hemolytic anemia due progressive enlargement of...
TRANSCRIPT
Hemolytic Anemia Due to ProgressiveEnlargement of Silastic Ball Component
of Aortic ProsthesisBy MARIO C. GARCIA, M.D., ALBERT M. CLARYSSE, M.D.,
CARL S. ALEXANDER, M.D., PH.D., YOSHIO SAKO, M.D., PH.D., AND
WILLIAM R. SWAIM, M.D.
SUMMARYThe patient described developed hemolytic anemia following insertion of a Starr-
Edwards aortic valve prosthesis. No diastolic murmur was heard and no insufficiencywas detected. The hemolytic anemia was progressively more severe and uncompensateddespite various medical measures.
The anemia was characterized by fragmented erythrocytes in the peripheral blood,reticulocytosis, elevation of plasma heme pigments augmented by exercise, increasedfecal urobilinogen, and iron loss in the urine. Studies of chromium-51-tagged erythro-cytes indicated an extracorpuscular mechanism of hemolysis.At reoperation the ball component of the prosthesis was found to be enlarged and
obstructing blood flow. Chemical analysis of the ball showed significant cholesterol andlipid deposits. The hemolysis disappeared after the prosthesis was replaced with a homo-graft valve. Ferrokinetic studies showed rapid plasma clearance and incorporation intocirculating erythrocytes. Triglycerides were elevated during the period of hemolysis.Red cell membrane lipids were normal.
Additional Indexing Words:Ferrokinetic studies of erythrocytesChromium-tagged erythrocyte studiesLipids in erythrocytic membrane
TriglyceridesCholesterol
THE DEVELOPMENT of artificial valveshas played a major role in correcting
the hemodynamic complications of diseasedaortic, mitral, and tricuspid valves. Althoughmost patients have an improvement in theircardiac function, some develop hemolyticanemia which is clinically distinct from thepost-perfusion hemolysis described by Kreeland associates." Hemolytic anemias have beendescribed in association with diseased aortic
From the Research, Medical and Surgical Services,Veterans Administration Hospital, and the Depart-ment of Medicine and Surgery, University of Minne-sota, Minneapolis, Minnesota.
Address for reprints: Dr. William R. Swaim,Veterans Administration Hospital, 54th Street and48th Avenue South, Minneapolis, Minnesota 55417.
Circulation, Volume XXXVIII, September 1968
and mitral valves,2-5 as well as aortic andmitral valve prostheses, with6'"' and withoutinsufficiency.3' 12, 13
This paper describes a patient with aStarr-Edwards aortic valve in whom pro-gressively more severe hemolytic anemia de-veloped in the absence of aortic valve in-sufficiency, over a 2-year period after surgery.Brachial artery pressure tracings obtainednear the end of the second year were sug-gestive of development of stenosis. Thehemolytic anemia could not be controlledby medical management. The prosthesis wastherefore replaced by a homograft aorticvalve. The silastic* ball component of the
*Dow-Corning Corporation, Midland, Michigan.
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Starr-Edwards valve was found to be en-larged, roughened, covered with lipids, andobstructing blood flow through the valve. Thisenlargement resulted in restriction of freemovement of the ball within its cage.
