A 59-year-old male with spherocytosis, splenectomy and chest pain: Does he have an increased risk of thrombosis?A 59-year-old male with spherocytosis, splenectomy and chest pain: Does he have an increased risk of thrombosis?

Kam Newman, Junaid Mansuri, Salim Shackour, Shahriar DadkhahKam Newman, Junaid Mansuri, Salim Shackour, Shahriar Dadkhah

Department of Medicine, St Francis Hospital, Evanston, ILDepartment of Medicine, St Francis Hospital, Evanston, IL

Learning Objectives

Recognizing the increased risk of thrombosis inpatients with hereditary spherocytosis.

Understanding the pathophysiology of thrombosisin spherocytosis.

Conclusion

Hereditary spherocytosis (HS) is the most common of the hereditary hemolytic anemias in Northern Europeans with an incidence of 1 in 5000.

Patients with HS have an increased risk of thrombosis.

Splenectomy for HS increases the risk of stroke and myocardial infarction.

St Francis HospitalEvanston

Discussion

Hereditary spherocytosis (HS) is the most common of the hereditary hemolytic anemias in Northern Europeans with an

incidence of 1 in 5000 (1,2). Humans with heritable hemolytic anemias suffer from a number of pathologic complications including vaso-occlusion, thrombosis, and stroke. Thrombotic

events affect about 20% to 30% of patients with sickle cell disease and 5% to 10% of patients with -thalassemia (3,4). Disease severity in human HS is variable; most patients exhibit only mild to moderate anemia, mild jaundice and splenomegaly. Erythrocytes have a membrane defect that makes them more rigid, yet fragile and prone to premature destruction. The resultant loss of lipid asymmetry is associated with increased procoagulant activity. Nevertheless, both venous and arterial thrombosis, including stroke, have been documented in patients with HS (5-8). Mice with deficiencies in erythroid -spectrin have the highest incidences of thrombosis and stroke (62%-100% of adult mice). HS mice with -spectrin and ankyrin mutations have the lowest incidence (15% to 22%) (9-11). Pathophysiologies that contribute to hemostatic changes and could predispose to thrombosis include hyperbilirubinemia, hemosiderosis, and the increasing demand for erythroid cells since the neonate doubles in size daily. These pathologies may be preceded or accompanied by changes in blood viscosity, in serum levels of free iron and homocysteine, or in the "stickiness" of aberrant RBCs. All could exacerbate damage to the endothelial vasculature. Normal RBCs could reverse some of the adverse hemostatic changes or provide a hemostatic response missing in the untreated mutant mice (9,12,13).

Splenectomy for HS increases the risk of stroke and myocardial infarction. After splenectomy Hb rises to a higher concentration than found in non-affected family members. In the Framingham study, the incidence of stroke was 2 times higher in patients with “high” Hb compared with “not high” Hb. Also, after

splenectomy, the average PLT count remains above the normal average and in HS cholesterol concentrations rise after splenectomy (14).

References

1. Morton NE, MacKinney AA, Kosower N. Genetics of spherocytosis. Am J Hum Genet. 1962; 14: 170-184.2. Smedley JC, Bellingham AJ. Current problems in Hematology 2: Hereditary spherocytosis. J Clin Pathol.

1991; 44: 441-444.3. Tse WT, Lux SE. Red blood cell membrane disorders. Br J Haematol. 1999; 104: 2-13.4. Palek J. Hereditary elliptocytosis, spherocytosis and related disorders: consequences of a deficiency or a

mutation of membrane skeletal proteins. Blood Rev. 1987; 1: 147-168.5. Tokunaga Y, Ohga S, Suita S, Matsushima T, Hara T. Moyamoya syndrome with spherocytosis: effect of

splenectomy on strokes. Pediatr Neurol. 2001; 25: 75-77.6. Schilling RF. Spherocytosis, splenectomy, strokes, and heat attacks. Lancet. 1997; 350: 1677-1678.7. Hayag-Barin JE, Smith RE, Tucker FC Jr. Hereditary spherocytosis, thrombocytosis, and chronic pulmonary

emboli: a case report and review of the literature. Am J Hematol. 1998; 57: 82-84.8. Nikol S, Huehns TY, Kiefmann R, Hofling B. Excessive arterial thrombus in spherocytosis: a case report.

Angiology. 1997; 48: 743-748.9. Wandersee NJ, Roesch AN, Hamblen NR, et al. Defective spectrin integrity and neonatal thrombosis in the first

mouse model for severe hereditary elliptocytosis. Blood. 2001; 97: 543-550.10. Kaysser TM, Wandersee NJ, Bronson RT, Barker JE. Thrombosis and secondary hemochromatosis play major

roles in the pathogenesis of jaundiced and spherocytic mice, murine models for hereditary spherocytosis. Blood. 1997; 90:4610-4619

11. Wandersee NJ, Lee JC, Kaysser TM, Bronson RT, Barker JE. Hematopoietic cells from alpha-spectrin deficient mice are sufficient to induce thrombotic events in hematopoietically ablated recipients. Blood. 1998; 92:4856-4863.

12. Andrews DA, Low PS. Role of red cells in thrombosis. Curr Opin Hematol. 1999; 6:76-82.13. Hillery CA, Du MC, Montgomery RR, Scott JP. Increased adhesion of erythrocytes to components of the

extracellular matrix: isolation and characterization of a red blood cell lipid that binds thrombospondin and laminin. Blood. 1996; 87:4879-4886.

14. Schilling RF. Spherocytosis, splenectomy, strokes, and heat attacks.Lancet. 1997; 350: 1677-1678.

Acknowledgements

The authors wish to thank Dr. Gery Luger (Chairman, Department of Medicine), Dr. Margaret Yungbluth (Histopathologist), Sheryl Bloom (Administrative Director of Medical Education, Kathie Kafa (Coordinator of Internal Medicine Residency Program) for their support.

Splenectomy in a patient with HS shows splenomegaly.

Spherocytes on peripheral blood smear.

Defects in vertical stabilization* of the phospholipid bilayer of the RBC membrane cause separation of the spectrin-phospholipid bilayer.

Portions of the phospholipid bilayer form vesicles and are lost from the RBC surface resulting in decreased surface area and spherocytosis.

Mechanism

Case

A 59-year-old Caucasian male was admitted due to left-sided chest pain, which woke the patient up. It was not pleuritic or accompanied with dyspnea or palpitations. Past medical history included hereditary spherocytosis (post splenectomy), hypertension and hyperlipidemia. The patient’s brother had spherocytosis too and died due to pulmonary embolism. The patient’s EKG showed evidence of ischemia in the lateral wall. Cardiac enzymes were not elevated. His CBC showed Hb 13.2 g/dL, MCV 88 fL, PLT 337 k/mm3 and WBC 17.8 k/mm3. The patient had coronary angiography, which showed a 95% lesion in the mid circumflex artery, a 40% lesion in the proximal LAD and a 40% lesion in the ostial diagonal. He had PTCA and stent for the circumflex lesion. The course of hospitalization was uneventful. Before being discharged, the patient asked the medical team if he had an increased risk for blood clots.