Correspondence

HIV-Related Thrombocytopenia

N Engl J Med 1993; 328:1785-1786June 17, 1993

Article

To the Editor:

Ballem and colleagues (Dec. 17 issue)1 make important contributions to the understanding of human immunodeficiency virus (HIV)-related thrombocytopenia, emphasizing the role of decreased production of platelets, possibly due to viral infection of “neglected” megakaryocytes, as the accompanying editorial puts it2. We studied the survival of ¹¹¹In-labeled autologous platelets in a group of intravenous drug users with HIV-related thrombocytopenia that was severe (<30 × 10³ platelets per cubic millimeter; 28 patients) or moderate (30 to 99 × 10³ platelets per cubic millimeter; 24 patients)3,4. Although our mean results were similar to those reported by Ballem et al., there were also some important differences. Of the 52 patients, 48 had normal numbers of megakaryocytes in the bone marrow-biopsy specimen. Nine of them (19 percent) had severe reductions in platelet survival (to less than 72 hours), 21 (44 percent) had only slight decreases, and 18 (38 percent) had normal platelet survival with substantial reductions in the rate of platelet recovery, suggesting splenic or hepatic “pooling.”

We too found reduced platelet turnover in most patients, and more often with moderate than with severe thrombocytopenia. According to Heyns et al.,5 this may be explained by diffuse sequestration of platelets rather than by bone marrow suppression. Two of our patients3 had persistent decreases in the recovery rate after splenectomy, with diffuse sequestration in the reticuloendothelial system. The same was observed in the patients unresponsive to zidovudine4.

There are several possible explanations for the differences in our findings. First, all our patients were intravenous drug users, usually with some hepatic impairment and positive serologic tests for viral hepatitis. Our observations about the pooling of platelets may relate to this hepatic involvement, which is less frequent in other risk groups (mainly homosexual men, like the subjects studied by Ballem and colleagues)1. Second, we think that the term “HIV-related thrombocytopenia” may include several forms of thrombocytopenia: megakaryocyte hypoplasia or impaired megakaryocyte maturation, “idiopathic thrombocytopenic purpura-like” thrombocytopenia, and splenic or hepatic pooling. These forms must be differentiated with respect to pathogenesis, clinical manifestations, and appropriate treatment.

Giuseppe Landonio, M.D.
Annamaria Nosari, M.D.
Franco Spinelli, M.D.
Niguarda Ca Granda Hospital, 20162 Milan, Italy

5 References

1. 1

   Ballem PJ, Belzberg A, Devine DV, et al. Kinetic studies of the mechanism of thrombocytopenia in patients with human immunodeficiency virus infection. N Engl J Med 1992;327:1779-1784
   Full Text | Web of Science | Medline

2. 2

   Nieuwenhuis HK, Sixma JJ. Thrombocytopenia and the neglected megakaryocyte. N Engl J Med 1992;327:1812-1813
   Full Text | Web of Science | Medline

3. 3

   Landonio G, Galli M, Nosari AM, et al. HIV-related severe thrombocytopenia in intravenous drug users: prevalence, response to therapy in a medium-term follow-up, and pathogenetic evaluation. AIDS 1990;4:29-34
   CrossRef | Web of Science | Medline

4. 4

   Landonio G, Nosari AM, Spinelli F, Vigorelli R, Caggese L, Schacht I. HIV-related thrombocytopenia: four different clinical subsets. Haematologica 1992;77:398-401
   Web of Science | Medline

5. 5

   Heyns A du P, Badenhorst PN, Lotter MG, Pieters H, Wessels P, Kotze HF. Platelet turnover and kinetics in immune thrombocytopenic purpura: results with autologous 111In-labeled platelets and homologous 51Cr-labeled platelets differ. Blood 1986;67:86-92
   Web of Science | Medline

To the Editor:

Zidovudine is effective treatment for HIV-related thrombocytopenia1 because it improves platelet production by the bone marrow2. Its effect on platelets may be distinct from its effect on HIV. Other anti-HIV drugs may not influence platelet production and may be ineffective against HIV-related thrombocytopenia. This hypothesis can be tested, because in August 1992 the Journal published an article indicating that in patients who had received zidovudine for a mean of 13 months, it was better to switch to didanosine than to continue zidovudine3. Among the patients we have described who were switched from zidovudine to didanosine, we attempted to identify those who had had thrombocytopenia before receiving zidovudine, whose thrombocytopenia had been partially corrected while the zidovudine therapy continued, and in whom zidovudine did not cause severe hematologic toxicity. Two such patients were found. Both had severe relapses of thrombocytopenia after changing to didanosine, but their platelet levels increased when zidovudine was reintroduced to their treatment along with didanosine. (Data for one of the two patients are shown in Figure 1Figure 1Platelet Counts in an HIV-Infected Patient, Showing the Effect of Zidovudine Therapy..) Hence, patients who have thrombocytopenia before treatment with zidovudine need to be watched carefully for relapses of thrombocytopenia if they are switched to didanosine.

