Acta Clinica Belgica International Journal of Clinical and Laboratory Medicine
ISSN: 1784-3286 (Print) 2295-3337 (Online) Journal homepage: http://www.tandfonline.com/loi/yacb20
HIV-Related Thrombocytopenia D. Blockmans & J. Vermylen To cite this article: D. Blockmans & J. Vermylen (1992) HIV-Related Thrombocytopenia, Acta Clinica Belgica, 47:2, 117-123, DOI: 10.1080/17843286.1992.11718217 To link to this article: http://dx.doi.org/10.1080/17843286.1992.11718217
Published online: 16 May 2016.
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D. Blockmans, J. Vennylen*
SUMMARY HIV-related chronic ITP is caused by an accelerated platelet destruction due to adsorption of circulating immune complexes and to specific anti -platelet anti bodies, but perhaps also by a defective thrombopoiesis resulting from invasion of the megakaryocytes by the retrovirus. Treatmen\ is needed when platelet numbers drop beneath 20. 109 /Lor when severe bleeding symptoms occur. Steroids, commercially avai lable immunoglobulin s for IV use, AZT and anti -Rh immunoglobulins can be admini stered, although relapses are frequent after withdrawal of the drugs. Recurrences after splenectomy are far less common, butthe progression towards AIDS might be accelerated. Acta Clin Belg. 47, 2: 117-23 INTRODUCTION Schematically, five fonns of thrombocytopenia may occur during human immunodeficiency virus (HIV) infection. A transient, mild form of thombocytopenia is sometimes seen during the phase of primo-infection, which may be accompanied by a mononucleosis-like picture with haemophagocytosis, fever, diarrhea, glandular enlargement, sore throat, weight loss.
*Dienst Inwendige Geneeskunde Afdeling Bloedings- en Vaatziekten U.Z. Gasthuisberg, K.U. Leuven Herestraat 49, 3000 Leuven, Belgie Reprints: D. Blockmans
Thrombocytopenia may also occur as a sideeffect of medication: cotrimoxazole, which is often used for the treatment or prevencion of pneumocystis carinii pneumonia in HIV-positive patients, is well known as an inducer of thrombocytopenia. When thrombocytopenia is associated with anemia and/or granulocytopenia, as occurs in the late AIDS phase, prognosis usually is bad. In these circumstances, it is a manifestation of a very poor general condition, probably with intercurrent infections and/or development of malignant disease. The cumulative myelotoxicity of different drugs is also responsible. Bone marrow examination findings may be similar to those seen in the myelodysplastic syndrome. These dysplastic morphological changes have not .the same clinical implications as in HIV negative patients with respect to the later development of acute leukemia, which is rather rare (I). By 1990, fourteen cases of thrombotic thrombocytopenic purpura (TIP) in HIV positive persons had been described, of whom 8 homosexuals, 3 narcotic addicts and 3 promiscuous heterosexuals. In these patients, TIP might be induced by endothelial damage and spontaneous platelet aggregation caused by endotoxin and immune complexes, and, in the case offull-blown AIDS, by the impaired immune system, the neoplasias and the chemotherapy. Treatment consists of fresh frozen plasma, high dose garnmaglobulins, exchange plasma transfusions, immunopheresis using staphy lococcus Acta Clinica Be/gica 47.2 ( 1992)
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Protein A co lum ns, high doses of steroids, acetylsalicylic acid, dipyridamole and intravenous vincristin admin istration. Finally, the fifth form of th rombocytopenia closely resembles the class ic form of chronic idiopathic thrombocytopenic purpura (clTP), usually seen in otherwi se healthy young fe males. In 925 patients at ri sk for HIV di sease, Coste llo fo und a 13 % incidence of th ro mbocytopenia. T welve pe rcent of the patients were healthy HIV carriers (2). lt is on this fo rm ofthrombocytopeni a that this review article will foc us.
HISTORICAL REMARKS In Septe mber 198 1, the fi rs t report on 8 abnormally agg ressive cases of Kaposi's sarcoma in homosexual men was publi shed in the Lancet (3). Three months later, an outbreak of pneumocystis carinii pneumonia in previously healthy homosexual men was reported in the New England Journal of Medic ine (4, 5). Less than one year later, the g roup of Simon Karpatki n from New York described an unusually high frequency of a utoimmune thrombocy to peni c purpu ra in sexually acti ve ho mosex ual men (6). In I 983, 5 case reports of . ITP in hemophilia A patients receiving fac tor VIII concentrates were publ ished (7). The fi rst cases of thro mbocytopenic purpura in narcotic addicts were seen in November I 982 (8), again before the discovery of the HIV in 1983. Thi s ne wl y desc ribe d form of ITP in homosexuals, narcotic addicts and hemophilia A patients resembled the classic fo rm of ITP in many ways: the bone marrow showed an increased number o f megakaryocytes, thrombocytopeni a was caused by peripheral destruction of antibodyloaded platelets, there was no splenomegaly, the antinuclear factor was negati ve and patients responded as we ll to prednisone or splenectomy as did patients with classic cITP. Some differences how e ver indicated that a ne w kind of thrombocytopenia was involved. Firstly, the
Acta Clinica Be/gica 47.2 ( 1992)
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au thors were surprised by the reversed male/ female rati o, classic cITP be ing predominantly a di sorder of women. Secondly, the presence of circulating immune complexes (CIC) and a clearly increased amount of platelet-associated immunoglobulins (Paig) and complement fac tors C3C4 (PaC3C4) were noted . . F inally, the relati ve lymphopeni a, the reversed T4/T8 rati o and the hypergammaglobulinemi a all pointed towards an immune regul ation disorder with impaired cell -mediated immunity. After the discovery of the AIDS producing retrovirus in I 983, by then called the human-T-lymphocytotropic virus type III, it became apparent that chronic thrombocytopeni a was one of the manifestati ons of thi s virus, which later on became known world wide as HIV.
