy. Alagille15 believed the qualitative platelet abnormalities which he described were also well controlled with steroid therapy. The patients whose cases are reported here, one cyanotic and the other acyanotic, demonstrated some of the previously reported abnormalities of the clotting mechanism. In addition, they both demonstrated a deficiency of P.T.A. (factor X I ) . Clinical and laboratory evidence initially suggested that the first patient was heterozygous for P.T.A. deficiency. However, the improvement of P.T.A. blood level to normal and the abrupt cessation of severe epistaxis postoperatively support an impression that this was not a genetic defect but that the mild coagulation deficiency was acquired and, in some way, possibly sec ondary to a deranged cardiovascular system. The second patient, A. S., initially appeared to have a well-substantiated congenital severe deficiency; both parents demonstrated a mild deficiency. She also had hypoprothrombinemia, low factor VII, and hypofibrinogenemia. These factors, which are formed in the liver, have been found to be low in hepatocellular disease of multiple etiology. 17 ' 1S It has been shown that anoxia at birth may produce liver damage with subsequent hyperbilirubinemia and slow matura tion of the coagulation factors in the newborn period. 19 This suggests that the altered hemodynamics of the patient with congenital heart disease may produce a liver anoxia of sufficient degree that dysfunction is reflected in low production of these coagulation proteins. Perhaps the improvement in all the clotting fac-
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P.T.A. D E F I C I E N C Y
981
tors found in the cyanotic patient, A. S., following beneficial surgery on the cardiovascular system was due to an improvement in hemodynamics and hepatocellular function. Thus the severity of factor X I deficiency in this second case was also acquired. A mild defect was probably exaggerated by the altered hemo dynamics and cyanosis. The actual congenital status of this patient should properly be termed the heterozygous state for P.T.A. deficiency. SUMMARY
The cases of 2 patients with congenital cardiac lesions, one acyanotic with a patent ductus arteriosus and the other cyanotic with a complicated malforma tion including pulmonie stenosis, have been presented. The acyanotic patient exhibited a mild P.T.A. deficiency but marked bleeding tendency; the cyanotic child exhibited a severe P.T.A. deficiency with minimal symptoms of bleeding. Following surgery, P.T.A. level improved in both children. The possibility is suggested that changes in the liver related to abnormal hemodynamics may have been partially responsible for the acquired deficiency. REFERENCES
1. Duke, W. W.: The Eelation of Blood Platelets to Hemorrhagic Disease: Description of a Method for Determining the Bleeding Time and Coagulation Time, and Report of 3 Cases of Hemorrhagic Disease Relieved by Transfusion, J . A. M. A. 14: 1185, 1910. 2. Lee, R. I., and White, P . D . : A Clinical Study of the Coagulation Time of Blood, Am. J . M. Sc. 145: 495, 1913. 3. Quick, A. J . : The Clinical Application of the Hippuric Acid and Prothrombin Tests, Am. J . Clin. P a t h . 10: 222, 1940. 4. Ware, A. G., and Stragnell, R.: An Improved One-Stage Prothrombin Method, Am. J . Clin. Path. 22: 791, 1952. 5. Dreskin, O. H . : The Prothrombin Consumption Test, Am. J . Clin. P a t h . 22: 140, 1952. 6. Borehgrevink, C. F., Pool, J . G., and Stormorken, H . : A New Assay for Factor V (Proaceelerin-Aceelerin) Using Russell's Viper Venom, J . Lab. & Clin. Med. 55: 625, 1960. 7. Owren, P . A., and Aas, K.: The Control of Dicumarol Therapy and the Quantitative Determination of Prothrombin and Proconvertin, Scandinav. J . Clin. & Lab. Invest. 3: 201, 1951. , 8. Biggs, R., and Douglas, A. S.: The Thromboplastin Generation Test, J . Clin. Path. 6: 23, 1953. 9. Fowell, A. H . : A Turbimetric Method for Assay of Fibrinogen, Am. J . Clin. Path. 25: 340, 1955. 