Open Heart Operation in Patients Suffering From Hereditary Spherocytosis Nasr L. Gayyed, MD, Nick Bouboulis, MD, and Mike P. Holden, FRCS Department of Cardiothoracic Surgery, Freeman Hospital, Newcastle-upon-Tyne, United Kingdom

Hereditary spherocytosis is a clinically heterogeneous, genetically determined red blood cell membrane disor- der resulting in hemolytic anemia. Structural or func- tional disorders of the cytoskeletal proteins result in the formation of spherocytes, which lack the strength, dura- bility, and flexibility to withstand the stresses of the circulation. This problem can be accentuated by the deleterious effects of the heart-lung machine. Three

patients with hereditary spherocytosis underwent open heart operation with no deaths and no serious complica- tions resulting from the hematologic defect. Splenec- tomy is recommended, although not essential, before a cardiac operation, and mechanical valves should perhaps be avoided.

(Ann Thorac Surg 1993;55:1497500)

ereditary spherocytosis (HS) is a clinically heteroge- H neous, genetically determined red blood cell mem- brane disorder resulting in hemolytic anemia. It is rela- tively common in all races, but occurs predominantly in white people. It may become manifest at any age, the majority of the patients presenting before the age of 25 years. The pattern of inheritance is typically autosomal dominant, with other affected family members being found in approximately 75% of cases. Sporadic cases occur, presumably as new mutations, and rare cases present in an autosomal recessive manner.

The membrane defect resulting in the shortened sur- vival of erythrocytes in HS has been found to be due to a deficiency in spectrin [l], a deficiency in ankyrin (21, ankyrin-gene deletion [2], or defective binding of pspec- trin and protein 4.1 [2]. These molecular defects lead to a gradual loss of red cell surface area such that the eryth- rocyte becomes spherical instead of remaining a biconcave disk. The spherocytes, being rather rigid, are incapable of changing their shape to traverse the splenic microcircula- tion, and become trapped in the splenic red pulp, where they are destroyed.

The clinical manifestations of HS are variable and are related to the severity of hemolysis. Rarely, the disease can be so severe that repeated blood transfusions are necessary in infancy and splenectomy is required early in childhood. Alternatively, the anemia can be so mild as to go unnoticed, with the diagnosis being established late in life after the development of symptomatic cholelithiasis. Most patients have a minimal increase in serum bilirubin level as a direct consequence of excessive red cell destruc- tion. Intermittent episodes of jaundice may occur, often in association with a viral illness. As a result of the chronic hemolysis, patients with HS have an increased incidence

Accepted for publication Sep 25, 1992.

Address reprint requests to Mr Holden, Department of Cardiothoraac Surgery, Freeman Hospital, Newcastle-upon-Tyne, NE7 7DN, United Kingdom.

of pigment gallstones. Splenomegaly of a mild to moder- ate degree is a characteristic physical finding. The diag- nosis can be established by demonstrating spherocytes in the peripheral blood smear, along with reticulocytosis, an increased osmotic fragility of fresh and incubated red cells, and a negative direct Coombs' test [l].

Normal formed elements in the blood are prone to destruction during cardiopulmonary bypass due to the trauma of cardiotomy suction, bubble oxygenation, and roller pumping. The problem of the imposition of cardio- pulmonary bypass on patients suffering from excessive fragility of their red cells gives rise to concern for the safe conduct of such a procedure.

A review of the literature produced only a few case reports [%7] of patients with HS having had open heart operation. In this study we present 3 patients with HS who underwent open heart operation, and we record how this abnormality might affect the surgical treatment of cardiac diseases.

Case Reports Patient 1 A woman aged 60 years presented in January 1987 with moderate mitral regurgitation, moderate pulmonary hy- pertension, and heart failure. The diagnosis of HS had already been established at the age of 8 years. There was a relevant family history of father, brother, and son suffering from HS. Preoperative physical examination revealed an icteric tinge and enlarged, tender liver and spleen. An ultrasound examination of the abdomen showed multiple gallstones with nonfunctioning gallblad- der. Hematologic investigation at this time showed the hemoglobin level to be 13.1 g/dL; reticulocytes, 12%; and total bilirubin level, 75 pmol/L. The direct antiglobulin test (Coombs) was negative, and there was increased osmotic fragility of the red blood cells.

The patient was cooled to 24"C, and mitral valve re- placement was performed with the implantation of a no.

0 1993 by The Society of Thoracic Surgeons 0003-4975/93/$6.00

1498 GAWEDETAL HEART OPERATION AND SPHEROCYTOSIS

Ann Thorac Surg 1993;551497-500

33 porcine valve. One unit of blood was added to the prime of the heart-lung machine, and only 600 mL of packed red cells was given postoperatively for 400 mL total blood loss. The bypass time was 80 minutes. The hemoglobin level was found to fluctuate between 12.1 and 13.4 g/dL with 5% reticulocytes and a total bilirubin level of 101 pmol/L over the first 3 postoperative days. The recovery was uneventful, and the patient was discharged 2 weeks postoperatively. One year later she had splenec- tomy without complications, and the postoperative hema- tologic investigations showed a hemoglobin level of 15.4 g/dL; reticulocytes, 2% to 5%; and total bilirubin level, 15 p o l / L . Six months ago the valve function was perfect and the hemoglobin level was 12.6 g/dL.