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PATHOGENESIS The clTP of HIV positi ve persons is caused by an increased peripheral destruction of platelets, although a fac tor of impaired production may be involved as well. Thi s accelerated peripheral platelet destruction could result from an increased concentration of CIC, from the development of specific antipl atelet antibodies and fro m di rect invas ion of megakaryocytes and platelets by the virus.
a. Increased concentration of CIC Karpatkin reported a 2.4 times higher amo unt of CIC in hemophiliacs with ITP, a 3.0 times higher concentration in homosexuals with ITP and even a 7.3 times higher concentration of C IC in narcotic addicts with ITP, compared to classic ITP. An increased amount of non-ether-elutable PaigG and PaC3C4 was noted as well in these 3 patient groups, when compared to class ic ITP patients (9). Ji Ren Yu et al. ( I 0) postulated that · these IC are composed of antibodies directed against the F(ab')2 portions of other antibodies, mostly directed against viral antigens (Epstein Barr virus, cytomegalovirus, herpes simplex virus or adenovirus) which themselves cannot be
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detected in these IC. HIV antibodies were also very consistently found in these IC and bound to the platelets, although no viral antigen could be detected, either in these CIC or bound to the platelets ( 11 ). It was postulated that anti -HIV antibodies complexed with anti-idiotypic anti bodies are at least partly responsible for the CIC and PaIG. Plate lets are then nothing more than innocent bystanders; following adsorption of these IC to the platelet membrane, the pl atelets are phagocytized by the cells of the reticuloendothe lia l system , throug h an interaction with macrophage Fe and C3b receptors.
compound in 72 % of HIV-related ITP patients. Karpatkin et al . (9) demonstrated 7S antiplatelet IgG in 9113 thrombocytopenic narcotics and in 61 6 thrombocytopen ic hemophiliacs but in none of the ir homosex ual ITP patients. They suggested that there might be a different pathogenesis among the different risk groups, the thrombocytopenia of homosex uals being medi ated through CIC,
b. Development ofspecific anti-platelet antibodies
Zucker- Franklin et al. ( 15) gave direct electronmicroscopic evidence that platelets can be invaded by the retrovirus. One can postulate that these platelets are preferably destroyed by the host's remaining immune mechanisms.
As in classic ITP, anti-platelet antibodies were found in HIV-related thrombocytopenia by a number of authors. Stricker et al. ( 12) could detect an antibody directed against a 25 kD platelet membrane antigen in the serum of 29 out of30 homosexual ITP patients. Thi s antigen was not present on other hematopoietic cells, but could be detected on skin fibroblasts and on herpes simplex viruses type 1 and 2, cultivated on a renal cell line from monkeys. The binding of this antibody occurred through its F(ab')2 part; there was no binding to Glanzmann thrombasthenia or Bernard-Soulier platelets. Stricker hypothezised that a cellular 25 kD protein is adsorbed to the herpes simplex virus and thereby becomes immunogenic. Antibodies formed after infection will cross-react with host cells, including platelets. Unfortunately, Stricker' s findings could not be confirmed by other investigators. Van der Lelie et al. ( 13) found PaigG, which could be eluted by ether, in 16116 AIDS patients (of whom 7 were thrombocytopenic), in 517 persons with the AIDS related complex (of whom 2 were thrombocytopenic) and in 7/10 healthy homosexuals (of whom 3 were seropositive and 2 were thrombocytopenic ). These antibodies were directed against an antigen related to glycoprotein lib/Ula, since they did not react with Glanzmann thrombasthenia platelets. Bettaiebet al. ( 14) found an auto-antibody directed against an intraplatelet
that in hemophiliacs through spec ific anti-platelet antibodi es, the thrombocytopenia of narcotic addicts being a mixture of both mechani sms.
c. Direct platelet invasion by HIV
Besides increased destruction of platelets, a disturbed platelet production might contribute to the thrombocytopenia of these HIV positive patients. A central mechani sm was suspected since the observations of Hymes ( 16) and Neil (17) who described correction of HIV associated cITP by zidovudine. The abundance of megakaryocytes in the bone marrow does not necessarily reflect a good platelet production, since platelet-shedding might be di sturbed in these circumstances, for example through the deposition of IC on megakaryocytes . Zucker-Franklin et al. afready described structural changes in the megakaryocytes of patients infected by HIV ( 18). In another study by the same authors, expression of HIV RNA inside the megakaryocytes was demonstrated ( 19). One year later, dir~ct invasion of viruses into the megakaryocytes was visualized ( 15). Expression of Fe receptors (20) and of the C4 receptor (21) by the megakaryocytes represents two different ways of HIV internalization. Emperipolesis is another potential mechanism. Occasionally, CD34+ cells could be directly infected by HIV (22). As has been proven for the stem cells of granulocytes and erythrocytes (23), the producActa Clinica Belgica 47.2 ( 1992)
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tion of hypothetical thrombopoietic inhibitors by the retroviru s might inhibit the growth or maturation of the megakaryocytic lineage.
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PROGNOSIS The cITP like picture can oc.cur during every stage of th e HIV infection: during the asymptomatic phase, during the ARC stadium or when full -blown AIDS has developed. Most authors agree that isolated thrombocytopenia is not an independent risk factor for a faster evolution towards AIDS, at least not in homosexual patients. Eyster et al. (24) however found a significantly worse prognosis among their 84 HIV positive hemophiliacs, when thrombocytopenia was present (p 0.02).
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platelet count does not react or if a maintenance dose higher than 15 mg/day is needed, they proceed to splenectomy. Using thi s scheme, Karpatkin et al. report on 35 successful treatments in 41 patients, followed however by 30 relapses after stopping prednisone treatment. Oksenhendler et al. (25) and Abrams et al. (26) obtain 15/ 26 and 19/24 fair responses with prednisone treatment; once again a stable platelet count is reached in only a minority of patients after withdrawing prednisone. There is no evidence that steroids might accelerate the evolution towards AIDS in HIV positive persons; the development of extensive oral candidiasis, the reactivation of latent herpes simplex virus infection or of chronic hepatitis may however occur.
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b. Splenectomy TREATMENT Spontaneous improvement or even di sappearance of thrombocytopenia have been described, although this happens in only a minority of the patients. Most authors agree that the best treatment for HIV-related thrombocytopenia is no treatment whenever possible, thi s means when the patient is asymptomatic' and when the platelet count is above 20.10 9/l. This abstinence is based on the side effects of most treatment modalities, which can be particularly severe in HIV positive immune-depleted patients. When made mandatory by bleeding complications or by a very low platelet number (with a high risk of intracerebral hemorrhage), a series of treatment possibilities are available which will be discussed here in some detail.
a. Steroids There is general agreement that the dose of steroids given schould be the lowest that increases the platelet count to more than 20.109/ I. Karpatkin et al. (9) give prednisone 30-40 mg/day for 1-2 weeks; thereafter prednisone is reduced to 10- I 5 mg/day for an additional IO months at most. If the Acta Clinica Belgica 47.2 ( 1992)
The results of splenectomy in HIV-related thrombocytopenia are consistently sati sfactory : success rates of 10/l 0 (27), 7/7 (28), 10/14 (25) and 10115 (26) have been reported . Relapses are much less frequent than with steroid s . Pneumococcal vaccination before and penicillin as a preventive .measure after splenectomy are necessary. Most authors do not find ev idence that splenectomy accelerates the progression towards AIDS in their patient groups. Barbui et al. (29) however, taking into account 4 different studies on a total of JOI patients of whom 36 underwent splenectomy, found a 4.1 fold increased ri sk of developing AIDS in the operated patients during the follow-up period. Therefore, splenectomy _ although highly effective - can only be advi sed when other strategies have failed . The surgical risk is higherthan in non-HIV related c-ITP (30). c. Intravenous immunoglobulins Commercially avai lable intravenous immunoglobulins, at a dose of0.4 g/kg/day during 5 days 'or 1 g/kg during l or 2 days, produce a fast but short-lasting rise in platelets in almost all HIV positive thrombocytopenic patients. They are useful when an acute rise in platelet number is needed, e.g. when intracranial hemorrhage occurs
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or when surgery is needed. Since their effect lasts only 7 to 10 days, since the patients' response to s ub sequ e nt infu s io ns o ft e n beco mes less pronounced and in view of the high costs of these preparations, intravenous imm unoglobulins are not suited for long-term treatment. Only 1/22 patients remained in re mission in the study of Bussel (3 1).
