Thrombotic thrombocytopenic purpura in human immunodeficiency (HIV)-seropositive males

American Journal of Hematology 27:212-215 (1988)

Thrombotic Thrombocytopenic Purpura in Human lmmunodeficiency (HIV)-Seropositive Males Barry R. Meisenberg, Warren L. Robinson, Coleman A. Mosley, Mark S. Duke, Gary M. Rabetoy, and Michael P. Kosty Departments of Internal Medicine (HematologylOncology [B.R.M., W.L.R., M.P.K.] and Nephrology Divisions [C.A.M., M.S.D., G.M.R.]). and Clinical Investigation, Naval Hospital, San Diego, California

Two male patients with thrombotic thrombocytopenic purpura (TTP) were found to have antibodies to the human immunodeficiency virus (HIV). In one patient, platelet-associated antibody levels were measured serially and were found to be initially elevated, but the levels decreased with lnltlation of successful therapy. The simultaneous occurrence of these two conditions in two of three patients admitted for TTP within the previous 2 years at this institution suggests an association between the two diseases. The precise nature of this association remains speculative inasmuch as the pathogenesis of TTP remains uncertain. Key words: thrombocytopenia, platelet associated antibodies

INTRODUCTION

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of unknown cause characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure, fluctuating neurologic abnormalities, and fever [ 11. Although most cases are idiopathic, specific infectious agents have rarely been reported in association with the syndrome [l]. We report two young male patients with TTP who had antibodies to the human immunodeficiency virus (HIV) but lacked other evidence of the acquired immunodeficiency syndrome (AIDS). Both patients denied recognized risk factors for HIV infection. CASE 1

A 25-year-old male was hospitalized complaining of weakness, nausea, vomiting, and jaundice of 2 days' duration. The vital signs were blood pressure 135/75, pulse 80, and temperature 37.l"C. The physical exam and the neurologic exam were remarkable only for pallor. Laboratory evaluation showed a hemoglobin of 8.3 g/dl, hematocrit 23 % , platelets 10,000/mm3,reticulocyte count 4.0% (2.0% corrected), white blood cell (WBC) count 6, 2oO/mm3 with a normal differential, creatinine 2.4 mg/dl, blood urea nitrogen (BUN) 48 mg/dl, lactate dehydrogenase (LDH) 945 U/L (normal 60-220), and total bilirubin 2.9 mg/dl; urinalysis was unremarkable.

0 1988 Alan R. Liss, Inc.

The peripheral smear revealed microangiopathic changes consisting of spherocytes, schistocytes, and nucleated red blood cells. A gingival biopsy showed bland capillary microthrombi. The patient was begun on a course of daily plasmapheresis and obtained a complete remission characterized by normalization of platelet counts and LDH levels after four treatments. Because of a history of multiple sexually transmitted diseases, an HIV antibody test was done and found to be positive by the ELISA and Western blot procedures. The T4/T8 lymphocyte ratio was 0.9. He has been followed for 5 months and has not had any recurrence of TTP or manifestation of AIDS. He did develop transient isolated thrombocytopenia and had a peripheral blood smear and bone marrow examination consistent with immune thrombocytopenia (ITP).

Received for publication April 20, 1987; accepted August 13, 1987. Address reprint requests to LCDR B.R. Meisenberg, MC. USNR. c/o Clinical Investigation Department, Naval Hospital, San Diego, CA 92134-5000. The opinions or assertions expressed herein are those of the authors and are not to be construed as official or as reflecting the views of the Navy Department or the naval service at large.

Case Report: TTP in HIV-Positive Males

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Fig. 1. Response of platelet count and platelet-associated mapheresis induced a rapid response in both LDH and IgG to initiation of therapy in case 2. Initial therapy with platelets. Vfncristlne therapy was required to sustain the plasma Infusion and prednisone was unsuccessful. Plas- response.

