Cardiac hemolytic anemia resolving after second mitral annuloplasty SEAN O'REGAN,* MB, B CH; A.J. NEWMAN, MS, MD
Following an episode of rheumatic carditis, severe mitral Incompetence developed in a 9-year-old girl. A mitral annuloplasty succeeded for a short time in ameliorating her symptoms of cardiac failure. However, mitral incompetence recurred and was accompanied by severe anemia and hemosiderinuria. Distortion of erythrocytes was evident on a peripheral blood smear. A second mitral annuloplasty resulted in resolution of the hemolytic anemia. Une insuffisance mitrale grave est apparue chez une fillette de 9 ans a Ia suite d'un acces de cardite rhumatismale. Une annuloplastie mitrale a permis d'ameliorer temporairement les sympt6mes d'insuffisance cardiaque. II y a eu toutefois recidive de l'insuffisance mitrale, accompagnee danemie severe et d'hemosid6rinurie. Le frottis du sang peripherique a mis en evidence une distorsion des erythrocytes. Une deuxieme annuloplastie mitrale a corrige lanemie hemolytique.
From the department of pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, Ohio *present address: Department of nephrology, Montreal Children's Hospital, 2300 Tupper St., Montreal, PQ H3H 1P3 Reprint requests to: Dr. AJ. Newman, Department of pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, 2103 Adelbert Rd., Cleveland, OH .l06, USA
An unexpected complication of the use of prosthetic devices in the surgical treatment of cardiac disease has been the development of hemolytic anemias of varying severity. This complication, most commonly noted after the insertion of prosthetic aortic valves, has been ascribed to mechanical damage of erythrocytes, with resulting hemolysis. The hemolysis is often accompanied by hemosiderinuria. In 1966 Ziperovich and Paley1 described the occurrence of severe hemolysis secondary to mitral regurgitation caused by a tear in the anterior leaflet of the mitral valve following valvuloplasty. In this paper we describe a patient with severe hemolytic anemia, which occurred after mitral valvuloplasty and was treated successfully by reoperation on the deformed mitral valve.
Case report A 9-year-old girl was admitted to hospital with a 3-day history of fever, lethargy, tachypnea and bilateral ankle edema. These symptoms occurred 2 months after untreated pharyngitis and intermittent knee pain. She was in moderate respiratory distress, with a respiratory rate of 46/mm. Pitting edema to the knees was demonstrated. Her apical heart rate was 140 and her temperature was beats/mm 38.5 0C. Auscultatory evidence of mitral incompetence and electrocardiographic abnormalities consistent with a diagnosis of rheumatic carditis were noted. A throat culture grew fl-hemolytic streptococci, group A. The antistreptolysin-O titre was 850 U, increasing to 1250 U 1 week later, and C-reactive protein was detectable in her serum. The diagnosis was congestive cardiac failure secondary to rheumatic carditis and mitral insufficiency. The patient responded slowly to therapy with digoxin and diuretics. Benzathine penicillin G was given intramuscularly. During this admission her hematocrit was 35 to 37% and erythrocyte structure was normal. At follow-up there was still clinical evidence of mitral incompetence. Cardiac catheterization, performed because of congestive cardiac failure, revealed severe mitral incompetence and mild aortic incompetence. Two years after initial diagnosis mitral annuloplasty was performed for correction of the mitral insufficiency. This procedure was initially successful in ameliorating the symptoms of congestive cardiac failure, but 6 weeks after the operation pallor and appreciable mitral incompetence were noted. Her hematocrit had decreased from
35% postoperatively to 21%. No hepatosplenomegaly was detectable. However, her erythrocytes were distorted on a peripheral blood smear (Fig. 1) and her reticulocyte count was 16.6%. She was slightly icteric and had hemoglobinemia, hemoglobinuria and hemosiderinuria (Fig. 2). Over the succeeding months her hematocrit failed to increase. Screening for hemoglobinopathies and erythrocyte enzyme defects revealed no abnormalities.
FIG. 1-Distorted erythrocytes in peripheral blood smear (x97).