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recombinant alpha-2a interferon fora reacti vation of chro nic hepati tis B. Danazo l mos t often does not provoke a substantial platelet rise. Oksenhendler (25) reports a response in 2/ 18 patients. Vincri stin cannot be used conside ring the ri sk of additional immunosuppression.
d. Zidovudine (AZT, Retrovir) AZT, at a dose of 800- 1500 mg/day, produces a rise in pl atelet count from the 2nd-3 rd week of therapy onwards in the majority o f HIV positi ve thro mbocytopenic pati ents (1 6, 17, 32, 33). Thi s effect mi ght last after the withdrawal of the drug. ln the light of the studies of Zucker-Frankl in et al. ( 15, 19), an antiretroviral e ffect directed against HIV infected megakaryocytes is probabl e. The e ffectiveness of AZT in these circumstances has been confirmed by a prospective controlled crossover double-blind study in 10 HIV positi ve persons conducted by the Swiss Group fo r Clinical Studies on AIDS (34). Although AZT is not reimbursed for thi s indication in Belgium , AZT might become the treatment of choice fo r HIV related th ro mbocytopenia in the future, now that it is proved that lower less toxic doses o f AZT are equally effecti ve.
SA MENYATIING De chronische vorm van ITP bij HIV positieve patienten wordt enerzij ds veroorzaakt door een versnelde bloedplaatjesafb raak door afzetting van immuuncomplexen op de bloedplaatjesmembraan en door specifieke anti -b loedpl aatj esanti stoffen, en anderzijds mogelijks door een verstoorde thrombopoiese met in vasie van de megakaryocyten door het retrovirus. Een behandeling dringt zich op indien het bloedplaatjesaantal onder 20. 109/L daalt of wanneer er emstige bloedingsproblemen ontstaan. Qua medikatie heeft me n de keuze tu sse n stero id en, IV immuunglobulines, AZT en anti -Rhesus immuunglobulines; recidieven na stoppen van het geneesmiddel zijn echter frekwent. Het resultaat na splenectomie is daarentegen meer blijvend, alhoewel nog niet volledig kan uitgesloten worden dat na splenectomie de progressie naar AIDS niet zou versneld worden.
e. Miscellaneous Good results with anti-Rh (D) immunoglobulins ( 12-25 µ g/kg IV on 2 consecutive days) have been obtained by O ksenhendler et al. (35) in 4 of 7 Rhesus positi ve homosexual and 8 of I 0 narcotic addicts, with a mean duration of response of 16 and 2 1 days respectively. In Rhesus negative patients, anti-c lg seem to be effective. Du rand et al. (36) and Biniek et al. (37) were able to increase pl atelet counts in I multiresistent patient each; doses of 3000 µ g/day during 3 days were however needed. This therapy has a lower cost than intravenous immunoglobulins. Ellis et al. (38) observed a higher platelet number and a lesser need for intravenous immunoglobulins in a HIV positive patient during his treatment with
RESUME La forme chronique de thrombopenie liee aI' infection par le VIH resulte d'une destruction acceleree secondaire au depot de complexes immuns sur les plaquettes et d' une production d' anti corps antiplaquettaires specifiques, mais peut-etre aussi d' une thrombopoiesedeficiente par invasion des megakaryocytes par le retrovirus. Un traitement s'i mpose quand le nombre de plaquettes est inferieur a 20.109 IL OU quand un syndrome hemorragique grave s' installe. Le choix existe entre la cortisone, !es immunoglobulines intraveineuses, I' AZT et !es immunoglobulines anti-Rhesus, bien que !es recidives soient frequentes apres I' arret du traitement. Apres spMnectomie, le risque de rechute est plus faible; cependant une progressio'n plus rapide vers le SIDA n'est pas encore exclue. Acta Clinica Belgica 47.2 ( 1992)
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REFERENCES I. Schneider DR, Picker CJ. Myelodysplasia in the acquired immunodeficiency syndrome. Am J Clin Pathol. 1985; 84: 144-52. 2. Costello C. Haematological abnormalities in human immunodeficiency virus (HIV) disease. J Clin Pathol. 1988; 41 : 711 -5. 3. Hymes KB, Greene JB, Marcus A et al. Kaposi's sarcoma in homosexual men. A report of eight cases. Lancet. 1981; ii: 598-600. 4. Gottlieb MS, Schroff R, Schanker HM et al. Pneumocystis carinii pneumonia and mucosa! candidiasis in previously healthy homosexual men. N EnglJ Med. 1981; 305: 1425-31. 5. Masur H, Michelis MA, Greene J et al. An outbreak of community-acquired pneumocystis carinii pneumonia. N Engl J Med. 1981; 305 : 1431-38. 6. Morris L, Distenfeld A, Amorosi E, Karpatkin S. Autoimmune thrombocytopenic purpura in homosexual men. Ann Intern Med. 1982; 96: 714-7. 7. Ratnoff OD, Menitove JE, Aster RH, Lederman MM. Coincident classic hemophilia and «idiopathic» thrombocytopenic purpura in patients under treatment with concentrates of antihemophilic fac tor (factor VIII). N EnglJ Med. 1983; 308: 439-
42 ·. 8. Savona S, Nardi MA, Leonette ET, Karpatkin S. Thrombocytopenic purpura in narcotic addicts. Ann Intern Med. 1985; 102: 737-41. 9. Karpatkin S. HIV- I related thrombocytopenia. Hematol Oncol Clin North Am. 1990; 4: 193-218. 10. Yu JR, Leonette ET, Karpatkin S. Anti-F(ab')2 antibodies in thrombocytopenic patients at risk for acquired immunodeficiency syndrome. J Clin Invest. 1986; 77 : 175.6-61. 11 . Karpatkin S, Nardi MA, Leonette ET et al. Antihuman immuno-deficiency vims type 1 antibody complexes on platelets of seropositive thrombocytopenic homosexuals and narcotic addicts. Proc Natl Acad Sci USA. 1988; 85: 9763-67. 12. Stricker RB, Abrams DI, Corash L, Shuman MA. Target platelet antigen in homosexual men with immune thrombocytopenia. N Engl J Med. 1985; 313: 1375-80. 13. van der Lelie J, Lange JMA, Vos JJE, van Dalen CM, Danner SA, von dem Borne AEGK. Autoimmunity against blood cells in human immunodeficiency-virus (HIV) infection. Br J Ha ematol. 1987; 67: 109-14. 14. Bettaieb A, Oksenhendler E, Fromont P, Duedari