10. Horowitz, H. I., Wilcox, W. P., and Fujimoto, M. M.: Assay of Plasma Thromboplastin Antecedent (P.T.A.) With Artificially Depleted Normal Plasma, Blood 22: 35, 1963. 11. Favre-Gilly, J., Bret, J., and Borel-Milhet, J . : Une trouble inattendu de la coagulation dans la maladie bleue: L'hypoprothrombinemie, Sang 22: 278, 1951. 12. Hartmann, R. C.: A Hemorrhagic Disorder Occurring in Patients With Cyanotic Con genital Heart Disease, Bull. Johns Hopkins Hosp. 91: 49, 1958. 13. Van Creveld, S.: Hemorrhagie Diathesis in Congenital Heart Disease. Influence of Opera tion Under Hypothermia and of Whole Blood Transfusions, Ann. Paediat. (Basel) 190: 342, 1958. 14. Jackson, D. P . : Hemorrhagic Diathesis in Patients With Cyanotic Congenital Heart Dis ease: Preoperative Management, Ann. New York Aead. Sc. 115: 235, 1964. 15. Alagille, D., Heim de Balsac, R., Guery, J., Passelecq, J., Blondeau, P., and Dubost, C.: Les thrombopathies associ^es aux cardiopathise congenitales, Rev. Fran§. Etudes Clin. Biol. 3: 322, 1958. 16. Paul, M. H., Currimbhoy, Z., Miller, R. A., and Schulman, I.: Thrombocytopenia in Cyanotic Congenital Heart Disease, Circulation 24: 1013, 1961. 17. Eapaport, S. I., Ames, S. B., Mikkelen, S., and Goodman, J . R.: Plasma Clotting Factors in Chronic Hepatocellular Disease, New England J . Med. 263: 278, 1960. 18. Hallen, A., and Nilsson, I. M.: Coagulation Studies in Liver Disease, Thromb. et Diath Haemorrh. 11: 51, 1964. 19. Aballi, A. J., and DeLamerens, S.: Coagulation Changes in the Neonatal Period and in Early Infancy, Pediat. Clin. North America 9: 785, 1962.
W
HEN a patient with heart disease gives a history of easy bruising or of unusual bleeding, his coagulation profile should be fully evaluated before the performance of specialized cardiac diagnostic studies involving cut-downs on veins or arteries and introduction of cardiac catheters. If the patient is then considered a suitable candidate for surgery, his safety during the operation and in the early postoperative period will require close teamwork of hematologist, cardiologist, and surgeon. The 2 patients to be presented illustrate this approach. One had congenital heart disease associated with an arteriovenous shunt of blood and no cyanosis; the other had a complicated malformation with cyanosis. Although the pre sumptive diagnosis in each case suggested that the patient could be benefited by surgery, it was deemed advisable to verify that diagnosis by catheterization and contrast visualization in advance of surgery rather than to risk a possible exploratory thoracotomy and chance of hemorrhage if the diagnosis proved to be erroneous. For the coagulation studies, specimens of venous blood were drawn with siliconized needle into a polyethylene syringe and transferred into a poly ethylene tube containing a balanced citrate solution (nine parts blood to one part anticoagulant). The plasma was separated in a refrigerated centrifuge at 4° C. and assayed immediately. Conventional methods were used for the coagula tion tests. 1-9 The method used for assay of P.T.A. (factor XI) was that of Horowitz and his co-workers with the use of a synthetic P.T.A. substrate. 10 Both patients were found to have deficiency of P.T.A. (factor X I ) . A sur prise bonus of the postoperative improvement in cardiac status of both children was the improvement of this deficiency. CASE REPORTS CASE 1.—E. O. was referred at the age of 9 years when a heart murmur was discovered. She had been healthy except for frequent nosebleeds, requiring packing and cauterization, From the Departments of Pediatrics and Surgery, The New York Hospital-Cornell Uni versity Medical Center, New York, N. Y, Presented at the XI International Congress of Hematology, Stockholm, Sweden, Sept. 1, 1964. Received for publication Jan. 4, 1965. 974
Vol. 49, No. 6
P.T.A. D E F I C I E N C Y
June, 1965
TABLE I. E. O.:
Clotting time Clot retraction P.T.A.