Report of CaseWV. G., a 40-year-old white farmer, gave a
history of migratory joint pains at age 12 yearsand was found to have a heart murmur whenhe entered the Armed Forces in 1940. Afterdischarge from the Army, he wvas asymptomaticexcept for an episode of pericarditis of unknownetiology in 1956. In April 1962, he was hospital-ized at the Minneapolis Veterans AdministrationHospital for congestive heart failure. His bloodpressure was 120/99 mm Hg, a thrill was pal-pable at the left second intercostal space, and agrade IV/ VI systolic murmur was heard in the
same area with transmission into the neck anddown to the apical area of the heart. Labora-tory studies showed the following values: hemo-globin of 15.6 g%, hematocrit of 44%, and serumcholesterol of 328 mg% (male normal, 170 to275 mg%), normal glucose tolerance, normalblood urea nitrogen, and a negative rheumatoidlatex fixation test. Other findings included leftventricular hypertrophy by chest roentgenog-raphy and electrocardiogram, aortic valve cal-cification by cinefluoroscopy, and aortic stenosiswithout regurgitation by left ventriculography.The patient responded well to salt restrictionand digitalization. Two years later, in April1964, he was readmitted because of orthopnea,paroxysmal nocturnal dyspnea, and lightheaded-ness. At this time the aortic valve was replacedwith an 11-A Starr-Edwards prosthesis. In the2 weeks following surgery, his hemoglobin level,which was 15 g% in the preoperative and im-mediate postoperative period, gradually fell to
Table 1Hematological Studies
Studies
1. Fragmented red cells in peripheralblood smear (%)
2. Hemosiderinuria (Prussian blue)3. Plasma heme pigments (mg% )144. Fecal urobilinogen (mg%/24 hr)5. Coombs' test: Direct
Indirect6. Autohemolysis (% in 48 hr)147. Donath-Landsteiner'58. Sugar hemolysis169. Acid hemolysisl5
10. Serum folic acid level (mAg/m1)l711. Serum B12 level (total) (yy/ml)12. Serum Fe (jug%) before iron therapy;
After or during iron therapy13. Osmotic fragility
14. Hemoglobin electrophoresis(acrylamide gel)
15. 5lCr red cell survival T/2 (days);Sequestration: spleen/liver
16. 59Fe plasma clearance, T/2 (min);Red cell 59Fe incorporation
17. Bone marrow, 1966
Bone marrow, 1967
18. Effect of physical activity on plasmahemoglobin level (total heme pig-ments) (mg%)
Values afterStarr-Edwards
prosthesis
8.5-8.8
Persistently (+ )41-90Up to 1,030(-)
2.3, control 1.6( -)(-)( -)9.6290245, 48, 73, 63Normal
Normal adult
Normal
<0.8
<520-280(-)(-)0.4 to 4.5
(-)( -)6.4 - 25155-583
55 to 175No hemolysis in0.85 to 0.51% NaCl
Pt. 9, donor 6 24-311.2 0.8 - 1.232, 27.5 60 -9080% in 7 days66% in 4 days 90% in 8-10 daysHypercellular section with normoblastichyperplasia, decreased iron storesHypercellular section with normoblastichyperplasia, increased iron storesRest: 60, 75, 72 <5Activity: 90 < 5
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HEMOLYTIC ANEMIA
Figu
Schistocytes, peripheral bli
'ri ~11.1 g%. Three plasma heme pigment determina-tions yielded 41, 51, and 85 mg%, with the
9-0 normal range being less than 5 mg%.One year later, in May 1965, the cardiac out-
4 put was 5.5 L/min, cardiac index was 2.8 L/minQ/M2, brachial artery pressure, 102/75 mm
-Xt-";;gI4 iXt,~ Hg, brachial artery peak velocity, 525 mm/sec,and brachial artery rise time of 0.18 sec wascorrected for rate to 0.20 sec. These data indicate
*0--0 - that aortic outflow was partially obstructed. The*il0f0-00--Dlto00- 0 hemoglobin was 10.6 g%, reticulocyte count was
6.8%, and marked poikilocytosis of the erythro-cytes was observed in the blood smear. The
fl<-0< serum bilirubin was 1.0 mg% total with 0.1a000̂t,,^ $ mg% direct, and the serum iron was 21 jug% with
fg0p3t.jX; ;0-- a total iron-binding capacity of 289 ,ug%. TheWE serum cholesterol was 160 mg%. Multiple guaiac
tests of stools were negative, and tests of urine- - ---;* for hemosiderin were repeatedly positive.
Special hematological studies were done be-) a Q cause of the progressive anemia, the results are
VS:,i1<;tv 00--f---listed in table 1. These data indicate that theSf0 0 tanemia was hemolytic in nature and was char-
o e j i acterized by the presence of numerous frag-mented erythrocytes (schistocytes) in the blood
*- -;;; f;0---Xsmear (fig. 1), reticulocytosis, elevation of plasmaWj> hheme pigments augmented by exercise, increased
fecal urobilinogen, decreased serum iron, persis-aa~~~~ S ~tently positive hemosiderinuria, and a striking
[re 1 normoblastic hyperplasia of the bone marrow.Studies of erythrocytes tagged with radiochro-
'ood smear. mium (51Cr) (fig. 2) showed a shortened survival
.Patient Cells r2 = 9daysO---wODonorCalls T/zz2bdaysx x Patient Cell5 2 =Z4days
100 After Homograft
0 I INormal}~~~~~~~~~~Rangs
0 10 ZO 30Days
Figure 2Survival of Chromium-51-tagged erythrocytes.