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N, Bierling P. Immunochernical analysis of platelet autoantibodies in HIV-related thrombocytopenic purpura: a study of 68 patients . Br J Haematol. 1989; 73: 241 -7. 15. Zucker-Franklin D, Seremetis S, Zheng ZY. Internalization of human immunodeficiency virus type I and other retroviruses by megakaryocytes and platelets. Blood. 1990; 10: 1920-23. 16. Hymes KB, Greene JB, Karpatkin S. The effect of azidothyrnidine on HIV-related thrombocytopenia. N Engl J Med. 1988; 3 18: 5 16. 17. Neil BJ, Johnson GI, Pomeroy C. Zidovudine therapy for severe human immunodeficiency virusrelated thrombocytopenia. Am J Med. 1988; 85: 744 -5. 18. Zucker-Franklin D, Termin CS, Cooper MC. Structural changes in the megakaryocytes of patients infected with th e human immune deficiency virus (HIV- I). Am J Pathol. 1989; 134: 1295-303. 19. Zucker-Franklin D, Cao Y. Megakaryocytes of human immunodeficiency virus-infected individuals express viral RNA. Proc NatlAcad Sci USA. 1989; 86: 5595 - 99. 20. Rabellino EM, Nachman RL, Williams N, Winchester RI, Ross GD. Human megakaryocytes. I. Characterization of the membrane and cytoplasmic components of isolated marrow megakaryocytes. J Exp Med. 1979; 149: 1273-87. 21. Basch RS, Kouri YH. Karpatkin S. Expression of CD4 by human megakaryocytes. Proc Natl Acad Sci USA. 1990; 87: 8085-89. 22. von Laer D, Hufert Ff, Fenner TE et al. CD34+ hematopoietic progenitor cells are not a major reservoir of the human immunodeficiency virus. Blood. 1990; 76: 128 1-86. 23. Donahue RE, Johnson MM, Zon LI, Clark SC, Groopman JE. Suppression of in vitro haematopoiesis following human immuno-deficiency virus infection. Nature. 1987; 326 : 200-3. 24. Eyster ME, Gail MH, Ballard JO, Al-Mondhiry H, Goedert JJ. Natural history of human immunodeficiency virus infections in hemophiliacs: effects of T-cell subsets, platelet counts, and age. Ann Intern Med. 1987; I 07 : 1-6. 25 . Oksenhendler E, Bierling P, Farcet J-P, Rabian C, Seligmann M, Clauvel J-P. Response to therapy in 37 patients with HIV-related thrombocytopenic purpura. Br J Haematol. 1987; 66: 491-5. 26. Abrams DI, Ki prov DD, GoedertJJ, Sarngadharan
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MG, Gallo RC, Volbe rding PA. Antibodies to human T-lymphotropic virus type III and deve lopment of the acquired immunodefi ciency sy ndrome in homosex ual men prese ntin g with immune thrombocytopeni a. Ann Intern Med. 1986; 104: 47-50. 27. Walsh C, Krigel R, Lennette E, Karpatkin S. Thrombocy topeni a in homosexual pati ents. Ann Intern Med. 1985; I 03: 542-5 . 28 . Go ldsweig HG, G rossman R, William D. Thrombocytopeni a in homosex ual men. Am J Hematol. 1986;2 1 : 243-7. 29. Barbui R, CortelazzoS, Minelli B, Galli M, Bue lli M. Does splenec to my enh ance risk of AIDS in HIV-positi ve pati e nts w ith chro ni c th rom bocy topenia? w ncet. 1987; ii : 342-3. 30. Schneider PA, Abrams DI , Ray ner AA, Hohr DC. Immunodefi ciency-associated thrombocytopeni c purpura (IDTP). Response to splenectomy. Arch Surg. 1987; 122: 1175-78. 3 1. Bussel JB , Haimi JS. Isolated thrombocytopeni a in pati ents infected with HIV : Treatment with intra-venous gammaglobulin. Ami Hematol. 1988; 28: 79-84. 32. Pena JM, Amalich F, Barbado FJ et al. Successful zidov udine therapy for HIV related severe thrombocytopeni a. Report of a sustained remi ssion. Acta Haematol. 1990; 83 : 86-8. 33. Oksenhendl er E, Bierling P, Ferchal F, Clauvel JP, Seligmann M. Zidovudine for thrombocytopenic purpura related to human immunode fi ciency virus (HIV) infection. Ann Intern Med. 1989; 110: 365-
8. 34. The Swiss Group for Clinical Studies on the Acquired Immunodefi ciency syndrome (AIDS ).
Zidovudi ne for the treatment of thrombocytopeni a associated wi th hu man im munodefi ciency virus (HI V). A prospective study .Ann Intern Med. 1988; 109: 7 18-2 1. 35 . Oksenhendl er E, Bierlin g P, Schenmetzler C et al. Anti- RH immunoglobulin therapy fo r hum an immun o de fi cie ncy viru s- re la ted immun e thrombocytopenic purpura. Blood. 1988; 5: 1499502. 36. Du rand JM , Harle JR, Verdot JJ , Weiller PJ, Mongin M. Anti -Rh (D) immunog lobulin for immune thrombocytopeni c purpu ra. w ncet. 1986; ii : 49-50. 37. Biniek R, Ma less a R, Broc kmeyer NH, Lubo ldt W. Ant i- Rh (D) immunoglobulin for AIDS-related thrombocytopenia. wncet. 1986; ii : 627. 38. Elli s ME, Neal KR, Leen C LS. Alfa-2a recombinant interferon in HIV assoc iated thrombocytope nia. Br Med 1. 1987; 295 : 15 19.
NOTE The article of Stricker et al. (reference 12) was recently retracted by the authors (except the first author) since it was discovered that some of the Western blots performed with «control» serum (i.e., serum from subjects without AIDS or AIDS related conditions) had also been positi ve for a band of approximately 25kd. Ors Shuman, Corash and Abrams concluded that this band was therefore not specific for HIV infection and the hypothesis that the antibody may partially account for immune thrombocytopeni a in homosexual men was invalid (N Engll Med. 1991 ; 325: 1487)
Acta Clinica Belgica 47.2 ( 1992)
ISSN: 1784-3286 (Print) 2295-3337 (Online) Journal homepage: http://www.tandfonline.com/loi/yacb20
HIV-Related Thrombocytopenia D. Blockmans & J. Vermylen To cite this article: D. Blockmans & J. Vermylen (1992) HIV-Related Thrombocytopenia, Acta Clinica Belgica, 47:2, 117-123, DOI: 10.1080/17843286.1992.11718217 To link to this article: http://dx.doi.org/10.1080/17843286.1992.11718217
Published online: 16 May 2016.