FIG. 2-Hemosiderin (dark areas) in casts in urinary sediment (x97).
CMA JOURNAL/SEPTEMBER 4, 1976/VOL. 115 419
Apresoline
the unique "ADD ON" antihypertensive INDICATIONS: Various forms of hypertension: fixed essential hypertension, whether of benign or malignant character; hypertension associated with acute and chronic glomerulonephritis; nephrosclerosis; hypertensive toxemias of pregnancy, pre-eclampsia, and eclampsia. DOSAGE: Hypertension: Orally: In general after initiating therapy gradually increase dosage, adjusting according to individual response. As a single agent, initially 10mg, four times daily increasing slowly to a maximum practical dosage of 200mg daily. In combination with other hypotensive agents, lower dosages of APRESOLINE will be appropriate. Parenteral/y: When there is urgent need, therapy in the hospitalized patient may be initiated intravenously or intramuscularly. Usual dose is 20 to 40 mg, repeated as necessary. Certain patients, especially those with marked renal damage, may require a lower dose. Pressure may begin to fall within afew minutes after injection, with an average maximal decrease occurring in 10 to 80 minutes. Most patients can be transferred to oral APRESOLINE within 24 to 48 hours. Toxemia of Pregnancy: a) Early toxemia and hypertension of pregnancy: One 10-mg tablet orally 4 times daily, slowly increasing the dosage up to 400mg per day, or until a therapeutic result is obtained. b) Late toxemia and pre-eclampsia: Give 20 to 40mg intramuscularly, or slowly by direct intravenous injection or infusion. Repeat as necessary. SIDE EFFECTS: Tachycardia, headache, palpitation, dizziness, weakness, nausea, vomiting, postural hypote'ision, numbness and tingling of the extremities, flushing, nasal congestion, lachrymation, conjunctival injection, dyspnea, anginal symptoms, rash, drug fever, reduction in hemoglobin and red cell count, giant urticaria, and a lupus-like syndrome (arthralgia) in some cases following administration for long periods. CAUTIONS: Usecautiouslyin the presence of advanced renal damage and recent coronary or cerebral ischemia.APRESOLINE may potentiate the narcotic effects of barbiturates and alcohol. Peripheral neuritis evidenced by paresthesias, numbness and tingling has been observed. Published evidence suggests an anti-pyridoxine effect and addition of pyridoxinetothe regimen if symptoms develop. OVERDOSAGE: Symptoms: Hypotension and tachycardia. Treatment: Gastric lavage or, in the absence of coma, emetics. In the presence of hypotension, cautiously give norepinephrine (intravenously) or ephedrineto raise the blood pressure without increasing tachycardia. Avoid epinephrine. General supportive measures include intravenous fluids, extemal heat, and elevation of footof bed. SUPPLIED: All forms contain hydralazine hydrochlorideTablets of 10mg (yellow, scored); bottles of lOOTablets of 25mg (blue, coated); bottles of 100 and SOOTablets of 50mg (pink, coated); bottles of 100 and 500. Ampoules of 1 ml aqueous solution containing 20mg; boxes of 10.
However, her erythrocytes became more distorted and "burr" cells, progressive microcytosis and hypochromia were noted. Her serum iron concentration was persistently low and massive hemosiderinuria developed. Serum folate concentrations were also low. Her hypochromia disappeared when she was treated with 200 mg of ferrous sulfate and 5 mg of folic acid daily, but her hematocrit remained about 18 to 21%. She was observed closely and her renal function assessed periodically to detect any damage from the massive hemosiderinuria. She remained reasonably well for 2 years, taking digoxin, but progressive diminution in exercise tolerance developed, with signs of congestive failure and increasing mitral incompetence. Because of the increasing severity of her symptoms and signs a second mitral annuloplasty was performed. The severely incompetent mitral valve was repaired successfully and subsequently her cardiac status improved greatly. Her hematocrit increased from 21 % preoperatively, prior to transfusion, and stabilized at 34%; normal erythrocytes reappeared and the hemosiderinuria ceased. No cause other than severe incompetence of her mitral valve could be established for her hemolysis. The prompt resolution of hemolysis with improvement in anemia, decrease in reticulocyte count and termination of hemosiderinuria strengthened this assumption.