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iziEqp11Z
P-Irl
lt'.M-CILn
%/oDOSb100 r
%Dose100-N5t
50 _
a
0
in-10
-0
DaCounts/min.
5.0 r
0 ZO 40 60 80 100
MinutosFigure 3
Iron-59 plasma clearance.
time using the patient's own cells as well as withnormal compatible donor cells. These findingsindicate that an extra corpuscular mechanismwas largely responsible for the hemolysis. Studiesfor an antibody-related mechanism were negative.Screening tests for intrinsic erythrocyte abnor-malities were either negative or within normallimits. Quantitative analysis (table 2) of lipidsin the erythrocytic membrane showed that theywere within normal limits. Plasma lipids studiedat the same time revealed a triglyceride levelof 420 mg% (normal, 100 to 160 mg%). Choles-terol and phospholipids were within normallimits. Ferrokinetic studies (fig. 3) revealed arapid plasma clearance of intravenously injected,radioisotope-labeled iron. External monitoring(fig. 4) showed a rapid increase in counts overthe bone marrow declining over the next 3 days
Table 2Erythrocyte Membrane Lipids*
Patient Normal range
Total lipid weight = 5.58 x 10-10 mg/RBC 4.0 to 5.8Cholesterol = 28.1% by weight
% of phospholipidsPhosphatidyl ethanolamine 26.1Phosphatidyl choline 30.9Phosphatidyl serine 14.7Sphingomyelin 25.1Phosphatidic acid 3.1
25.1 to 28.3
26.0 to 29.027.7 to 30.713.1 to 16.524.0 to 26.8
*Obtained during period of hemolysis associatedwith the Starr-Edwards valve.
,., 4.0
-T 3.0
._S2.0
t.O
75~
so
0
Normal Range
/1>
I, ,2 3 4 5 6 7 8 9 10
Days
// - --7_ *
* = Bon Marrow-/// = Spleen
x = Liver^ , ..
OII
2 4 6 8 12 3Hours
4 5 6 7 8 9DaLJs
Figure 4
Erythrocyte incorporation and tissue distribution ofiron-59.
to a plateau. With the decline in marrow radio-activity there was a simultaneous increase andplateau in the liver and spleen radioactivity. Thepeak incorporation of 59Fe into circulatingerythrocytes was reached by the fourth day andwas followed by a progressive decrease for thenext 5 days of study. During this 5-day periodthe radioactivity of both the liver and spleenincreased. Thus, iron incorporation into theerythrocytes was rapid and reached a peakvalue earlier than the normal expected peakbetween 7 to 10 days.'8 19 The decrease inthe 59Fe-tagged erythrocyte population coupledwith the increased spleen and liver counts in-dicates that these organs were participating inthe clearance of damaged erythrocytes. Ordi-narily the spleen is the prime remover of damagederythrocytes, but when cell damage is severe,the liver participates as well.20
Figure 5 depicts the clinical course of thispatient and the various measures attempted tostabilize the hemoglobin level. Following surgeryin 1964, there was a progressive decrease inhemoglobin with a corresponding brisk reticulo-cytosis. Transfusions of packed erythrocytes givento reduce the high output state associated withthe anemia, were only partially successful inameliorating the brisk hemolysis. Periods of retic-ulocytopenia regularly followed blood trans-fusion. Oral iron therapy, given to cover theurinary iron losses, resulted in a return of iron
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P 2 0 Operation Blood Transfusions Reoperation-
0-.w- .- s . .aS
*s 10 ' -'1s\\j/ //E12 5 -v
0 19*2 J1904 119&5 W1966 [#1967 -
-8 15
o 10
.4-
0~~~~~~j19611964 11957S 1966 J19(7
5 mg/d. Folic A;id-*
900 mg/r.Ferrous Gluo.-o/
40mgl/d. Prednisone- ////*SOn300mg/d. Pyridoxin0-./
Z00mg q 3 d. Testosfkrone- /May |April-May |May April-June, Aug.Sept OtNOv.DPC Jan.Feb.Mar.Apr May June July Aug.19(2 1964 1965 1966 1967
Figure 5
Clinical course.
to the bone marrow. Nevertheless, this irontherapy did not result in compensation of theanemia. Folic acid, prednisone, and pyridoxinewere of no obvious benefit. Testosterone was
not successful in stimulating erythropoiesis inthe already hyperplastic bone marrow. An ac-
centuation of hemolysis associated with physicalactivity was documented by an increase in the
level of plasma heme pigments. The hemolyticanemia was progressively severe and was only
partially responsive to conservative measures.