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Citing articles: 2 View citing articles
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Date: 12 August 2017, At: 23:23
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D. Blockmans, J. Vennylen*
SUMMARY HIV-related chronic ITP is caused by an accelerated platelet destruction due to adsorption of circulating immune complexes and to specific anti -platelet anti bodies, but perhaps also by a defective thrombopoiesis resulting from invasion of the megakaryocytes by the retrovirus. Treatmen\ is needed when platelet numbers drop beneath 20. 109 /Lor when severe bleeding symptoms occur. Steroids, commercially avai lable immunoglobulin s for IV use, AZT and anti -Rh immunoglobulins can be admini stered, although relapses are frequent after withdrawal of the drugs. Recurrences after splenectomy are far less common, butthe progression towards AIDS might be accelerated. Acta Clin Belg. 47, 2: 117-23 INTRODUCTION Schematically, five fonns of thrombocytopenia may occur during human immunodeficiency virus (HIV) infection. A transient, mild form of thombocytopenia is sometimes seen during the phase of primo-infection, which may be accompanied by a mononucleosis-like picture with haemophagocytosis, fever, diarrhea, glandular enlargement, sore throat, weight loss.
*Dienst Inwendige Geneeskunde Afdeling Bloedings- en Vaatziekten U.Z. Gasthuisberg, K.U. Leuven Herestraat 49, 3000 Leuven, Belgie Reprints: D. Blockmans
Thrombocytopenia may also occur as a sideeffect of medication: cotrimoxazole, which is often used for the treatment or prevencion of pneumocystis carinii pneumonia in HIV-positive patients, is well known as an inducer of thrombocytopenia. When thrombocytopenia is associated with anemia and/or granulocytopenia, as occurs in the late AIDS phase, prognosis usually is bad. In these circumstances, it is a manifestation of a very poor general condition, probably with intercurrent infections and/or development of malignant disease. The cumulative myelotoxicity of different drugs is also responsible. Bone marrow examination findings may be similar to those seen in the myelodysplastic syndrome. These dysplastic morphological changes have not .the same clinical implications as in HIV negative patients with respect to the later development of acute leukemia, which is rather rare (I). By 1990, fourteen cases of thrombotic thrombocytopenic purpura (TIP) in HIV positive persons had been described, of whom 8 homosexuals, 3 narcotic addicts and 3 promiscuous heterosexuals. In these patients, TIP might be induced by endothelial damage and spontaneous platelet aggregation caused by endotoxin and immune complexes, and, in the case offull-blown AIDS, by the impaired immune system, the neoplasias and the chemotherapy. Treatment consists of fresh frozen plasma, high dose garnmaglobulins, exchange plasma transfusions, immunopheresis using staphy lococcus Acta Clinica Be/gica 47.2 ( 1992)
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Protein A co lum ns, high doses of steroids, acetylsalicylic acid, dipyridamole and intravenous vincristin admin istration. Finally, the fifth form of th rombocytopenia closely resembles the class ic form of chronic idiopathic thrombocytopenic purpura (clTP), usually seen in otherwi se healthy young fe males. In 925 patients at ri sk for HIV di sease, Coste llo fo und a 13 % incidence of th ro mbocytopenia. T welve pe rcent of the patients were healthy HIV carriers (2). lt is on this fo rm ofthrombocytopeni a that this review article will foc us.
HISTORICAL REMARKS In Septe mber 198 1, the fi rs t report on 8 abnormally agg ressive cases of Kaposi's sarcoma in homosexual men was publi shed in the Lancet (3). Three months later, an outbreak of pneumocystis carinii pneumonia in previously healthy homosexual men was reported in the New England Journal of Medic ine (4, 5). Less than one year later, the g roup of Simon Karpatki n from New York described an unusually high frequency of a utoimmune thrombocy to peni c purpu ra in sexually acti ve ho mosex ual men (6). In I 983, 5 case reports of . ITP in hemophilia A patients receiving fac tor VIII concentrates were publ ished (7). The fi rst cases of thro mbocytopenic purpura in narcotic addicts were seen in November I 982 (8), again before the discovery of the HIV in 1983. Thi s ne wl y desc ribe d form of ITP in homosexuals, narcotic addicts and hemophilia A patients resembled the classic fo rm of ITP in many ways: the bone marrow showed an increased number o f megakaryocytes, thrombocytopeni a was caused by peripheral destruction of antibodyloaded platelets, there was no splenomegaly, the antinuclear factor was negati ve and patients responded as we ll to prednisone or splenectomy as did patients with classic cITP. Some differences how e ver indicated that a ne w kind of thrombocytopenia was involved. Firstly, the
Acta Clinica Be/gica 47.2 ( 1992)
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au thors were surprised by the reversed male/ female rati o, classic cITP be ing predominantly a di sorder of women. Secondly, the presence of circulating immune complexes (CIC) and a clearly increased amount of platelet-associated immunoglobulins (Paig) and complement fac tors C3C4 (PaC3C4) were noted . . F inally, the relati ve lymphopeni a, the reversed T4/T8 rati o and the hypergammaglobulinemi a all pointed towards an immune regul ation disorder with impaired cell -mediated immunity. After the discovery of the AIDS producing retrovirus in I 983, by then called the human-T-lymphocytotropic virus type III, it became apparent that chronic thrombocytopeni a was one of the manifestati ons of thi s virus, which later on became known world wide as HIV.