1
NORMAL
16 min. 63-136%
975
ABNORMAL COAGULATION FINDINGS |
PREOP.
14.5 min. Poor 54%
|
POSTOP. 3 MO.
13 min. Good 97%
from the age of 2 years. She was hospitalized in shock following one severe episode of epistaxis. She bled profusely after tonsillectomy and adenoidectomy at the age of 5 years. Physical examination revealed a noncyanotic child who had a continuous systolic and diastolic murmur localized to the second left intercostal space. The murmur was characteristic of patent ductus arteriosus. Electrocardiogram, cardiac fluoroscopy, and x-ray study were consistent with that diagnosis. Because of the history of bleeding, a comprehensive coagulation study was undertaken. This led to the discovery of mild P.T.A. deficiency (Table I ) . Her only living relative, the mother, was found to have neither the cardiac nor the hematologic abnormality. Although the most likely cardiac diagnosis was patent ductus arteriosus, it was con sidered advisable to seek confirmation by selective aortography. Accordingly, the child was given fresh frozen plasma, 10 e.c. per kilogram of body weight for a total of 500 c.c, be ginning half an hour before the percutaneous insertion of the cardiac catheter into the femoral artery and then into the descending arch of the aorta. Injection of contrast medium there was followed by immediate, dense opacification of the pulmonary arteries, thus proving that the arteriovenous communication was a patent ductus arteriosus (Fig. 1 ) . After with drawal of the catheter, pressure was maintained with a sandbag over the region of the
Fig-. 1.—Case 1, R. O. Selective aortogram in frontal (A.) and lateral (B) views shows catheter in descending aorta with tip in patent ductus arteriosus. Opacification of main pul monary artery and branches simultaneously with descending aorta confirms presence of a patent ductus.
976
HILGARTNEK, ENGLE, KEDO
J. Thoracic and Cardiovas. Surg.
Fig. 2.—Case 2, A. S. Roentgenogram of chest shows apex of heart in right chest. Pulmonary vascularity is decreased. Stomach is on the left. femoral artery, and she was given an additional infusion of 5 e.c. per kilogram of body weight of fresh frozen plasma. Although blood was in the room for use if needed, bleeding did not occur. When the pressure dressing was removed 24 hours later, there was no more than the usual amount of ecchymosis in the area. The pulses in the leg were normal. The next day the patient was operated upon. Administration of fresh frozen plasma was begun 30 minutes before induction of anesthesia and continued throughout the operation for a total of 750 c.c. Measured blood loss was 375 e.c. Bleeding caused no problem and, though blood was available in the operating room, transfusion was not needed. The patent ductus, 6 mm. long and 5 mm. wide, was multiply ligated and sutured. Postoperatively the patient received two more infusions of fresh frozen plasma in a dosage of 5 mg. per kilogram of body weight at 8 hour intervals. Drainage through the chest tube was only 150 c.c. that day and had ceased by the third postoperative day, when the tube was removed. Her convalescence was uneventful, and she was discharged on the ninth day following surgery. The continuous murmur was heard no more. Remarkably, the mild P.T.A. deficiency also improved postoperatively (Table I ) . Epistaxes have not recurred. CASE 2.—-A. S. was also 9 years of age when she was referred to have the decision made as to whether heart surgery might help her. She had been cyanotie from birth and could walk only 4 blocks before becoming short of breath and tired. For the past year she had complained of headaches and occasional chest pain. Tonsillectomy and adenoidectomy at the age of 7 had been associated with bleeding that was excessive but had not required trans fusion. Easy bruising was acknowledged on questioning. She showed marked cyanosis, clubbing of fingers and toes, and suffusion of mucus membranes. The apex impulse was in the right chest. A loud, ejection-type systolic murmur, indicative of pulmonic stenosis, was heard. Only the aortic component of the second heart sound was audible. Cardiac fluoroscopy and roentgenograms with barium swallow showed an average-sized heart with the apex in the right chest ( M g . 2 ) . The pulmonary artery segment was not seen, and the pulmonary arterial markings were decreased. There was a left aortic arch and de scending aorta. The liver and stomach were normally situated. Electrocardiogram indicated that the heart was dextro-rotated, rather than being a mirror-image dextroeardia. There was a bizarre intraventricular conduction disturbance. The patient was polycythemic. The hemoglobin was 24.5 Gm. per cent, and the hematocrit was 74 per cent (Table I I ) . Because of the polycythemia and the suggestive history
P.T.A. D E F I C I E N C Y
Vol. 49, No. 6 June, 1965
TABLE I I . A. S.: NORMAL
Hematocrit ( % ) Hemoglobin (Gm. % ) Platelets (mm.3)
|
Quick Prothrombin Factor V Factor V I I Fibrinogen (plasma)
A. S.:
BLOOD COUNT PREOP.