Discussion Cardiac hemolytic anemia is now generally ascribed to high shear stress causing mechanical damage to erythrocytes, with consequent hemolysis.1 The stress is usually produced by abnormal hemodynamics secondary to, though not always caused by, prosthetic malfunction. Aortic valve replacement is the most common type of cardiac repair associated with hemolysis. The size, construction and material of the prosthesis influence the severity of the resulting anemia,3 and the activity of the patient may influence the degree of hemolysis.4 The anemia, by increasing cardiac work and therefore cardiac output, results in greater turbulence and may further exacerbate the hemolysis.
Pirofsky and colleagues in I 965. reported hemolytic anemia in seven patients who had had aortic valve replacements. An autoimmune mechanism was thought to be involved and a favourable response to steroid therapy was obtained in four patients. However, most reports describe factors suggesting a mechanical component in the CIBA 0-5003 cause of the hemolysis. DORVAL, QUEBEC 420 CMA JOURNAL/SEPTEMBER 4, 1976/VOL. 115
Cardiac hemolytic anemia has been observed in the absence of an operation. Miller and colleagues6 described the appearance of hemolytic anemia sufficient to cause a decrease in hematocrit in a patient with rheumatic mitral and aortic valvular disease. Mild hemolysis has also been reported in association with aortic valvular disease prior to the insertion of an artificial valve.7 Hemoglobinemia and hemosiderinuna may be apparent if hemolysis is severe. The persistent hemosiderinuria rapidly depletes iron stores and results in microcytosis and hypochromia if iron supplementation is not instituted. Massive tubular hemosiderosis due to prolonged hemosiderinuria has been observed at autopsy.8'0 DeCesare, Rath and Hufnagel4 observed severe hemolytic anemia in two of three patients who had diseased aortic valves replaced with Dacron leaflets. The hematocrit improved greatly following replacement of the dysfunctioning prosthesis in both patients. Ziperovich and Paley' in 1966 reported the occurrence of hemolytic anemia secondary to turbulence caused by a tear in the anterior leaflet of the mitral valve in a patient who had undergone mitral valvuloplasty because of incompetence of that valve. The hemolysis was corrected by insertion of a prosthetic mitral valve. In our patient the hemolysis was considered secondary to mechanical trauma caused by the turbulent regurgitation through the mitral valve. Neither leaflet was torn. Successful correction of the incompetence resulted in prompt resolution of anemia and cessation of hemosiderinuria. References 1. Zipaaovicoi 5, PALEY 11w: Severe mechanical hemolytic anemia due to valvular heart disease without prosthesis. Ann Intern Med 65: 342, 1966 2. MARSH OW, LawNs SM: Cardiac haemolytic anaemia. Semin Hematol 6: 133, 1969 3. MYHRE E. DALE J, RAsMussEN K: Erythrocyte destruction in different types of StarrEdwards aortic ball valves. Circulation 42: 515, 1970 4. DstCasARa W, RATH C, HUFNAGEL C: Hemolytic anemia of mechanical origin with aorticvalve prosthesis. N Engi I Med 272: 1045. 1965 5. PiRoFaK's'
6.
7.
8. 9.