Patient 2 This 67-year-old man presented with a history of calcific aortic stenosis, having experienced the first symptoms 8 years earlier. During his admission for catheterization the hematologic investigation showed his hemoglobin level to be 10.7 g/dL; reticulocytes, 40%; and total bilirubin level, 87 pmol/L. There were many spherocytes, osmotic fragd- ity of the red blood cells was shifted to the right (compat- ible with HS), and the levels of folic acid and B,, were normal. An abdominal ultrasound examination revealed an enlarged spleen without parenchymal lesions, and a gallbladder without stones. His father and sister were known to suffer from HS.

The patient had serious hemolysis and severe aortic stenosis; we opted to perform aortic valve replacement fist (October 1990), avoiding the splenectomy for the time being. After consultation with the hematologists, he re- ceived transfusions of 2 units of packed red cells twice a week for 3 consecutive weeks; the 12 units of blood would exchange all the patient’s fragde red cells. Three days after the last transfusion, the patient was cooled to 28°C and a no. 25 porcine valve was inserted in the aortic position; bypass time was 68 minutes.

He had a good recovery from the cardiovascular point of view, but his hemoglobin level fell from 12.1 g/dL (preoperative result) to 7.5 g/dL on the first postoperative day. The total blood loss in the intensive care unit was 1,050 mL. The coagulation screen (prothrombin time, partial thrombin time, activated clotting time, platelets) was within normal limits. During the next 6 days, multi- ple transfusions raised the hemoglobin level to 10.7 g/dL, the reticulocytes were 8%, and the total bilirubin level was 44 pmol/L.

Because of continued hemolysis despite the transfused blood, splenectomy was performed 4 months after the cardiac operation. The spleen was found to be three times the normal size with substantial adhesions; it weighed 807 g and had congested red pulp, prominent lining cells containing hemosiderin, hyperplastic white pulp, fi- brosed spiral arterioles, and no extramedullary hemopoi- esis. The postoperative course was complicated by throm- bocythemia; the platelet count was 140 X 109/L. Aspirin and dipyridamole administration was commenced; a month later, because of persistent thrombocythemia, war- farin was added. Follow-up at 2 months showed the

platelet count to be 490 x 109/L, and the aortic valve was functioning perfectly.

Pa tien t 3 A 64-year-old man was urgently transferred from another peripheral hospital with heart failure and pulmonary edema due to postmyocardial infarction ventricular septal defect. The catheterization showed an occluded left ante- rior descending coronary artery, stenotic circumflex artery distally, normal right coronary artery, a left ventricular aneurysm, and a large ventricular septal defect. An in- traaortic counterpulsation balloon pump was inserted through the right femoral artery, and administration of inotropes was commenced. At the age of 40 years the patient had had splenectomy and cholecystectomy be- cause of symptomatic HS. Since then he remained asymp- tomatic. His son was known to suffer from HS.

Two days after his admission (February 1992), ventric- ular septal defect closure with a Dacron patch was per- formed with cooling to 24°C and a bypass time of 110 minutes. The postoperative blood loss was 1,950 mL, and 6 units of packed red cells was transfused. He had a stormy postoperative course requiring high doses of ino- tropes, total parenteral nutrition, and special care for his renal failure. The preoperative hemoglobin level was 11.3 g/dL, and it remained steady between 10 and 11 g/dL postoperatively. The reticulocytes were 1% on each occa- sion, a few spherocytes were identified postoperatively, and the total bilirubin level was raised to 71 WmoYL.

Three weeks after the operation the patient was dis- charged with a hemoglobin level of 10 g/dL and a total bilirubin level of 14 pmol/L. One month later the patient was seen in the outpatient clinic in good health (New York Heart Association class 11).

Comment During the past 15 years, research into the structural organization of the red cell has contributed to a better understanding of many hemolytic anemias. Structurally, the red-cell membrane contains four types of components: the lipid bilayer; transmembrane proteins (band 3 and glycophorins); the spectrin lattice, formed by a functional unit of tetramers of two a-spedrin and two Pspectrin chains; and the bridging proteins that tie the spectrin tetramers to one another or to the transmembrane pro- teins (actin, adducin, ankyrin, and proteins 4.1, 4.2, and 4.9). The picture is not complete, because we do not yet know where band 7 fits into all of this. In addition, the complex interaction between the bridging proteins has not been completely elucidated [2].

It is likely that HS is a heterogeneous group of disor- ders, rather simply than a deficiency of a and /3 spectrin, described in a number of studies [8-111 as the main defect in HS. Studies of blood groups, HLA antigens, and abnormal chromosomal complement try to delineate the defect by searching for a gene responsible for spherocy- tosis [12].