POSTOP. 15 MO.
47 14.5 320,000
74 24.5 190,000
40 12.0 180-400,000
TABLE I I I .
977
ABNORMAL COAGULATION FINDINGS
NORMAL
12.0 sec. 70-120% 70-120% 70-120% 180-400 mg. %
|
PREOP.
13/12 sec. 42% 72% 30% 135%
|
POSTOP. 15 MO.
10.4/11 sec. 100% 95% 90% 230%
of hemorrhagic diathesis, comprehensive coagulation studies were undertaken. Along with the polycythemia and relatively decreased plasma volume and platelets, these studies revealed hypoprothrombinemia, low factor V I I , and hypoflbrinoginemia (Table I I I ) . I n addition, she had severe P.T.A. deficiency. The mother and father were found to have mild deficiencies of factor X I . A complicated cardiac defect is likely when the patient has cyanosis and the heart lies in the right chest. Additional cardiac diagnostic studies were therefore undertaken to evaluate the venous return to the heart and the intracardiac anatomy. Fresh frozen plasma, 10 c.c. per kilogram of body weight, was used for protection against bleeding. Selective angiocardiography was performed, first, through an incision in the groin with the catheter introduced through the saphenous vein. I t was found that she had no inferior vena cava but that the inf radiaphragmatic venous return was through the azygos system into the superior vena cava (Fig. 3, A). I n the next study, the catheter was inserted through a cut-down in the right antecubital fossa and thus into the heart (Fig. 3, B). Injection of contrast medium disclosed a right-to-left shunt at the atrial level. Only one ventricle was identified. This supplied the aorta as the anterior and lateral vessel and the pulmonary artery as the posterior and medial vessel. There was evidence of infundibular and valvular pulmonic stenosis (Fig. 4 ) . I t was evident that the complex cardiac malformation rendered her unsuitable for open-heart surgery, but, with evidence of a right-to-left shunt and pulmonic stenosis, she might be benefited by an anastomosis between the subelavian and pulmonary arteries. I n preparation for operation, phlebotomies were undertaken in an attempt, first, to decrease the red cell mass to gain some correction of the coagulation abnormalities asso ciated with polycythemia, and, second, to obtain a larger plasma volume for control of the P.T.A. deficiency. The patient was hospitalized and kept at bed rest to minimize any worsening of symptoms, such as sometimes occurs with blood loss in a cyanotic patient. Removal of 800 c.c. of blood in the 3 days prior to surgery produced a drop in hemoglobin from 24.5 to 18.9 Gm. and a decrease in hematocrit from 74 to 62 per cent. Although the polycythemia was lessened by phlebotomy, there were no other changes in the coagulation studies. Fresh frozen plasma, 10 c.c. per kilogram of body weight, beginning half an hour before the procedure was used throughout the operation under hypothermia the next day. An artificial ductus arteriosus was created by an anastomosis between the right subelavian artery and the side of the right pulmonary artery. I t was necessary to insert a graft of Teflon to bridge the gap between the two arteries. The surgeon noted continuous oozing of blood which did not clot, but a t no time was bleeding out of control. Measured blood loss of 1,100 c.c, about twice the expected amount for this operation, was covered by administration in the operating room and recovery room of 500 c.c. of whole blood and 1,250 c.c. of fresh