B,
SUTHERLAND
DW,
STARR
A,
et al: Hemolytic anemia complicating aorticvalve surgery. An autoimmune syndrome. Ibid. p 235 MILLER DS, MENOEL CE, KRaMER WB, et al: lntravascular hemolysis in a patient with valvular heart disease. Ann Intern Med 65: 210, 1966 BRODEUR MT. SUTHERLAND DW, KOLER RD. et al: Red blood cell survival in patients with aortic valvular disease and ball-valve prosthesis. Circulation 32: 570, 1965 Case Records of the Massachusetts General Hospital. Case 52-1964. N Engi I Med 271: 898, 1964 WESTRING DW: Aortic valve disease and hemolytic anemia. Ann Intern Med 65: 203, 1966
Following an episode of rheumatic carditis, severe mitral Incompetence developed in a 9-year-old girl. A mitral annuloplasty succeeded for a short time in ameliorating her symptoms of cardiac failure. However, mitral incompetence recurred and was accompanied by severe anemia and hemosiderinuria. Distortion of erythrocytes was evident on a peripheral blood smear. A second mitral annuloplasty resulted in resolution of the hemolytic anemia. Une insuffisance mitrale grave est apparue chez une fillette de 9 ans a Ia suite d'un acces de cardite rhumatismale. Une annuloplastie mitrale a permis d'ameliorer temporairement les sympt6mes d'insuffisance cardiaque. II y a eu toutefois recidive de l'insuffisance mitrale, accompagnee danemie severe et d'hemosid6rinurie. Le frottis du sang peripherique a mis en evidence une distorsion des erythrocytes. Une deuxieme annuloplastie mitrale a corrige lanemie hemolytique.
From the department of pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, Ohio *present address: Department of nephrology, Montreal Children's Hospital, 2300 Tupper St., Montreal, PQ H3H 1P3 Reprint requests to: Dr. AJ. Newman, Department of pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, 2103 Adelbert Rd., Cleveland, OH .l06, USA
An unexpected complication of the use of prosthetic devices in the surgical treatment of cardiac disease has been the development of hemolytic anemias of varying severity. This complication, most commonly noted after the insertion of prosthetic aortic valves, has been ascribed to mechanical damage of erythrocytes, with resulting hemolysis. The hemolysis is often accompanied by hemosiderinuria. In 1966 Ziperovich and Paley1 described the occurrence of severe hemolysis secondary to mitral regurgitation caused by a tear in the anterior leaflet of the mitral valve following valvuloplasty. In this paper we describe a patient with severe hemolytic anemia, which occurred after mitral valvuloplasty and was treated successfully by reoperation on the deformed mitral valve.
Case report A 9-year-old girl was admitted to hospital with a 3-day history of fever, lethargy, tachypnea and bilateral ankle edema. These symptoms occurred 2 months after untreated pharyngitis and intermittent knee pain. She was in moderate respiratory distress, with a respiratory rate of 46/mm. Pitting edema to the knees was demonstrated. Her apical heart rate was 140 and her temperature was beats/mm 38.5 0C. Auscultatory evidence of mitral incompetence and electrocardiographic abnormalities consistent with a diagnosis of rheumatic carditis were noted. A throat culture grew fl-hemolytic streptococci, group A. The antistreptolysin-O titre was 850 U, increasing to 1250 U 1 week later, and C-reactive protein was detectable in her serum. The diagnosis was congestive cardiac failure secondary to rheumatic carditis and mitral insufficiency. The patient responded slowly to therapy with digoxin and diuretics. Benzathine penicillin G was given intramuscularly. During this admission her hematocrit was 35 to 37% and erythrocyte structure was normal. At follow-up there was still clinical evidence of mitral incompetence. Cardiac catheterization, performed because of congestive cardiac failure, revealed severe mitral incompetence and mild aortic incompetence. Two years after initial diagnosis mitral annuloplasty was performed for correction of the mitral insufficiency. This procedure was initially successful in ameliorating the symptoms of congestive cardiac failure, but 6 weeks after the operation pallor and appreciable mitral incompetence were noted. Her hematocrit had decreased from
35% postoperatively to 21%. No hepatosplenomegaly was detectable. However, her erythrocytes were distorted on a peripheral blood smear (Fig. 1) and her reticulocyte count was 16.6%. She was slightly icteric and had hemoglobinemia, hemoglobinuria and hemosiderinuria (Fig. 2). Over the succeeding months her hematocrit failed to increase. Screening for hemoglobinopathies and erythrocyte enzyme defects revealed no abnormalities.
FIG. 1-Distorted erythrocytes in peripheral blood smear (x97).
FIG. 2-Hemosiderin (dark areas) in casts in urinary sediment (x97).
