Williams Hematology


Etiology and Pathogenesis
Clinical Features
Laboratory Features
Differential Diagnosis
Therapy, Course, and Prognosis
Chapter References

The abrasive effect on red cells of arteriosclerotic or stenotic cardiac valves is usually minimal, resulting at most in a mild, often compensated hemolytic anemia. However, the introduction of artificial valves was initially associated with marked red cell destruction and the development of an overt hemolytic anemia. Recently, the design of the artificial valves and the use of more compatible plastics or biologic materials have greatly reduced their traumatic effects and minimized hemolysis. Actually, the potential thrombogenic effect of artificial valves far outstrips their destructive effect on red cells, and cardiac hemolytic anemia is now an almost nonexistent problem.

In the 1950s cardiac corrective surgery became possible, and it was almost immediately observed that patients in whose aorta a Hufnagel valve was inserted developed anemia.1 This anemia was shown to be caused by mechanical injury and fragmentation of red cells impacted at high speed on a foreign surface.2,3 Since then the prevention of such injury has been a challenge in the construction of prosthetic valves and surfaces, and successful innovations have led to a decreased incidence of valve-related traumatic cardiac hemolytic anemia. Currently, hemolytic anemia is considered a minor complication in reviews of large series of patients4,5,6,7 and 8 and is mainly relegated to case reports of patients with old or dysfunctional prosthetic valves.9,10,11,12,13 and 14
In aqueous suspension the red cell membrane can withstand shear-producing stress of up to 15,000 dyne/cm2.15 Such a stress is rarely encountered in vivo, but determination of red cell survival, serum haptoglobin level, and serum lactic dehydrogenase concentration in patients with valvular disorders suggests that some hemolysis takes place. This hemolysis, however, is mild and rarely causes overt hemolytic anemia except in patients with severe aortic16 or subaortic17 stenosis generating pressure gradients across the valve of more than 50 torr.18 The abnormalities that have been found to produce hemolytic anemia are summarized in Table 50-1.


All prosthetic cardiac valves have an orifice size smaller than that of the natural valve, and after implantation this orifice is further reduced by tissue ingrowth and endothelialization.19 The Starr-Edwards cage ball valve has a slightly smaller aperture than the more commonly used tilting disc valve (Bjork-Shiley or St. Jude), but the hemodynamic differences between well-functioning prosthetic valves and natural valves are small. Several complications, however, may cause turbulence in the blood flowing around or through a prosthetic valve and expose the red cells to very high shear stresses. The blood may flow around the valve through openings created by improper positioning or by spontaneous separation of the valve from the annular ring.20,21 It may also flow through a constricted outlet in the Starr-Edwards model because of “ball variance,” in which the plastic ball takes up lipids, swells, and fails to move freely in the cage.22,23
Nevertheless, the turbulence and shear stresses encountered in patients with artificial valves are rarely much higher than those in patients with uncorrected aortic stenosis or mitral regurgitation. Consequently, the severe red cell destruction seen in some patients with artificial valves cannot be caused only by hemodynamic turbulence but requires that this turbulence occur in a space enclosed or bordered by a foreign surface. Studies of red cells in a cone-plate viscosimeter show that hemolysis occurs when shear forces at plastic interfaces exceed 2000 dyne/cm2 (Fig. 50-1).24 Such shear forces are encountered across artificial prosthetic devices that are coated with various plastic compounds or constructed of carbon or metallic material. These coatings are eventually covered by a layer of endothelial cells. Unfortunately, this covering is not firmly bonded to the materials, and if it is denuded, red cells in rapidly flowing blood will become damaged by contact with the artificial surface. This damage will result in mild, usually compensated anemia,25 but severe hemolytic anemia may occur.26 Of more clinical importance is the fact that nonendothelialized surfaces are thrombogenic and may cause platelet activation, thrombus formation, and distant embolization (see Chap. 130). In patients undergoing artificial heart transplantation, the hemolysis, although significant and requiring transfusion replacement, is overshadowed by complications from thrombosis and embolization.27,28 When blood is exposed to foreign surfaces under less turbulent conditions, as in an oxygenator,7 dialysis tubing,29 or endocardiac30 or aortofemoral prostheses,31 hemolysis may occur but is rarely pronounced. In such cases it has been proposed that the hemolysis is due in part to complement activation.32

FIGURE 50-1 (a) Normal human erythrocytes. (b) Human erythrocytes subjected to shearing stress of 2616 dyne/cm2. (c) Erythrocytes from a patient with a hemolytic anemia associated with a malfunctioning prosthetic aortic valve. Each blood film stained with Wright stain. (From Nevaril et al.24)