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HILGAKTNEE, ENGLE, REDO
J. Thoracic and Cardiovas. Surg.
F i g . 3.—Case 2, A. S. Selective a n g i o c a r d i o g r a m . A, C a t h e t e r i n s e r t e d from t h e gToin ; tip in a z y g o s vein (AZ) w h i c h d r a i n s into s u p e r i o r v e n a c a v a . I n f e r i o r v e n a c a v a is a b s e n t B C a t h e t e r t i p is i n t r o d u c e d t h r o u g h s u p e r i o r v e n a c a v a into v e n o u s a t r i u m o n t h e r i g h t (RAJ C o n t r a s t m e d i u m injected t h e r e p a s s e s t o a r t e r i a l a t r i u m on lower left c a r d i a c b o r d e r (LA) a n d t h e n into a v e n t r i c l e (V) on r i g h t lower c a r d i a c b o r d e r , from w h i c h b o t h g r e a t vessels a r i s e . T h e e n l a r g e d a o r t a (AO) f o r m s t h e u p p e r left c a r d i a c b o r d e r ; t h e p u l m o n a r y a r t e r y (PA) is m e d i a l to t h e a o r t a .
P i g . 4.—Case 2, A. S. T h e a o r t a (AO) is a n t e r i o r to t h e p u l m o n a r y a r t e r y (PA). d i c a t e t h e n a r r o w e d region of p u l m o n a r y s t e n o s i s .
A r r o w s in
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979
TABLE I V . A. S.: ABNORMAL COAGULATION FINDINGS
Clot retraction Partial thromboplastin time
1
NORMAL
|
|
POSTOP. 15 MO.
Poor
142 sec.
80 sec.
Abnormal
Improved
22%
40%
45-83 see.
Thromboplastin generation test (inosithin) Factor X I
PREOP.
Very poor
63-136%
TABLE V. F A M I L Y OP A.
S.
P. T. A. LEVELS
Normal Mother Father Sister L. Sister S.
63-130% 38% 45% 120% 120%
Bleeding with tonsil and adenoid surgery Bleeding with surgery 0 0
frozen plasma. Five cubic centimeters of plasma per kilogram of body weight was given every 12 hours during the first 5 days postoperatively and 5 c.c. per kilogram of body weight for 2 additional days for a total of 7 days. Chest drainage tubes were left in place longer than usual, 1 for 3 days and the other for 5 days. There was no further bleeding. Immediately after the anastomosis was established, a continuous murmur gave auscultatory evidence of a functioning shunt. The patient's color improved, so that there was no visible cyanosis at rest, and, with exercise, only mild cyanosis appeared. Marked improvement in exercise tolerance and in color has been sustained. As anticipated with lessening of cyanosis, there has been a decrease in polycythemia postoperatively. Fifteen months after operation, the hemoglobin was 14.5 Gm. and the hematocrit 47 per cent (Table I I ) . From being relatively thrombopenie preoperatively, the patient has regained a normal platelet count. A comprehensive coagulation survey was repeated (Tables I I I and I V ) . This showed that the Quick prothrombin time, the prothrombin activity, factors V and V I I , and plasma fibrinogen were now normal. I n addition to these changes, there was the surprise finding of improvement in P.T.A. deficiency, which was now mild and comparable to that of her parents. DISCUSSION
Alterations in the coagulation mechanism have been found in patients of all ages with congenital heart disease. Many workers in this field, such as FavreGilly, Hartmann, van Creveld, and Jackson,11"14 have documented the changes in patients with cyanotic heart disease. These include polycythemia, thrombocytopenia, hypoprothrombinemia, low factor V, hypofibrinogenemia, and poor clot retraction. In addition to these problems in the cyanotic patients, Alagille 15 reported hypoeoagulability due to some of the aforementioned protein deficits in 13 of 30 acyanotie patients. He also noted a qualitative platelet abnormality in children with both cyanotic and acyanotie heart disease. These patients had an increased bleeding time in the absence of thrombocytopenia.