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PATHOGENESIS The clTP of HIV positi ve persons is caused by an increased peripheral destruction of platelets, although a fac tor of impaired production may be involved as well. Thi s accelerated peripheral platelet destruction could result from an increased concentration of CIC, from the development of specific antipl atelet antibodies and fro m di rect invas ion of megakaryocytes and platelets by the virus.
a. Increased concentration of CIC Karpatkin reported a 2.4 times higher amo unt of CIC in hemophiliacs with ITP, a 3.0 times higher concentration in homosexuals with ITP and even a 7.3 times higher concentration of C IC in narcotic addicts with ITP, compared to classic ITP. An increased amount of non-ether-elutable PaigG and PaC3C4 was noted as well in these 3 patient groups, when compared to class ic ITP patients (9). Ji Ren Yu et al. ( I 0) postulated that · these IC are composed of antibodies directed against the F(ab')2 portions of other antibodies, mostly directed against viral antigens (Epstein Barr virus, cytomegalovirus, herpes simplex virus or adenovirus) which themselves cannot be
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detected in these IC. HIV antibodies were also very consistently found in these IC and bound to the platelets, although no viral antigen could be detected, either in these CIC or bound to the platelets ( 11 ). It was postulated that anti -HIV antibodies complexed with anti-idiotypic anti bodies are at least partly responsible for the CIC and PaIG. Plate lets are then nothing more than innocent bystanders; following adsorption of these IC to the platelet membrane, the pl atelets are phagocytized by the cells of the reticuloendothe lia l system , throug h an interaction with macrophage Fe and C3b receptors.
compound in 72 % of HIV-related ITP patients. Karpatkin et al . (9) demonstrated 7S antiplatelet IgG in 9113 thrombocytopenic narcotics and in 61 6 thrombocytopen ic hemophiliacs but in none of the ir homosex ual ITP patients. They suggested that there might be a different pathogenesis among the different risk groups, the thrombocytopenia of homosex uals being medi ated through CIC,
b. Development ofspecific anti-platelet antibodies
Zucker- Franklin et al. ( 15) gave direct electronmicroscopic evidence that platelets can be invaded by the retrovirus. One can postulate that these platelets are preferably destroyed by the host's remaining immune mechanisms.
As in classic ITP, anti-platelet antibodies were found in HIV-related thrombocytopenia by a number of authors. Stricker et al. ( 12) could detect an antibody directed against a 25 kD platelet membrane antigen in the serum of 29 out of30 homosexual ITP patients. Thi s antigen was not present on other hematopoietic cells, but could be detected on skin fibroblasts and on herpes simplex viruses type 1 and 2, cultivated on a renal cell line from monkeys. The binding of this antibody occurred through its F(ab')2 part; there was no binding to Glanzmann thrombasthenia or Bernard-Soulier platelets. Stricker hypothezised that a cellular 25 kD protein is adsorbed to the herpes simplex virus and thereby becomes immunogenic. Antibodies formed after infection will cross-react with host cells, including platelets. Unfortunately, Stricker' s findings could not be confirmed by other investigators. Van der Lelie et al. ( 13) found PaigG, which could be eluted by ether, in 16116 AIDS patients (of whom 7 were thrombocytopenic), in 517 persons with the AIDS related complex (of whom 2 were thrombocytopenic) and in 7/10 healthy homosexuals (of whom 3 were seropositive and 2 were thrombocytopenic ). These antibodies were directed against an antigen related to glycoprotein lib/Ula, since they did not react with Glanzmann thrombasthenia platelets. Bettaiebet al. ( 14) found an auto-antibody directed against an intraplatelet
that in hemophiliacs through spec ific anti-platelet antibodi es, the thrombocytopenia of narcotic addicts being a mixture of both mechani sms.
c. Direct platelet invasion by HIV
Besides increased destruction of platelets, a disturbed platelet production might contribute to the thrombocytopenia of these HIV positive patients. A central mechani sm was suspected since the observations of Hymes ( 16) and Neil (17) who described correction of HIV associated cITP by zidovudine. The abundance of megakaryocytes in the bone marrow does not necessarily reflect a good platelet production, since platelet-shedding might be di sturbed in these circumstances, for example through the deposition of IC on megakaryocytes . Zucker-Franklin et al. afready described structural changes in the megakaryocytes of patients infected by HIV ( 18). In another study by the same authors, expression of HIV RNA inside the megakaryocytes was demonstrated ( 19). One year later, dir~ct invasion of viruses into the megakaryocytes was visualized ( 15). Expression of Fe receptors (20) and of the C4 receptor (21) by the megakaryocytes represents two different ways of HIV internalization. Emperipolesis is another potential mechanism. Occasionally, CD34+ cells could be directly infected by HIV (22). As has been proven for the stem cells of granulocytes and erythrocytes (23), the producActa Clinica Belgica 47.2 ( 1992)
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tion of hypothetical thrombopoietic inhibitors by the retroviru s might inhibit the growth or maturation of the megakaryocytic lineage.
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PROGNOSIS The cITP like picture can oc.cur during every stage of th e HIV infection: during the asymptomatic phase, during the ARC stadium or when full -blown AIDS has developed. Most authors agree that isolated thrombocytopenia is not an independent risk factor for a faster evolution towards AIDS, at least not in homosexual patients. Eyster et al. (24) however found a significantly worse prognosis among their 84 HIV positive hemophiliacs, when thrombocytopenia was present (p 0.02).
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platelet count does not react or if a maintenance dose higher than 15 mg/day is needed, they proceed to splenectomy. Using thi s scheme, Karpatkin et al. report on 35 successful treatments in 41 patients, followed however by 30 relapses after stopping prednisone treatment. Oksenhendler et al. (25) and Abrams et al. (26) obtain 15/ 26 and 19/24 fair responses with prednisone treatment; once again a stable platelet count is reached in only a minority of patients after withdrawing prednisone. There is no evidence that steroids might accelerate the evolution towards AIDS in HIV positive persons; the development of extensive oral candidiasis, the reactivation of latent herpes simplex virus infection or of chronic hepatitis may however occur.
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b. Splenectomy TREATMENT Spontaneous improvement or even di sappearance of thrombocytopenia have been described, although this happens in only a minority of the patients. Most authors agree that the best treatment for HIV-related thrombocytopenia is no treatment whenever possible, thi s means when the patient is asymptomatic' and when the platelet count is above 20.10 9/l. This abstinence is based on the side effects of most treatment modalities, which can be particularly severe in HIV positive immune-depleted patients. When made mandatory by bleeding complications or by a very low platelet number (with a high risk of intracerebral hemorrhage), a series of treatment possibilities are available which will be discussed here in some detail.
a. Steroids There is general agreement that the dose of steroids given schould be the lowest that increases the platelet count to more than 20.109/ I. Karpatkin et al. (9) give prednisone 30-40 mg/day for 1-2 weeks; thereafter prednisone is reduced to 10- I 5 mg/day for an additional IO months at most. If the Acta Clinica Belgica 47.2 ( 1992)
The results of splenectomy in HIV-related thrombocytopenia are consistently sati sfactory : success rates of 10/l 0 (27), 7/7 (28), 10/14 (25) and 10115 (26) have been reported . Relapses are much less frequent than with steroid s . Pneumococcal vaccination before and penicillin as a preventive .measure after splenectomy are necessary. Most authors do not find ev idence that splenectomy accelerates the progression towards AIDS in their patient groups. Barbui et al. (29) however, taking into account 4 different studies on a total of JOI patients of whom 36 underwent splenectomy, found a 4.1 fold increased ri sk of developing AIDS in the operated patients during the follow-up period. Therefore, splenectomy _ although highly effective - can only be advi sed when other strategies have failed . The surgical risk is higherthan in non-HIV related c-ITP (30). c. Intravenous immunoglobulins Commercially avai lable intravenous immunoglobulins, at a dose of0.4 g/kg/day during 5 days 'or 1 g/kg during l or 2 days, produce a fast but short-lasting rise in platelets in almost all HIV positive thrombocytopenic patients. They are useful when an acute rise in platelet number is needed, e.g. when intracranial hemorrhage occurs
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or when surgery is needed. Since their effect lasts only 7 to 10 days, since the patients' response to s ub sequ e nt infu s io ns o ft e n beco mes less pronounced and in view of the high costs of these preparations, intravenous imm unoglobulins are not suited for long-term treatment. Only 1/22 patients remained in re mission in the study of Bussel (3 1).