Largely to overcome these thromboembolic problems, nonthrombogenic bioprosthetic valves have been developed. These can be allographs, derived from human aortic leaflets, or xenographs (Carpenter-Edwards or Hancock’s), derived from porcine aortic leaflets.19 The valvular orifice is slightly smaller than in the ball or disc artificial valve, but overt hemolysis does not occur unless the stitching fails and permits perivalvular leakage.13,14 The valves usually have a potentially thrombogenic Teflon sewing ring, but since it becomes endothelialized within a few months, permanent anticoagulant therapy is not needed. Unfortunately, these valves are less durable than mechanical prosthetic valves and may need replacement 5 to 10 years after insertion.19 In order to limit the need for anticoagulation, bioprosthetic material has been preferred for valve replacement in the elderly, in whom long-term durability may be of lesser concern. In the future such considerations may be less important, since improved design appears to have rendered bioprosthetic valves as durable as mechanical valves.33
The severity of the anemia is highly variable in patients with heart valve prostheses. Mild compensated hemolysis is usually present, but overt anemia is unusual, and only in a rare individual will the anemia be severe enough to require transfusions. However, since patients with cardiac diseases generally have less capacity to adapt to an anemia, even a mild reduction in hemoglobin concentration may cause angina or congestive heart failure.
Even when the hemoglobin level is almost normal, the reticulocyte count is usually elevated, as is the serum lactic acid dehydrogenase activity. Blood films display helmet cells, triangular cells, and other fragmented red cell forms having characteristically sharp points.
The plasma hemoglobin level may be elevated, and the haptoglobin concentration may be diminished, resulting in hemosiderinuria,34 and occasionally there is a significant loss of iron in the urine, with reduced serum ferritin levels and, not uncommonly, with frank iron deficiency.35
The white cell count may be normal or slightly elevated. The platelet count may be decreased, suggesting intravascular consumption of platelets on the foreign surfaces.36
The diagnosis is usually straightforward and is based on the presence of fragmented red cells and evidence of chronic hemolysis in a patient with an artificial valve. The use of transesophageal electrocardiography may be useful in identifying paravalvular regurgitation.37 It is, of course, important to remember that even patients with artificial valves may have unrelated autoimmune or nutritional deficiency anemias.
If the anemia is sufficiently severe, the most effective treatment consists of replacement of the prosthesis. In most cases, however, the anemia is very mild or completely compensated, and it is merely necessary to ensure good erythropoietic activity in order to maintain this compensation. For that purpose it is recommended to replace urinary iron loss with 300 mg/day of ferrous sulfate orally. Folic acid, 1 mg/day, may also be beneficial. Recombinant erythropoietin has also been successful in alleviating the anemia in a few transfusion-dependent patients.38

Ross JC, Hufnagel CA, Fries ED, et al: The hemodynamic alterations produced by plastic valvular prosthesis for severe aortic insufficiency in man. J Clin Invest 33:891, 1954.

Sayed HM, Dacie JV, Handley DA, et al: Haemolytic anaemia of mechanical origin after open heart surgery. Thorax 16:356, 1961.

Marsh GW, Lewis SM: Cardiac haemolytic anaemia. Semin Hematol 6:133, 1969.

Starr A: Ball valve prostheses: a perspective after 22 years, in Advances in Cardiac Valves, edited by ME DeBakey, pp 1–13. Yorke Medical Books, New York, 1983.

DeBakey ME, Lawrie GM, Morris GC, et al: Experience with 366 St. Jude valve prostheses in 346 patients, in Advances in Cardiac Valves, edited by ME DeBakey, pp 14–21. Yorke Medical Books, New York, 1983.

Thompson ME, Lewis JH, Porkolab FL, Hasiba U, Spero JA: Indexes of intravascular hemolysis, quantification of coagulation factors and platelet survival in patients with porcine heterograft valves. Am J Cardiol 51:489, 1983.

Arom K: Aortic valve replacement: long-term results with various mechanical prostheses. Asian Cardiovasc Thorac J 1:39, 1993.

Aoyagi S, Oryoji A, Nishi Y, Tanaka K, Kosuga K, Oishi K: Long-term results of valve replacement with the St. Jude medical valve. J Thorac Cardiovasc Surg 108:1021, 1994.

Schaer DH, Cheng TO, Aaron BL: Hemolytic anemia and acute mitral regurgitation caused by a torn cusp of a porcine mitral prosthetic valve 7 years after its implantation. Am Heart J 113:404, 1987.

Kutsche LM, Alexander JA, VanMierop LH: Hemolytic anemia secondary to erosion of a Silastic band into the lumen of the pulmonary trunk. Am J Cardiol 55:1438, 1985.

Barmada H, Starr A: Clinical hemolysis with the St. Jude heart valve without paravalvular leak. Med Prog Technol 20:191, 1994.