CASE 2

A 31-year-old male was admitted to the hospital with hemolytic anemia, progressive renal failure, and thrombocytopenia. One year prior to the current admission the patient developed nephrotic syndrome. Renal biopsy at that time demonstrated advanced stages of focal glomerulosclerosis (FGS). Serologic findings at that time including VDRL, antinuclear antibody, rheumatoid factor, hepatitis B surface antibody and antigen, complement levels, and antistreptococcal antibodies were negative or normal. At the latest admission the vital signs were blood pressure 112/96, pulse 84/min, and temperature 37.0"C. Physical examination was remarkable only for mild splenomegaly . Laboratory evaluation revealed WBC count 9, 1W/mm3 with normal differential, hemoglobin 10.6 g/ dl, hematocrit 30.5%, reticulocyte count 4.5% (2.9% corrected), platelets 54,000/mm3, creatinine 4.8 mg/dl, BUN 51 mg/dl, and LDH 600 U/L. Urinalysis demonstrated 10-12 red blood cells, 4-5 white blood cells/hpf, and 3 + proteinuria on dipstick. The peripheral blood smear confirmed the low platelet count and revealed numerous schistocytes and nucleated red blood cells. Because of the history of FGS, a renal lesion that has

been frequently noted in association with HIV infection [2], an HIV antibody test was done and found to be positive by the ELISA method and confirmed by the Western blot technique. The T4/T8 ratio was 0.38 with a total lymphocyte count of 1,759/mm3 (normal 1,OOO4,oOo/mm3). The patient's hospital course was marked by a transient episode of expressive aphasia and right hemiparesis (Fig. 1). A computed tomography scan of the head was negative. Initial therapy with prednisone and plasma infusion was unsuccessful. Daily plasmapheresis was instituted simultaneously with aspirin 325 mg daily and persantine 75 mg three times daily. After 7 days the platelet count had increased to 139,000/mm3 and the LDH decreased to 239 U/L. The patient relapsed within 48 hr of stopping therapy and intensive plasmapheresis was resumed. Subsequently, vincristine 1.5 mg was given intravenously every 5 days for four doses and plasmapheresis utilized for an additional 2 weeks. Platelet-associated antibodies were measured serially (Fig. 1) according to the McMillan technique [3] and found to be elevated at the time of therapy initiation. With effective treatment, platelet antibody level decreased preceding the changes in the platelet count and LDH value. The hematologic remission has lasted 30 weeks, though chronic renal failure