Marc Pechere, M.D.
Kaveh Samii, M.D.
Bernard Hirschel, M.D.
Hopital Cantonal Universitaire, CH-1211 Geneva 14, Switzerland

3 References

1. 1

   Swiss Group for Clinical Studies on the Acquired Immunodeficiency Syndrome (AIDS). Zidovudine for the treatment of thrombocytopenia associated with human immunodeficiency virus (HIV): a prospective study. Ann Intern Med 1988;109:718-721
   Web of Science | Medline

2. 2

   Ballem PJ, Belzberg A, Devine DV, et al. Kinetic studies of the mechanism of thrombocytopenia in patients with human immunodeficiency virus infection. N Engl J Med 1992;327:1779-1784
   Full Text | Web of Science | Medline

3. 3

   Kahn JO, Lagakos SW, Richman DR, et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. N Engl J Med 1992;327:581-587
   Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We agree with the comments of Landonio et al. about the different pathogenetic mechanisms in HIV-associated thrombocytopenia. Their work demonstrates the marked variability in these patients. Our cohort did not include any intravenous drug users. Many patients in the study of Landonio et al. had evidence of concomitant infection with hepatitis virus, which is known to be associated with immune-complex disease. Splenic blood flow, an important determinant of splenic pooling, is often increased in patients with immune-complex-related disease, in the absence of any increase in splenic size1. This may partly explain some of the variability seen in their patients. However, we disagree that Heyns et al.2 explained reduced platelet turnover by the diffuse sequestration of platelets. They identified a group of patients with idiopathic thrombocytopenic purpura and low spleen:liver ratios who they believed had diffuse reticuloendothelial uptake of platelets. With regard to a subgroup of patients who had reduced platelet recovery and longer platelet survival, they argued that the estimate of recovery may be influenced by the pattern of platelet sequestration, but they did not question the validity of the low platelet turnover. In fact, in a consideration of the calculation of platelet turnover,3 the finding of a low platelet recovery would tend to overestimate the platelet turnover rather than underestimate it. Our findings are still different, however, in that we found that the majority of our patients had neither increased splenic nor increased hepatic uptake of labeled platelets. As we stated, this would implicate either the intravascular or the intramedullary destruction of platelets.

The comments of Pechere et al. are important. There is evidence in a murine model of AIDS that zidovudine is a potent inducer of thrombocytosis, that this effect is dose-and time-dependent, and that it is seen in both infected and uninfected mice4. Thus, the point is well taken that if the beneficial effect of zidovudine on the platelet count is due to a nonspecific stimulatory effect of the drug, the effect may not be seen with other drugs, and this information should be considered in therapeutic decisions. It will be interesting to see whether patients with refractory classic idiopathic thrombocytopenic purpura who have impaired platelet production as part of the pathogenesis of their disease benefit from a trial of zidovudine. Further study of the mechanism by which zidovudine affects thrombopoiesis may help in the development of better therapeutic regimens.

P. Ballem, M.D.
Grace Hospital, Vancouver, BC V6H 3V4, Canada

A. Belzberg, M.D.
St. Paul's Hospital, Vancouver, BC V6Z 1Y6, Canada

D. Devine, Ph.D.
Canadian Red Cross Society Blood Transfusion Service, Vancouver, BC V6H 2N9, Canada

4 References

1. 1

   Peters AM, Saverymuttu SH, Wonke B, Lewis SM, Lavender JP. Interpretation of platelet kinetic studies for the identification of sites of abnormal platelet destruction. Br J Haematol 1984;57:637-649
   CrossRef | Web of Science | Medline

2. 2

   Heyns A du P, Badenhorst PN, Lotter MG, Pieters H, Wessels P, Kotze HF. Platelet turnover and kinetics in immune thrombocytopenic purpura: results with autologous 111In-labeled platelets and homologous 51Cr-labeled platelets differ. Blood 1986;67:86-92
   Web of Science | Medline

3. 3

   Harker LA, Finch CA. Thrombokinetics in man. J Clin Invest 1969;48:963-974
   CrossRef | Web of Science | Medline

4. 4

   Chow FPR, Sutton PA, Hamburger AW. 3'-Azido-3'-deoxythymidine ameliorates the thrombocytopenia observed in a murine model of AIDS. Exp Hematol 1990;18:1038-1041
   Web of Science | Medline

Citing Articles (7)

Citing Articles

1. 1

   Robert Colebunders, Caroline De Schacht, Thomas Vanwolleghem, Steven Callens. (2004) Lopinavir/ritonavir- and indinavir-induced thrombocytopenia in a patient with HIV infection. International Journal of Infectious Diseases 8:5, 315-316
   CrossRef

2. 2

   Mauro Moroni, Spinello Antinori. (2003) HIV and direct damage of organs. AIDS 17, S51-S64
   CrossRef

3. 3

   Nuria Camino, Marina Núñez, Francisco Blanco, Daniel González-Requena, Juan González-Lahoz, Vincent Soriano. (2003) Indinavir-Induced Thrombocytopenia. AIDS Patient Care and STDs 17:3, 103-104
   CrossRef

4. 4

   A. Scaradavou. (2002) HIV-related thrombocytopenia. Blood Reviews 16:1, 73-76
   CrossRef

5. 5

   David M. Aboulafia, Denise Bundow, Sarah Waide, Charles Bennet, David Kerr. (2000) Initial Observations on the Efficacy of Highly Active Antiretroviral Therapy in the Treatment of HIV-Associated Autoimmune Thrombocytopenia. The American Journal of the Medical Sciences 320:2, 117-123
   CrossRef

6. 6

   Wah Kiam Chia, Victor Blanchette, Meera Mody, J. Fraser Wright, John Freedman. (1998) Characterization of HIV-1-specific antibodies and HIV-1-crossreactive antibodies to platelets in HIV-1-infected haemophiliac patients. British Journal of Haematology 103:4, 1014-1022
   CrossRef

7. 7

   Thomas Behr, Hans-Jürgen Bair, Wolfgang Becker, Friedrich Wolf, Johannes Schwab. (1994) Aetiology of HIV-associated thrombocytopenia. The Lancet 343:8895, 479
   CrossRef