CMA JOURNAL/SEPTEMBER 4, 1976/VOL. 115 419
Apresoline
the unique "ADD ON" antihypertensive INDICATIONS: Various forms of hypertension: fixed essential hypertension, whether of benign or malignant character; hypertension associated with acute and chronic glomerulonephritis; nephrosclerosis; hypertensive toxemias of pregnancy, pre-eclampsia, and eclampsia. DOSAGE: Hypertension: Orally: In general after initiating therapy gradually increase dosage, adjusting according to individual response. As a single agent, initially 10mg, four times daily increasing slowly to a maximum practical dosage of 200mg daily. In combination with other hypotensive agents, lower dosages of APRESOLINE will be appropriate. Parenteral/y: When there is urgent need, therapy in the hospitalized patient may be initiated intravenously or intramuscularly. Usual dose is 20 to 40 mg, repeated as necessary. Certain patients, especially those with marked renal damage, may require a lower dose. Pressure may begin to fall within afew minutes after injection, with an average maximal decrease occurring in 10 to 80 minutes. Most patients can be transferred to oral APRESOLINE within 24 to 48 hours. Toxemia of Pregnancy: a) Early toxemia and hypertension of pregnancy: One 10-mg tablet orally 4 times daily, slowly increasing the dosage up to 400mg per day, or until a therapeutic result is obtained. b) Late toxemia and pre-eclampsia: Give 20 to 40mg intramuscularly, or slowly by direct intravenous injection or infusion. Repeat as necessary. SIDE EFFECTS: Tachycardia, headache, palpitation, dizziness, weakness, nausea, vomiting, postural hypote'ision, numbness and tingling of the extremities, flushing, nasal congestion, lachrymation, conjunctival injection, dyspnea, anginal symptoms, rash, drug fever, reduction in hemoglobin and red cell count, giant urticaria, and a lupus-like syndrome (arthralgia) in some cases following administration for long periods. CAUTIONS: Usecautiouslyin the presence of advanced renal damage and recent coronary or cerebral ischemia.APRESOLINE may potentiate the narcotic effects of barbiturates and alcohol. Peripheral neuritis evidenced by paresthesias, numbness and tingling has been observed. Published evidence suggests an anti-pyridoxine effect and addition of pyridoxinetothe regimen if symptoms develop. OVERDOSAGE: Symptoms: Hypotension and tachycardia. Treatment: Gastric lavage or, in the absence of coma, emetics. In the presence of hypotension, cautiously give norepinephrine (intravenously) or ephedrineto raise the blood pressure without increasing tachycardia. Avoid epinephrine. General supportive measures include intravenous fluids, extemal heat, and elevation of footof bed. SUPPLIED: All forms contain hydralazine hydrochlorideTablets of 10mg (yellow, scored); bottles of lOOTablets of 25mg (blue, coated); bottles of 100 and SOOTablets of 50mg (pink, coated); bottles of 100 and 500. Ampoules of 1 ml aqueous solution containing 20mg; boxes of 10.
However, her erythrocytes became more distorted and "burr" cells, progressive microcytosis and hypochromia were noted. Her serum iron concentration was persistently low and massive hemosiderinuria developed. Serum folate concentrations were also low. Her hypochromia disappeared when she was treated with 200 mg of ferrous sulfate and 5 mg of folic acid daily, but her hematocrit remained about 18 to 21%. She was observed closely and her renal function assessed periodically to detect any damage from the massive hemosiderinuria. She remained reasonably well for 2 years, taking digoxin, but progressive diminution in exercise tolerance developed, with signs of congestive failure and increasing mitral incompetence. Because of the increasing severity of her symptoms and signs a second mitral annuloplasty was performed. The severely incompetent mitral valve was repaired successfully and subsequently her cardiac status improved greatly. Her hematocrit increased from 21 % preoperatively, prior to transfusion, and stabilized at 34%; normal erythrocytes reappeared and the hemosiderinuria ceased. No cause other than severe incompetence of her mitral valve could be established for her hemolysis. The prompt resolution of hemolysis with improvement in anemia, decrease in reticulocyte count and termination of hemosiderinuria strengthened this assumption.
