Schistocytes: A Brief Overview

Amanda G. Cox, BS; Bruce E. LeRoy, DVM, PhD; Paula M. Krimer, DVM, PhD; Perry J. Bain, DVM, PhD; and Kenneth S. Latimer, DVM, PhD

Class of 2003 (Cox) and Department of Pathology (LeRoy, Krimer, Bain, Latimer), College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

There are many different spellings for this distinct poikilocyte, including schistocyte, schizocyte, and shizocyte. Schistocyte is derived from the Greek word "schistos" meaning "divided, divisible, or split." The term schizocyte comes from the Greek word "schizein" meaning "cut, cleave, or split."¹ From the etymology of these terms, it can be concluded that a schistocyte is a fragmented erythrocyte. A schistocyte is defined as an irregularly shaped erythrocyte fragment caused by mechanical trauma or an intrinsic abnormality of erythrocytes.^1,2 Morphologically, it is jagged and asymmetrical with sharp pointed projections (Figs. 1 and 2).² Schistocytes are often seen in conjunction with other poikilocytes such as acanthocytes, keratocytes, spherocytes, and echinocytes.^2,3,4 This occurs because some of these latter cells also are associated with fragmentation of erythrocytes.

Figure 1. Schistocytes (arrows) in the blood of a dog with splenic hemangiosarcoma and disseminated intravascular coagulation (Wright-Leishman stain).

Figure 2. Scanning electron micrograph of a normal biconcave erythrocyte (from Bessis M: Blood Smears Reinterpreted, Springer-Verlag, 1977, p. 95).

Pathophysiology of Schistocyte Formation

There are only a few mechanisms by which erythrocytes become fragmented. The primary mechanism is via shearing of erythrocytes by fibrin strands (Fig. 3). This occurs when erythrocytes rapidly pass through microvasculature that is lined or meshed with fibrin strands.^5,6,7 An in vitro study by Bull & Kuhn documented the formation of schistocytes as they passed through fine fibrin strands using a scanning electron microscope.⁵ Endothelial lesions result in platelet aggregation, which subsequently leads to thrombosis and fragmentation of red blood cells.^8,9 Diseases that are characterized by turbulent blood flow also form schistocytes.^2,6 Intrinsic abnormalities that cause schistocytes include oxidative damage,² severe iron-deficiency,² chronic doxorubicin toxicosis,¹⁰ and pyruvate kinase deficiency in dogs.^4,6

Figure 3. Schematic diagram of the formation of schistocytes following bisection by fibrin strands (from Bessis M: Blood Smears Reinterpreted, Springer-Verlag, 1977, p. 92).

Diseases Associated with Schistocytes in Domestic Animals

Intuitively, schistocytes can be formed in any disease in which the above mechanisms are present. Thus, the list of diseases is extensive. Schistocytes have been characterized in many human diseases. Some of these include disseminated intravascular coagulation (DIC), microangiopathic hemolytic anemia (MAHA), severe burns, and heart valve prosthesis.¹ It has been characterized in dogs with DIC,^1-3,6,13-15 MAHA,^1,6,7,9,14 heart failure,^1,2,6,13 glomerulonephritis,^1,6,13 myelofibrosis,^1,6,11-13 hemangiosarcoma,^{1,2,7,13,14,16} chronic doxorubicin toxicosis,^1,10,13 and hypersplenism.^1,13 The table below lists just some of the diseases in which schistocytes are found.

Schistocytes: Mechanisms & Diseases

Microangiopathic hemolytic anemia: Microangiopathic hemolysis (MAH) can be viewed as a general term under which many diseases can be placed. Microangiopathic hemolytic anemia is a syndrome characterized by abnormal microvasculature from damage to endothelium or intravascular fibrin deposits.¹⁴ DIC, hemangiosarcoma,¹⁴ and hemolytic uremic syndrome are just some examples of diseases where this syndrome is present. In one study of dogs with hemolytic uremic syndrome, MAH was defined as the presence of schistocytes.⁹ Another study found that the amount of red blood cell fragmentation closely correlated to the severity of the microangiopathic hemolysis.⁵ The same researchers found that experimentally induced intravascular coagulation produces fragmented red blood cells and MAH.⁵

Disseminated intravascular coagulation: DIC is characterized by extensive intravascular thrombosis of the microvasculacture.¹ Schistocytes have been labeled as the "hallmark" of erythrocyte fragmentation due to DIC.¹ This is somewhat controversial within the research community. In one study, the number of schistocytes was not a specific diagnostic criterion for DIC, especially since schistocytes are formed in many other diseases.³ Another study found that 71% of the patients with DIC had schistocytes in blood smears;¹⁵ however, the fibrin deposition that occurs in DIC can also create other poikilocytes such as spherocytes and keratocytes.³ Therefore, the presence of schistocytes is not pathognomic for DIC.