Kihara S, Kasegawa H, Kobayashi N, et al: Severe hemolysis due to artificial chordae displacement. J Heart Valve Dis 6:69, 1997.

Amidon TM, Chou TM, Rankin JS, Ports TA: Mitral and aortic paravalvular leaks with hemolytic anemia. Am Heart J 125:266, 1993.

Formolo JM, Reyes P: Refractory hemolytic anemia secondary to perivalvular leak diagnosed by transesophageal echocardiography. J Clin Ultrasound 23:185, 1995.

Blackshear PL Jr, Dorman FD, Steinbach JH, Maybach EJ, Singh A, Collingham RE: Shear wall interaction and hemolysis. Trans Am Soc Artif Intern Organs 12:113, 1966.

Miller DS, Mengel CE, Kremer WB, et al: Intravascular hemolysis in a patient with valvular heart disease. Ann Intern Med 65:210, 1966.

Solanski DL, Sheikh MU: Fragmentation and hemolysis in idiopathic hypertrophic subaortic stenosis. South Med J 71:599, 1978.

Jacobson AJ, Rath CE, Perloff SK: Intravascular hemolysis and thombocytopenia in left ventricular outflow obstruction. Br Heart J 35:49, 1973.

Braunwald E: Artificial cardiac valves, in Heart Disease, 5th ed, edited by E Braunwald, pp 1061–1076. Saunders, Philadelphia, 1997.

Kastor JA, Akburian M, Buckley MJ: Paravalvular leaks and hemolytic anemia following Starr-Edwards aortic and mitral valves. J Thorac Cardiovasc Surg 56:279, 1968.

Viner ED, Frost W: Hemolytic anemia due to a Teflon aortic valve prosthesis. Ann Intern Med 63:295, 1965.

Eyster E: Traumatic hemolysis with hemoglobinuria due to ball variance. Blood 33:391, 1969.

Stohlman F Jr, Sarnoff SJ, Case RB, Ness AT: Hemolytic syndrome following the insertion of a Lucite ball valve prosthesis into the cardiovascular system. Circulation 13:586, 1956.

Nevaril CG, Lynch EC, Alfrey CP, Hellums JD: Erythrocyte damage and destruction induced by shearing stress. J Lab Clin Med 71:784, 1968.

Brodeur MTH, Sutherland DW, Koler RD, et al: Red blood cell survival in patients with aortic valvular disease and ball valve prostheses. Circulation 32:570, 1965.

Marsh GW: Intravascular haemolytic anemia after aortic-valve replacement. Lancet 2:986, 1964.

Kormos RL, Borovetz HS, Griffith BP, Huns TC: Rheologic abnormalities in patients with the Jarvik-7 total artificial heart. Trans Am Soc Artif Intern Organs 33:413, 1987.

DeVries WC: The permanent artificial heart: four case reports. JAMA 259:849, 1988.

Francos GC, Burke JF Jr, Besarab A, Baumer LH, Paek SU, Sebening F: An unsuspected cause of acute hemolysis during hemodialysis. Trans Am Soc Artif Intern Organs 29:140, 1983.

Sigler AT, Forman EN, Zinkham WH, Neill CA: Severe intravascular hemolysis following surgical repair of endocardial cushion defects. Am J Med 35:407, 1963.

Manny J, Manny N, Abu-Dallo K, et al: Traumatic hemolysis after aortofemoral bypass. Isr J Med Sci 13:50, 1977.

Salama A, Hugo P, Heinrich D, et al: Deposition of terminal C5b-9 complement complexes on erythrocytes and leukocytes during cardiopulmonary bypass. N Engl J Med 318:408, 1988.

Holper K, Wottke M, Lewe T, et al: Bioprosthetic and mechanical valves in the elderly: benefits and risks. Ann Thorac Surg 60:S443, 1995.

Slater SD, Rahman M, Lindsay RM: Renal function in chronic intravascular haemolysis associated with prosthetic cardiac valves. Clin Sci 44:511, 1973.

Heilman E, Bender F, Gulker H, Bonke J: Investigations of iron and folate levels in serum after implantation of heart valve prostheses. Herz 4:298, 1979.

Harker LA, Slichter SJ: Studies of platelet and fibrinogen kinetics in patients with prosthetic heart valves. N Engl J Med 283:1302, 1970.

Garcia MJ, Vandervoort P, Stewart WJ, et al: Mechanisms of hemolysis with mitral prosthetic regurgitation study using transesophageal echocardiography and fluid dynamic simulation. J Am Coll Cardiol 27:399, 1996.

Kornowski R, Schwartz D, Jaffe A, Pines A, Aderka D, Levy Y: Erythropoietin therapy obviates the need for recurrent tranfusions in a patient with severe hemolysis due to prosthetic valves. Chest 102:315, 1992.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



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