The patient's activities were increasingly re-
stricted because of the brisk hemolysis.
In February 1967, physical findings included
marked pallor and a grade II!VI systolic murmur
at the base of the heart. The liver and spleen were
not enlarged by physical examination or roent-
genography. Brachial artery pressure tracings sug-gested moderate aortic valvular stenosis. There
was no valvular insufficiency by aortography (fig.6). A homograft aortic valve was inserted inJune 1967 by Dr. John W. Kirklin in Birmingham,Alabama. At operation, the Starr-Edwards ball Figure 6
was found to be "extremely enlarged and almost Aortogram.Circulation, Volume XXXVIII. September 1968
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Figure 8Ball component of patient's prosthesis.
Figure 7
Starr-Edwards prosthesis. (Top) New prosthesis. (Bot-tom) Patient's prosthesis.
immobile within the cage" creating an outflowobstruction (fig. 7). The postoperative course was
uneventful. A grade II/VI systolic murmur, heardat the base has persisted but is considered to haveno hemodynamic sifinificance.21 The patient was
discharged without any medications.Examination of the ball by Edwards Labora-
tories, Inc., manufacturer of the valve, revealedthat it was yellow-white with several deep strutmarks and shallow abrasions (fig. 8). The ballweighed 4.066 g, an increase of 20.2% over theoriginal weight of 3.384 g. There was a 3.7 to8.7% increase in the overall dimensions of theball. The degree of hardness was unchanged.Analysis of a chloroform methanol extract ofthe ball indicated that there was approximately54 mg of cholesterol (total) on the ball. Thinlayer chromatography of the cholesterol assay
mixture revealed cholesterol and cholesterol
esters, triglycerides, free fatty acids, and phos-pholipids (no quantitative data). Silicic acidcolumn chromatography and thin layer chroma-tography of the residue of the chloroform-meth-anol extraction revealed these same materials pluscardiolipin. Streaking was noted in the area oflecithin and lysolecithin, but they were not posi-tively identified.
Examination of the patient 2 months afterinsertion of the homograft showed he had asystolic murmur at the base transmitted to theneck and apex and a faint early diastolic mur-mur in the same area. The hemoglobin concen-tration was 14 g%, reticulocyte count was 0.9%,and red cell fragments had disappeared fromthe peripheral blood. The serum bilirubin was0.3 mg% total and 0.1 mg% direct. Serum ironwas 55 ,g% with a total iron-binding capacity of168 ,tg%. The concentration of serum glutamic-oxalacetic transaminase was 48 units and that ofcholesterol was 176 mg%. Urine tests for hemo-siderin were positive. This finding was inter-preted as spillage of residual renal tubular irondeposits22 since serum haptoglobin levels werenormal. The urine hemosiderin tests remainedpositive for 9 months following insertion of thehomograft valve. The patient's 5tCr-tagged eryth-rocyte survival was normal with a half-life of24 days.