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recombinant alpha-2a interferon fora reacti vation of chro nic hepati tis B. Danazo l mos t often does not provoke a substantial platelet rise. Oksenhendler (25) reports a response in 2/ 18 patients. Vincri stin cannot be used conside ring the ri sk of additional immunosuppression.
d. Zidovudine (AZT, Retrovir) AZT, at a dose of 800- 1500 mg/day, produces a rise in pl atelet count from the 2nd-3 rd week of therapy onwards in the majority o f HIV positi ve thro mbocytopenic pati ents (1 6, 17, 32, 33). Thi s effect mi ght last after the withdrawal of the drug. ln the light of the studies of Zucker-Frankl in et al. ( 15, 19), an antiretroviral e ffect directed against HIV infected megakaryocytes is probabl e. The e ffectiveness of AZT in these circumstances has been confirmed by a prospective controlled crossover double-blind study in 10 HIV positi ve persons conducted by the Swiss Group fo r Clinical Studies on AIDS (34). Although AZT is not reimbursed for thi s indication in Belgium , AZT might become the treatment of choice fo r HIV related th ro mbocytopenia in the future, now that it is proved that lower less toxic doses o f AZT are equally effecti ve.
SA MENYATIING De chronische vorm van ITP bij HIV positieve patienten wordt enerzij ds veroorzaakt door een versnelde bloedplaatjesafb raak door afzetting van immuuncomplexen op de bloedplaatjesmembraan en door specifieke anti -b loedpl aatj esanti stoffen, en anderzijds mogelijks door een verstoorde thrombopoiese met in vasie van de megakaryocyten door het retrovirus. Een behandeling dringt zich op indien het bloedplaatjesaantal onder 20. 109/L daalt of wanneer er emstige bloedingsproblemen ontstaan. Qua medikatie heeft me n de keuze tu sse n stero id en, IV immuunglobulines, AZT en anti -Rhesus immuunglobulines; recidieven na stoppen van het geneesmiddel zijn echter frekwent. Het resultaat na splenectomie is daarentegen meer blijvend, alhoewel nog niet volledig kan uitgesloten worden dat na splenectomie de progressie naar AIDS niet zou versneld worden.
e. Miscellaneous Good results with anti-Rh (D) immunoglobulins ( 12-25 µ g/kg IV on 2 consecutive days) have been obtained by O ksenhendler et al. (35) in 4 of 7 Rhesus positi ve homosexual and 8 of I 0 narcotic addicts, with a mean duration of response of 16 and 2 1 days respectively. In Rhesus negative patients, anti-c lg seem to be effective. Du rand et al. (36) and Biniek et al. (37) were able to increase pl atelet counts in I multiresistent patient each; doses of 3000 µ g/day during 3 days were however needed. This therapy has a lower cost than intravenous immunoglobulins. Ellis et al. (38) observed a higher platelet number and a lesser need for intravenous immunoglobulins in a HIV positive patient during his treatment with
RESUME La forme chronique de thrombopenie liee aI' infection par le VIH resulte d'une destruction acceleree secondaire au depot de complexes immuns sur les plaquettes et d' une production d' anti corps antiplaquettaires specifiques, mais peut-etre aussi d' une thrombopoiesedeficiente par invasion des megakaryocytes par le retrovirus. Un traitement s'i mpose quand le nombre de plaquettes est inferieur a 20.109 IL OU quand un syndrome hemorragique grave s' installe. Le choix existe entre la cortisone, !es immunoglobulines intraveineuses, I' AZT et !es immunoglobulines anti-Rhesus, bien que !es recidives soient frequentes apres I' arret du traitement. Apres spMnectomie, le risque de rechute est plus faible; cependant une progressio'n plus rapide vers le SIDA n'est pas encore exclue. Acta Clinica Belgica 47.2 ( 1992)
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REFERENCES I. Schneider DR, Picker CJ. Myelodysplasia in the acquired immunodeficiency syndrome. Am J Clin Pathol. 1985; 84: 144-52. 2. Costello C. Haematological abnormalities in human immunodeficiency virus (HIV) disease. J Clin Pathol. 1988; 41 : 711 -5. 3. Hymes KB, Greene JB, Marcus A et al. Kaposi's sarcoma in homosexual men. A report of eight cases. Lancet. 1981; ii: 598-600. 4. Gottlieb MS, Schroff R, Schanker HM et al. Pneumocystis carinii pneumonia and mucosa! candidiasis in previously healthy homosexual men. N EnglJ Med. 1981; 305: 1425-31. 5. Masur H, Michelis MA, Greene J et al. An outbreak of community-acquired pneumocystis carinii pneumonia. N Engl J Med. 1981; 305 : 1431-38. 6. Morris L, Distenfeld A, Amorosi E, Karpatkin S. Autoimmune thrombocytopenic purpura in homosexual men. Ann Intern Med. 1982; 96: 714-7. 7. Ratnoff OD, Menitove JE, Aster RH, Lederman MM. Coincident classic hemophilia and «idiopathic» thrombocytopenic purpura in patients under treatment with concentrates of antihemophilic fac tor (factor VIII). N EnglJ Med. 1983; 308: 439-
42 ·. 8. Savona S, Nardi MA, Leonette ET, Karpatkin S. Thrombocytopenic purpura in narcotic addicts. Ann Intern Med. 1985; 102: 737-41. 9. Karpatkin S. HIV- I related thrombocytopenia. Hematol Oncol Clin North Am. 1990; 4: 193-218. 10. Yu JR, Leonette ET, Karpatkin S. Anti-F(ab')2 antibodies in thrombocytopenic patients at risk for acquired immunodeficiency syndrome. J Clin Invest. 1986; 77 : 175.6-61. 11 . Karpatkin S, Nardi MA, Leonette ET et al. Antihuman immuno-deficiency vims type 1 antibody complexes on platelets of seropositive thrombocytopenic homosexuals and narcotic addicts. Proc Natl Acad Sci USA. 1988; 85: 9763-67. 12. Stricker RB, Abrams DI, Corash L, Shuman MA. Target platelet antigen in homosexual men with immune thrombocytopenia. N Engl J Med. 1985; 313: 1375-80. 13. van der Lelie J, Lange JMA, Vos JJE, van Dalen CM, Danner SA, von dem Borne AEGK. Autoimmunity against blood cells in human immunodeficiency-virus (HIV) infection. Br J Ha ematol. 1987; 67: 109-14. 14. Bettaieb A, Oksenhendler E, Fromont P, Duedari