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HILGARTNER, ENGLE, REDO
J. Thoracic and Cardiovas. Surg.
Paul, 16 working in Schulman's laboratory, found that thrombocytopenia in children was rare unless the hematocrit was greater than 65 per cent and/or oxygen saturation was less than 70 per cent. In addition, he stressed the in fluence of age on the incidence of thrombocytopenia. Only 10 per cent of his patients under 1 year of age had thrombocytopenia, whereas the incidence in those who were older approached 60 per cent. Even though the degree of thrombocytopenia was similar, only patients over the age of 6 years had sig nificant operative hemorrhage. Hartmann 12 reported fatal hemorrhage following cardiac surgery in 7 per cent of adults and adolescents, presumably due to their hemorrhagic diathesis, but only 0.7 per cent in children under 14 years of age. Jackson 14 proposed phlebotomy for these patients who had polycythemia, throm bocytopenia, impaired clot retraction, low blood fibrinogen, and the formation of soft friable clots, and reported that this procedure was beneficial in selected adults and adolescents. Such benefits were not observed, however, in the cyanotic patient (A. S.) whose case is presented here. Furthermore, phlebotomy is haz ardous in such patients; several of ours have noted an increase in symptoms of fatigue and shortness of breath, and one adult with a tetralogy of Fallot ex perienced severe syncope for the first time after phlebotomy. In him, the benefits of increased platelets and an improved clot retraction were minimal. The experience in this clinic with cyanotic patients in the pediatrie age group reveals a mild thrombocytopenia below 180,000/mm.3 in relatively few patients with polycythemia. These patients exhibited petechiae with coughing and/or bruising following minor trauma. None who have come to surgery have had significant bleeding. Only 1 patient has had a platelet count less than 100,000/mm.3; this rose to normal levels following steroid therapy. Alagille15 believed the qualitative platelet abnormalities which he described were also well controlled with steroid therapy. The patients whose cases are reported here, one cyanotic and the other acyanotic, demonstrated some of the previously reported abnormalities of the clotting mechanism. In addition, they both demonstrated a deficiency of P.T.A. (factor X I ) . Clinical and laboratory evidence initially suggested that the first patient was heterozygous for P.T.A. deficiency. However, the improvement of P.T.A. blood level to normal and the abrupt cessation of severe epistaxis postoperatively support an impression that this was not a genetic defect but that the mild coagulation deficiency was acquired and, in some way, possibly sec ondary to a deranged cardiovascular system. The second patient, A. S., initially appeared to have a well-substantiated congenital severe deficiency; both parents demonstrated a mild deficiency. She also had hypoprothrombinemia, low factor VII, and hypofibrinogenemia. These factors, which are formed in the liver, have been found to be low in hepatocellular disease of multiple etiology. 17 ' 1S It has been shown that anoxia at birth may produce liver damage with subsequent hyperbilirubinemia and slow matura tion of the coagulation factors in the newborn period. 19 This suggests that the altered hemodynamics of the patient with congenital heart disease may produce a liver anoxia of sufficient degree that dysfunction is reflected in low production of these coagulation proteins. Perhaps the improvement in all the clotting fac-