Schistocytes are rarely seen in cats and horses with DIC, since their erythrocytes are smaller in size than those of dogs. This enables the red blood cell to squeeze through microvasculature that is laden with fibrin strands without becoming fragmented.⁶

Hemangiosarcoma: Hemangiosarcoma (HSA) is another common disease associated with the presence of schistocytes (Figure 1). As mentioned above, HSA often results in microangiopathic hemolytic anemia. The presence of schistocytes is a result of MAH as well as turbulent blood flow.² Studies revealed that 46% to 80% of dogs with HSA had schistocytes on blood smears.^7,16 In patients with splenomegaly, the presence of schistocytes and other poikilocytes can be used as predictors of splenic neoplasia.¹⁷

Chronic doxorubicin toxicosis: Doxorubicin is an anthracycline antibiotic that also has excellent activity against human neoplasms.¹⁰ It is especially used in the treatment of soft tissue sarcomas, breast cancer, and acute leukemias. However, doxorubicin is cardiotoxic. A study was performed to determine the incidence of poikilocytosis with chronic doxorubicin administration. The information was used as to way to monitor drug toxicity. Schistocytes were one of the poikilocytes used to monitor toxicity. Doxorubicin may cause poikilocytosis via several proposed mechanisms such as intracellular electrolyte imbalances, ATPase dysfunction, and abnormal lipid metabolism with membrane peroxidation.¹⁰

Conclusion

Schistocytes are fragmented red blood cells that can be formed in several ways. Schistocytes are often suggestive of a microvascular disturbance, but also occur when there is turbulent blood flow or intrinsic erythrocyte abnormalities. There are many different diseases in humans and domestic animal that cause microangiopathies and schistocytes. Schistocytes are not pathognomonic for a specific disease, but do alert the clinician to a number of diseases and conditions associated with this alteration in erythrocyte morphology.

References

1. Jain NC. Essentials of Veterinary Hematology. Lea & Febiger:Philadelphia, 1993 p 147-153.

2. Cowell RL, Tyler RD, Meinkoth JH. Diagnostic Cytology and Hematology of the Dog and Cat, 2^nd edition. Mosby:St. Louis, 1999 p 267-268.

3. Bateman SW, Mathews KA, Abrams-Ogg AC, Lumsden JH, Johnstone IB, Hillers TK. Evaluation of point-of-care tests for diagnosis of disseminated intravascular coagulation in dogs admitted to an intensive care unit. J Am Vet Med Assoc. 1999 Sep 15;215(6):805-810.

4. Schaer M, Harvey JW, Calderwood-Mays M, et al. Pyruvate Kinase deficiency causing hemolytic anemia with secondary hemochromatosis in a cairn terrier. J Am Anim Hosp Assoc 1992;28:233-239.

5. Bull BS, Kuhn IN. The production of schistocytes by fibrin strands (a scanning electron microscope study). Blood 1970 Jan;35(1):104-111.

6. Harvey JW. Atlas of Veterinary Hematology. WB Saunders:Philadelphia, 2001 p32.

7. Hammer AS, Couto CG, Swardson C, Getzy D. Hemostatic abnormalities in dogs with hemangiosarcoma. J Vet Intern Med. 1991 Jan-Feb;5(1):11-14.

8. Rebar AH, Lewis HB, DeNicola DB, et al. Red cell fragmentation in the dog: an editorial review. Vet Path 1981;18:415-426.

9. Holloway S, Senior D, Roth L, Tisher CC. Hemolytic uremic syndrome in dogs. J Vet Intern Med. 1993 Jul-Aug;7(4):220-227.

10. Badylak SF, Van Vleet JF, Herman EH, Ferrans VJ, Myers CE. Poikilocytosis in dogs with chronic doxorubicin toxicosis. Am J Vet Res. 1985 Feb;46(2):505-508.

11. English RV, Breitschwerdt EB, Grindem CB, et al. Zollinger-Ellision syndrome and myelofibrosis in a dog. J Am Vet Med Assoc 1988 May 15;192 (10):1430-1434.

12. Weiss DJ, Armstrong PH. Secondary myelofibrosis in 3 dogs. J Am Vet Med Assoc 1985;187:423-425.

13. Feldman BF, Zinkl JG, Jain NC. Schalm’s Veterinary Hematology, 5^th edition. Lippincott Williams & Wilkins:Philadelphia, 2000 p 147, 201.

14. Couto CG, Hematologic abnormalities in small animal cancer patients. Part 1: Red blood cell abnormalities. Comp Cont Educ 1984;12:1059-1065.

15. Feldman BF, Madewell BR, O’neill S. Disseminated intravascular coagulation: antithrombin, plasminogen, and coaguation abnormalities in 41 dogs. J Am Vet Med Assoc 1981;179:151-154.

16. Rebar AH, Hahn FF, Halliwell WH, et al. Microangiopathic hemolytic anemia associated with radiation induced hemangiosarcoma. Vet Pathol 1980;17:443-454.

17. Johnson KA, Powers BE, Withrow SJ, et al. Splenomegaly in dogs: predictors of neoplasia and survival after splenectomy. J Vet Intern Med 1989;3:160-166.

Acknowledgement

"Dog Daze" © by Sharon Hudson is from the Miscellany Gallery of her website and is used with permission of the artist.

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