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N, Bierling P. Immunochernical analysis of platelet autoantibodies in HIV-related thrombocytopenic purpura: a study of 68 patients . Br J Haematol. 1989; 73: 241 -7. 15. Zucker-Franklin D, Seremetis S, Zheng ZY. Internalization of human immunodeficiency virus type I and other retroviruses by megakaryocytes and platelets. Blood. 1990; 10: 1920-23. 16. Hymes KB, Greene JB, Karpatkin S. The effect of azidothyrnidine on HIV-related thrombocytopenia. N Engl J Med. 1988; 3 18: 5 16. 17. Neil BJ, Johnson GI, Pomeroy C. Zidovudine therapy for severe human immunodeficiency virusrelated thrombocytopenia. Am J Med. 1988; 85: 744 -5. 18. Zucker-Franklin D, Termin CS, Cooper MC. Structural changes in the megakaryocytes of patients infected with th e human immune deficiency virus (HIV- I). Am J Pathol. 1989; 134: 1295-303. 19. Zucker-Franklin D, Cao Y. Megakaryocytes of human immunodeficiency virus-infected individuals express viral RNA. Proc NatlAcad Sci USA. 1989; 86: 5595 - 99. 20. Rabellino EM, Nachman RL, Williams N, Winchester RI, Ross GD. Human megakaryocytes. I. Characterization of the membrane and cytoplasmic components of isolated marrow megakaryocytes. J Exp Med. 1979; 149: 1273-87. 21. Basch RS, Kouri YH. Karpatkin S. Expression of CD4 by human megakaryocytes. Proc Natl Acad Sci USA. 1990; 87: 8085-89. 22. von Laer D, Hufert Ff, Fenner TE et al. CD34+ hematopoietic progenitor cells are not a major reservoir of the human immunodeficiency virus. Blood. 1990; 76: 128 1-86. 23. Donahue RE, Johnson MM, Zon LI, Clark SC, Groopman JE. Suppression of in vitro haematopoiesis following human immuno-deficiency virus infection. Nature. 1987; 326 : 200-3. 24. Eyster ME, Gail MH, Ballard JO, Al-Mondhiry H, Goedert JJ. Natural history of human immunodeficiency virus infections in hemophiliacs: effects of T-cell subsets, platelet counts, and age. Ann Intern Med. 1987; I 07 : 1-6. 25 . Oksenhendler E, Bierling P, Farcet J-P, Rabian C, Seligmann M, Clauvel J-P. Response to therapy in 37 patients with HIV-related thrombocytopenic purpura. Br J Haematol. 1987; 66: 491-5. 26. Abrams DI, Ki prov DD, GoedertJJ, Sarngadharan
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MG, Gallo RC, Volbe rding PA. Antibodies to human T-lymphotropic virus type III and deve lopment of the acquired immunodefi ciency sy ndrome in homosex ual men prese ntin g with immune thrombocytopeni a. Ann Intern Med. 1986; 104: 47-50. 27. Walsh C, Krigel R, Lennette E, Karpatkin S. Thrombocy topeni a in homosexual pati ents. Ann Intern Med. 1985; I 03: 542-5 . 28 . Go ldsweig HG, G rossman R, William D. Thrombocytopeni a in homosex ual men. Am J Hematol. 1986;2 1 : 243-7. 29. Barbui R, CortelazzoS, Minelli B, Galli M, Bue lli M. Does splenec to my enh ance risk of AIDS in HIV-positi ve pati e nts w ith chro ni c th rom bocy topenia? w ncet. 1987; ii : 342-3. 30. Schneider PA, Abrams DI , Ray ner AA, Hohr DC. Immunodefi ciency-associated thrombocytopeni c purpura (IDTP). Response to splenectomy. Arch Surg. 1987; 122: 1175-78. 3 1. Bussel JB , Haimi JS. Isolated thrombocytopeni a in pati ents infected with HIV : Treatment with intra-venous gammaglobulin. Ami Hematol. 1988; 28: 79-84. 32. Pena JM, Amalich F, Barbado FJ et al. Successful zidov udine therapy for HIV related severe thrombocytopeni a. Report of a sustained remi ssion. Acta Haematol. 1990; 83 : 86-8. 33. Oksenhendl er E, Bierling P, Ferchal F, Clauvel JP, Seligmann M. Zidovudine for thrombocytopenic purpura related to human immunode fi ciency virus (HIV) infection. Ann Intern Med. 1989; 110: 365-
8. 34. The Swiss Group for Clinical Studies on the Acquired Immunodefi ciency syndrome (AIDS ).
Zidovudi ne for the treatment of thrombocytopeni a associated wi th hu man im munodefi ciency virus (HI V). A prospective study .Ann Intern Med. 1988; 109: 7 18-2 1. 35 . Oksenhendl er E, Bierlin g P, Schenmetzler C et al. Anti- RH immunoglobulin therapy fo r hum an immun o de fi cie ncy viru s- re la ted immun e thrombocytopenic purpura. Blood. 1988; 5: 1499502. 36. Du rand JM , Harle JR, Verdot JJ , Weiller PJ, Mongin M. Anti -Rh (D) immunog lobulin for immune thrombocytopeni c purpu ra. w ncet. 1986; ii : 49-50. 37. Biniek R, Ma less a R, Broc kmeyer NH, Lubo ldt W. Ant i- Rh (D) immunoglobulin for AIDS-related thrombocytopenia. wncet. 1986; ii : 627. 38. Elli s ME, Neal KR, Leen C LS. Alfa-2a recombinant interferon in HIV assoc iated thrombocytope nia. Br Med 1. 1987; 295 : 15 19.
NOTE The article of Stricker et al. (reference 12) was recently retracted by the authors (except the first author) since it was discovered that some of the Western blots performed with «control» serum (i.e., serum from subjects without AIDS or AIDS related conditions) had also been positi ve for a band of approximately 25kd. Ors Shuman, Corash and Abrams concluded that this band was therefore not specific for HIV infection and the hypothesis that the antibody may partially account for immune thrombocytopeni a in homosexual men was invalid (N Engll Med. 1991 ; 325: 1487)
Acta Clinica Belgica 47.2 ( 1992)