As a result of the defect in the erythrocytes of patients with HS, the erythrocytes are more fragile and gradually

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CAYYED ET AL 1499 HEART OPERATION AND SPHEROCYTOSIS

Table 1 . Incidence of Open Heart Operation in Patients With Hereditary Spherocytosis

Author Year Patients Age (y) Type of Operation in the Past Additional Prevention

Moyes et a1 [3] 1971 1 16 MV repair Yes “Mock’ bypass Moyes et a1 [4] 1974 1 5 Correction of Fallot’s No “Mock’ bypass

de Leval et a1 [5] 1974 1 NF M + TVR, BC Yes None

Takeda et a1 [6] 1981 1 16 ASD repair Yes Travenol membrane

No. of Splenectomy

tetralogy

prosthesis

oxygenator and haptoglobin

Romashov [7] 1985 2 36 Closed MVy No None 36 Closed MVy, None

splenectomy + Cholecystectomy (simultaneously)

ASD = atrial septa1 defect; BC = Braunwald-Cutter; MV = mitral valve; MVy = mitral valvotomy; NF = not found; TVR = tricuspid valve replacement.

lose membrane vesicles, with resultant loss of surface area and sphering. These spherocytic red cells are limited in their ability to deform, and because of their inability to squeeze through the small pores between endothelial cells of the splenic sinuses to enter the venous circulation, they are readily trapped in the splenic pulp.

Splenectomy is indicated in virtually every patient with HS. In early childhood the risk of overwhelming postsple- nectomy sepsis makes it advisable, if possible, to delay elective splenectomy until after 6 years of age. Although spherocytosis persists after splenectomy, hemolysis is alleviated and a clinical cure of the anemia is achieved for most patients. However, the increased osmotic and me- chanical fragility persists throughout life [ 131. Acute in- jury to the blood cells during cardiopulmonary bypass, and the chronic mechanical trauma related to the presence of prosthetic valve in the circulation, must therefore be considered. In this study, patient 2 had one more cause for direct erythrocyte damage; he was on an intraaortic balloon pump.

In Table 1 we summarize the international experience with patients suffering from HS requiring cardiac opera- tions; 6 patients are reported who underwent open heart operations without early or late deaths and with no evident complications resulting from the hematologic defect.

Moyes and associates [3, 41, on 2 occasions (1971 and 1974), assessed the response of a sample of the patient’s blood to an experiment designed to simulate those aspects of cardiopulmonary bypass most damaging to blood (“mock“ bypass). Important destruction of the blood did not occur, so heart-lung bypass was set up for the original operation, which appeared to be well tolerated. Assess- ment of haptoglobin level, as suggested by Takeda and associates [6], may be of value in the future.

The first of our patients, with his spleen intact, had his mitral valve replaced and made a quick and uneventful recovery. The second patient, also without prior splenec- tomy, presented with marked hemolysis preoperatively; the critical condition of his aortic stenosis did not permit us to proceed initially to splenectomy. The 12 units of

packed red cells transfused before the aortic valve replace- ment protected against the effects of further hemolysis and helped him to go through the operative stress and cardiopulmonary bypass, but we acknowledge that this could be controversial.

We believe that splenectomy performed simultaneously with the cardiac procedures would increase the risk of excessive bleeding. Romashov [7] performed closed mitral valvotomy simultaneously with splenectomy and chole- cystectomy, but this was without use of the cardiopulmo- nary bypass machine with its probable injury to red cells and derangement of clotting processes. Our third patient had already undergone splenectomy, but, as was men- tioned above, he was on an intraaortic balloon pump for 8 days; despite this, the cardiopulmonary bypass and his critical condition did not trigger hemolysis.

The previous reports support our view that patients with HS should have splenectomy before any cardiac procedure because it protects them from severe hemoly- sis. The use of biological instead of mechanical valves might be preferable in these patients who require valve replacement, but the greater risk of repeat valve operation exists. De Leval and associates [5] used a mechanical prosthesis for mitral and tricuspid valve replacement without any complications, yet they commented that a biologic valve might have been preferred.

The achievements of modern hematology and the im- provement of surgical and anesthetic techniques and heart-lung machine technology will doubtless reduce the problems of surgical intervention in patients with HS.

We are grateful to Mr P. R. Behl for allowing us to include patient 2. We thank Dr A. Masmanides for translating reference 6, originally written in the Russian language.

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1500 GAWED ET AL HEART OPERATION AND SPHEROCYTOSIS

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4. Moyes DG, Holloway AM, Hutton WS. Correction of Fallot’s tetralogy in a patient suffering from hereditary spherocyto- sis. S Afr Med J 1974;48:1535-6.

5. De Leva1 MR, Taswell HF, Bowie EJ, Danielson GK. Open heart surgery in patients with inherited hemoglobinopathies, red cell dyscrasias, and coagulopathies. Arch Surg 1974;109:

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7. Romashov FN. Surgical tactics in the treatment of patients with hereditary hemolytic anemia associated with a mitral valve defect. Khirurgiia (Mosk) 1985;June 613%.

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