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DiscussionThe patient described developed severe
hemolytic anemia as a result of enlargementof the silastic ball component of a Starr-Edwards valve. The development of stenosiswas suspected and documented prior to re-operation. The patient's activities were in-creasingly limited because of the severity andprogressive nature of the hemolytic anemia.Because of this the Starr-Edwards prosthesiswas replaced by a homograft valve.Cases of enlargement of the ball have been
reported in the literature, but the nature ofthe enlargement has not been described.These have been associated with cardiacdecompensation due to severe outflow ob-struction.12 13,18-26 The anemia associatedwith the enlarged ball has not previouslybeen characterized. The anemia in this pa-tient was the result of extracorpuscular mech-anisms of erythrocyte destruction related toan enlarged, roughened ball which obstructedoutflow across the Starr-Edwards prosthesis.The mechanism of erythrocyte destruction
is unclear. Patients with prosthetic valves orpatch prostheses generally have a mild com-pensated hemolytic anemia unless the valvesare grossly malfunctioning. Several theorieshave been advanced to explain the mech-anism of hemolysis, including: trapping ofcells between the rigid case and ball,27trauma to the red cells as they collide withTeflon,28, 29 autoimmunity,30 cell collision withDacron cloth valves,31 and turbulent bloodflow.32' 33 Turbulent blood flow has beenpresent in all cases of severe hemolysis as-sociated with prosthetic valves. Regurgitationwas present in most. In the present case,despite an absence of regurgitation, severehemolytic anemia was observed in associationwith a progressive increase in the size ofthe ball component of the valve. Since thiscreated an obstruction to outflow, it is reason-able to expect an increase in turbulence.Also, the roughened surface of the ball mayhave accentuated the turbulence, or perhapscontributed to the destruction of erythrocytesstriking its surface. The presence of numer-ous fragmented erythrocytes in the periph-Circulation, Volume XXXVIII, September 1968
eral smear, the elevated plasma heme pigmentlevels, and the persistent hemosiderinuriaclearly pointed to intravascular hemolysis.Chemically induced hemolysis was unlikelysince the materials used in the Starr-Edwardsvalve are inert substances and incubation ofred cells with these materials does not resultin hemolysis.32 Many intrinsic and some ex-trinsic erythrocytic abnormalities leading tohemolysis20 were searched for in this patientbut were not detected. The slightly positiveindirect Coombs' test was due to an anti-Kjell antibody and was most probably relatedto multiple transfusions. Ferrokinetic studiesrevealed rapid plasma clearance and rapidreappearance of iron in circulating erythro-cytes. The percentage of iron-59 incorporatedinto erythrocytes was less than expected.This was falsely low because of the briskrandom hemolysis of tagged and untaggedcirculating erythrocytes. The early 59Fe peakreappearance in circulating erythrocytes, plusthe normoblastic hyperplasia of the marrowand the reticulocytosis indicated that themarrow was responding, but was not fullyeffective in compensating for the intensedestruction of erythrocytes. The anemia failedto respond to a variety of drugs, singly orin combination. Exercise intensified theanemia. In contrast, may patients with hemo-lytic anemia, associated with prostheticvalves, have been compensated by adminis-tration of iron 6, 22, 34,35 or by iron and areduction in physical activity.36The mechanism of ball enlargement is un-
clear but appears to be related, in part, tocholesterol and lipid deposition on the ball.It is of interest that our patient's cholesterollevel prior to his initial valve replacementwas 328 mg%. It would be important to knowwhether hypercholesterolemia or hyperlipide-mia is an additional hazard to patients withthe Starr-Edwards type of prosthesis usinga silastic ball.
Several months after insertion of a homo-graft valve, the patient is active and hasnormal blood parameters except for a choles-terol level of 284 mg%. His cardiac functionhad improved to the point that he was able
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to participate in a 9-day deer hunting ex-pedition.
Barratt-Boyes, Kirklin, Nelson, and theirassociates have reported that a homograftvalve has little or no obstruction to flow andno need for chronic anticoagulation.21' 37,38Our studies of 5'Cr-tagged erythrocytes withnormal serum haptoglobin levels indicatethere is minimal or no destruction of erythro-cytes with the homograft valve. Only the mat-ter of durability is still in doubt.
AcknowledgmentsWe are indebted to Dr. S. Koorajian, Edwards
Laboratories, Inc., Santa Ana, California, for thelipid analysis of the ball component of the Starr-Edwards valve; to Dr. William Krivit, Professor ofPediatrics, Department of Pediatrics, University ofMinnesota School of Medicine, for the red cell mem-brane and plasma lipid analyses; to Dr. RalphAnderson, Superior, Wisconsin, for referring the pa-tient to us for our evaluation and care; to Donna H.Ripley, Specialist Hematologist, Special HematologyLaboratory, and Marija B. Feders, Research Tech-nologist, Minneapolis Veterans Administration Hos-pital.
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SAKO and WILLIAM R. SWAIMMARIO C. GARCIA, ALBERT M. CLARYSSE, CARL S. ALEXANDER, YOSHIO
Aortic ProsthesisHemolytic Anemia Due to Progressive Enlargement of Silastic Ball Component of
Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1968 American Heart Association, Inc. All rights reserved.
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