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requiring hemodialysis ensued. No other manifestation destruction. It is not certain whether this antibody represents an adherent immune complex or an antibody diof TTP or AIDS has developed. rected against a platelet membrane antigen. Circulating immune complexes were not assayed in this patient, but in other studies the results were variable [6,10]. In one reported case, the immune complexes were identified as DISCUSSION being directed against an unspecified platelet antigen [101. Previous reviews of TTP emphasized the importance The precise role of platelet-associated antibody in TTP of aggressive therapy as was required in these cases. remains controversial; it has been variably reported as Plasma infusions or pheresis are generally recommended elevated [6,9,11] or normal [12]. To our knowledge this as initial management, although other modalities may be is only the second report [6] in which the antibody level required [l]. Our two patients demonstrate the wide was serially measured. The decrease in antibody level spectrum of clinical response to this therapy. The first with the initiation of successful therapy of TTP in both patient had an unremarkable course, while the second papers suggests that the antibody may play a role in the patient followed a refractory course and required vincris- destruction of platelets. Additional studies should be done tine to achieve a lasting remission. Unfortunately no to confirm this finding. We suggest that other manifestations of TTP be sought clinical or laboratory parameters can predict which pawhen patients with known or potential HIV infection tients will prove refractory. HIV infection has not previously been reported in as- present with thrombocytopenia. Optimal management of sociation with TTP, though a strong link has been estab- these patients relies upon distinguishing between TTP lished between HIV and ITP [4]. In addition, a case of and other causes of thrombocytopenia. Further identifihemolytic-uremic syndrome, a closely related disorder, cation and study of similar patients may result in continhas been described in a patient with AIDS [5]. While it ued advancement in our understanding of the pathogenesis is conceivable that these two conditions coincided in of this interesting and complex disorder. these two patients purely by chance, we suspect some sort of etiologic association. These two cases represented two of the three patients with TTP seen at this hospital REFERENCES within the last 2 years. As with other infectious agents I . Byrnes JJ, Moake JL: Thrombotic thrombocytopenic purpura and linked to TTP, the treatment remains empiric and the haemolytic-uremic syndrome: Evolving concepts of pathogenesis and therapy. Clin Haemotol 15:413442, 1986. pathogenesis uncertain. However, existing knowledge on the pathogenesis of TTP allows speculation of how HIV 2. Rao TKS, Filippone El, Nicastri AD, Landesman SH, Frank E, Chen CK, Friedman EA: Associated focal and segmental glomeinfection might be related. rulosclerosis in the acquired immunodeficiency syndrome. N TTP often occurs in states of altered immunity or high Engl J Med 310~669-673. 1984. antigenic challenge such as pregnancy and infection [ 1,6]. 3. McMillan R, Longmire RL, Yelenosky R, Donnell RL, Armstrong S: Quantitation of platelet-binding IgG produced in vitro Persistent HIV infection or antibody positivity may repby spleens from patients with idiopathic thrombocytopenia. N resent just such an ongoing antigenic challenge that in Engl J Med 291:812-817, 1974. these cases favors the development of TTP. 4. Abrams DI, Kiprov DD, Goedert JJ, Sarngadharan MG, Gallo Recent theories of TTP pathogenesis have been adRC, Volberding PA: Antibodies to human T-lymphotrophic virus vanced by the finding that normal plasma contains a type In and development of acquired immunodeficiency syndrome in homosexual men presenting with immune thrombocysubstance which inhibits a platelet aggregating factor topenia. Ann Intern Med 104:47-50, 1986. present in the plasma of TTP patients [7]. This protective 5. Boccia RV, Gelman EP, Baker CC, Marti G, Longo DL: A substance was isolated and found to be contained in the hemolytic-uremic syndrome with the acquired immunodeficiency IgG fraction of plasma [7]. From this data it has been syndrome. Ann Intern Med 101:716,717, 1984. postulated that the deficiency in the plasma of TTP pa- 6. Sims PJ, Boswell EB: Elevated platelet-bound IgG associated with an episode of thrombotic thrombocytopenic purpura. Blood tients results from subtle defects in the cellular or hu57~682-684,1981. moral immune system, possibly as a consequence of Lian ECY, Mui PTK, Siddiqui FA, Chiu AY, Chiu LL: Inhibition circulating immunogens from infectious agents or pro- 7. of platelet aggregating activity in thrombotic thrombocytopenic cesses [8]. Within this theoretical framework, HIV infecpurpura plasma by normal adult immunoglobulin G . J Clin Invest tion with its welldescribed immune defects and its 73:548-555, 1984. persistent circulating antibody might create a favorable 8. Aster RH: Plasma therapy for thrombotic thrombocytopenic purpura-sometimes it works but why? N Engl J Med 312:985-987, environment for the development of TTP. 1985. The elevated platelet-associated antibodies in our sec- 9. Morrison J , McMillan R: Elevated platelet-associated IgG in ond patient combined with the similar findings in other thrombotic t h r o m ~ y t o p e n i c JAMA 238:1944-1945, reports [6,9] suggest an immunologic role in the platelet 1977.

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10. Meister RJ, Sacher RA, Phillips T: Lmmune complexes in thromdiagnosis of idiopathic thrombocytopenic purpura. Blood 60:1050-1053, 1982. botic thrombocytopenic purpura. (letter) Ann Intern Med 90:717, 12. Court WS, Bozeman JM. Soong S , Saleh MN, Shaw DR. Lo1979. Buglio AF: Platelet surface-bound IgG in patients with immune 11. Kelton JG, Powers PJ, Carter CJ: A prospective study of the and non-immune thrombocytopenia. Blood 69:278-283, 1987. usefulness of the measurement of platelet-associated IgG for the