Discussion Cardiac hemolytic anemia is now generally ascribed to high shear stress causing mechanical damage to erythrocytes, with consequent hemolysis.1 The stress is usually produced by abnormal hemodynamics secondary to, though not always caused by, prosthetic malfunction. Aortic valve replacement is the most common type of cardiac repair associated with hemolysis. The size, construction and material of the prosthesis influence the severity of the resulting anemia,3 and the activity of the patient may influence the degree of hemolysis.4 The anemia, by increasing cardiac work and therefore cardiac output, results in greater turbulence and may further exacerbate the hemolysis.
Pirofsky and colleagues in I 965. reported hemolytic anemia in seven patients who had had aortic valve replacements. An autoimmune mechanism was thought to be involved and a favourable response to steroid therapy was obtained in four patients. However, most reports describe factors suggesting a mechanical component in the CIBA 0-5003 cause of the hemolysis. DORVAL, QUEBEC 420 CMA JOURNAL/SEPTEMBER 4, 1976/VOL. 115
Cardiac hemolytic anemia has been observed in the absence of an operation. Miller and colleagues6 described the appearance of hemolytic anemia sufficient to cause a decrease in hematocrit in a patient with rheumatic mitral and aortic valvular disease. Mild hemolysis has also been reported in association with aortic valvular disease prior to the insertion of an artificial valve.7 Hemoglobinemia and hemosiderinuna may be apparent if hemolysis is severe. The persistent hemosiderinuria rapidly depletes iron stores and results in microcytosis and hypochromia if iron supplementation is not instituted. Massive tubular hemosiderosis due to prolonged hemosiderinuria has been observed at autopsy.8'0 DeCesare, Rath and Hufnagel4 observed severe hemolytic anemia in two of three patients who had diseased aortic valves replaced with Dacron leaflets. The hematocrit improved greatly following replacement of the dysfunctioning prosthesis in both patients. Ziperovich and Paley' in 1966 reported the occurrence of hemolytic anemia secondary to turbulence caused by a tear in the anterior leaflet of the mitral valve in a patient who had undergone mitral valvuloplasty because of incompetence of that valve. The hemolysis was corrected by insertion of a prosthetic mitral valve. In our patient the hemolysis was considered secondary to mechanical trauma caused by the turbulent regurgitation through the mitral valve. Neither leaflet was torn. Successful correction of the incompetence resulted in prompt resolution of anemia and cessation of hemosiderinuria. References 1. Zipaaovicoi 5, PALEY 11w: Severe mechanical hemolytic anemia due to valvular heart disease without prosthesis. Ann Intern Med 65: 342, 1966 2. MARSH OW, LawNs SM: Cardiac haemolytic anaemia. Semin Hematol 6: 133, 1969 3. MYHRE E. DALE J, RAsMussEN K: Erythrocyte destruction in different types of StarrEdwards aortic ball valves. Circulation 42: 515, 1970 4. DstCasARa W, RATH C, HUFNAGEL C: Hemolytic anemia of mechanical origin with aorticvalve prosthesis. N Engi I Med 272: 1045. 1965 5. PiRoFaK's'
6.
7.
8. 9.
B,
SUTHERLAND
DW,
STARR
A,
et al: Hemolytic anemia complicating aorticvalve surgery. An autoimmune syndrome. Ibid. p 235 MILLER DS, MENOEL CE, KRaMER WB, et al: lntravascular hemolysis in a patient with valvular heart disease. Ann Intern Med 65: 210, 1966 BRODEUR MT. SUTHERLAND DW, KOLER RD. et al: Red blood cell survival in patients with aortic valvular disease and ball-valve prosthesis. Circulation 32: 570, 1965 Case Records of the Massachusetts General Hospital. Case 52-1964. N Engi I Med 271: 898, 1964 WESTRING DW: Aortic valve disease and hemolytic anemia. Ann Intern Med 65: 203, 1966