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tors found in the cyanotic patient, A. S., following beneficial surgery on the cardiovascular system was due to an improvement in hemodynamics and hepatocellular function. Thus the severity of factor X I deficiency in this second case was also acquired. A mild defect was probably exaggerated by the altered hemo dynamics and cyanosis. The actual congenital status of this patient should properly be termed the heterozygous state for P.T.A. deficiency. SUMMARY
The cases of 2 patients with congenital cardiac lesions, one acyanotic with a patent ductus arteriosus and the other cyanotic with a complicated malforma tion including pulmonie stenosis, have been presented. The acyanotic patient exhibited a mild P.T.A. deficiency but marked bleeding tendency; the cyanotic child exhibited a severe P.T.A. deficiency with minimal symptoms of bleeding. Following surgery, P.T.A. level improved in both children. The possibility is suggested that changes in the liver related to abnormal hemodynamics may have been partially responsible for the acquired deficiency. REFERENCES
1. Duke, W. W.: The Eelation of Blood Platelets to Hemorrhagic Disease: Description of a Method for Determining the Bleeding Time and Coagulation Time, and Report of 3 Cases of Hemorrhagic Disease Relieved by Transfusion, J . A. M. A. 14: 1185, 1910. 2. Lee, R. I., and White, P . D . : A Clinical Study of the Coagulation Time of Blood, Am. J . M. Sc. 145: 495, 1913. 3. Quick, A. J . : The Clinical Application of the Hippuric Acid and Prothrombin Tests, Am. J . Clin. P a t h . 10: 222, 1940. 4. Ware, A. G., and Stragnell, R.: An Improved One-Stage Prothrombin Method, Am. J . Clin. Path. 22: 791, 1952. 5. Dreskin, O. H . : The Prothrombin Consumption Test, Am. J . Clin. P a t h . 22: 140, 1952. 6. Borehgrevink, C. F., Pool, J . G., and Stormorken, H . : A New Assay for Factor V (Proaceelerin-Aceelerin) Using Russell's Viper Venom, J . Lab. & Clin. Med. 55: 625, 1960. 7. Owren, P . A., and Aas, K.: The Control of Dicumarol Therapy and the Quantitative Determination of Prothrombin and Proconvertin, Scandinav. J . Clin. & Lab. Invest. 3: 201, 1951. , 8. Biggs, R., and Douglas, A. S.: The Thromboplastin Generation Test, J . Clin. Path. 6: 23, 1953. 9. Fowell, A. H . : A Turbimetric Method for Assay of Fibrinogen, Am. J . Clin. Path. 25: 340, 1955. 10. Horowitz, H. I., Wilcox, W. P., and Fujimoto, M. M.: Assay of Plasma Thromboplastin Antecedent (P.T.A.) With Artificially Depleted Normal Plasma, Blood 22: 35, 1963. 11. Favre-Gilly, J., Bret, J., and Borel-Milhet, J . : Une trouble inattendu de la coagulation dans la maladie bleue: L'hypoprothrombinemie, Sang 22: 278, 1951. 12. Hartmann, R. C.: A Hemorrhagic Disorder Occurring in Patients With Cyanotic Con genital Heart Disease, Bull. Johns Hopkins Hosp. 91: 49, 1958. 13. Van Creveld, S.: Hemorrhagie Diathesis in Congenital Heart Disease. Influence of Opera tion Under Hypothermia and of Whole Blood Transfusions, Ann. Paediat. (Basel) 190: 342, 1958. 14. Jackson, D. P . : Hemorrhagic Diathesis in Patients With Cyanotic Congenital Heart Dis ease: Preoperative Management, Ann. New York Aead. Sc. 115: 235, 1964. 15. Alagille, D., Heim de Balsac, R., Guery, J., Passelecq, J., Blondeau, P., and Dubost, C.: Les thrombopathies associ^es aux cardiopathise congenitales, Rev. Fran§. Etudes Clin. Biol. 3: 322, 1958. 16. Paul, M. H., Currimbhoy, Z., Miller, R. A., and Schulman, I.: Thrombocytopenia in Cyanotic Congenital Heart Disease, Circulation 24: 1013, 1961. 17. Eapaport, S. I., Ames, S. B., Mikkelen, S., and Goodman, J . R.: Plasma Clotting Factors in Chronic Hepatocellular Disease, New England J . Med. 263: 278, 1960. 18. Hallen, A., and Nilsson, I. M.: Coagulation Studies in Liver Disease, Thromb. et Diath Haemorrh. 11: 51, 1964. 19. Aballi, A. J., and DeLamerens, S.: Coagulation Changes in the Neonatal Period and in Early Infancy, Pediat. Clin. North America 9: 785, 1962.