Thrombocytopenia means an abnormally low number of platelets in the blood.

Platelets are small cells which are involved in blood clotting. They are quite different from the blood proteins which are missing in haemophilia, which also cause clotting problems. Platelets are made in the bone marrow from other cells called megakaryocytes.

In HIV infection, the number of platelets can be low for several reasons. Bone marrow cells may produce fewer platelets either because they are directly infected by HIV or inhibited by abnormal immune responses, such as high levels of the cytokines tumour necrosis factor α (TNF-α) or tumour growth factor β (TGF-β), or the development of antibodies against platelets. They may also be being removed from the blood.

Low platelet counts occur in about 20% of people with HIV, at all stages of infection. Some treatment drugs, such as AZT (zidovudine, Retrovir) and co-trimoxazole (Septrin / Bactrim), can also cause thrombocytopenia. There is also evidence that HIV-positive patients with low platelet counts have lower CD4 cell counts, higher viral loads and poor virological responses to highly active antiretroviral therapy (Miguez-Burbano 2004).

Symptoms and diagnosis

The first symptoms may be easy bruising in the skin: the technical word for this is purpura. More severe loss of platelets causes internal bleeding, which may cause people to cough up blood or pass blood in stools. The most severe complication is bleeding into the brain. These problems are all much more severe for people with haemophilia, who already have an underlying bleeding defect.

A blood test will confirm that the platelet count is low and, unless the cause is obvious, a bone marrow biopsy may be required to see if this is due to poor production or loss from the blood.

Treatment

Treatment for thrombocytopenia depends on the cause of the condition. For HIV-associated thrombocytopenia, highly active antiretroviral therapy (HAART) can boost platelet levels (Carbonara 2001; Servais 2001). There is some debate among experts about whether HAART can resolve all cases of HIV-associated thrombocytopenia. Some studies suggest that when factors other than HIV itself are contributing to thrombocytopenia, such as injecting drug use, selenium deficiency or hepatitis, thrombocytopenia may not resolve after introduction of HAART (Burbano 2001; Miguez 2002).

Other treatments which have shown benefits in some studies are interferon alfa (IntronA / Roferon-A / Viraferon) and megestrol acetate (Megace; Ellis 1987; Stellini 1992; Gomez 2001).

Platelet production by the bone marrow is also very frequently impaired by drugs. Medications which can induce thrombocytopenia include ganciclovir (Cymevene), valganciclovir (Valcyte), co-trimoxazole, indinavir (Crixivan), hydroxycarbamide (Hydrea) and other drugs used to treat opportunistic infections such as Mycobacterium avium intracellulare (MAI), tuberculosis and cytomegalovirus (CMV). Treatment for hepatitis C virus with ribavirin and α-interferon can also cause thrombocytopenia. The best treatment in these cases is to change the drugs to ones that have fewer bone marrow side-effects, if possible.

When the immune system is out of control, it may damage platelets by making antibodies against them or mopping them up with excess antibodies in the blood. The damaged platelets are removed from the blood by the spleen. When this happens in other immune diseases, it is possible to remove the spleen or to give steroids. Both of these could be dangerous in HIV infection as they can further damage the immune system.

Intravenous immunoglobulin (IVIG) has been shown to help this problem, as has dapsone. Both of these probably modify the immune response against platelets. A highly concentrated form of IVIG called WinRho SD has been approved for treating HIV-related thrombocytopenia.

About 10 to 20% of people with thrombocytopenia recover without any treatment.

Research

Miguez-Burbano (2004) carried out a case-control study of 50 HIV-positive patients with thrombocytopenia (<150,000 cells/mm³), compared to 50 HIV-positive, gender-, age- and treatment-matched controls. Patients with thrombocytopenia had lower CD4 cell counts (mean 161 vs. 414 cells/mm³, p = 0.006), higher CD8 T-cell percentages (59 vs. 47%, p = 0.01) and higher viral loads (249,000 vs. 74,600 copies/ml, p = 0.03). Among the patients on HAART, viral loads were higher (24,800 vs. 6520 copies/ml) and CD4 cell counts were lower (239 vs. 447 cells/mm³). After controlling for anaemia, neutropenia, antiviral therapy and drug use, viral load (odds ratio [OR] 2.5, p = 0.049) and thrombocytopenia (OR 1.9, p = 0.02) were independent predictors of CD4 cell count below 200 cells/mm³.

Ballem (1992) reported that both platelet survival and in particular platelet production are decreased in HIV-related thrombocytopenia. This finding, together with the in vitro result that HIV can infect megakaryocytes, suggest that HIV infection of megakaryocytes may be a direct cause of thrombocytopenia.

Several groups (Swiss Group for Clinical Studies on AIDS; Jackson 1988) have reported that AZT can rapidly increase platelet counts in patients with HIV-related thrombocytopenia. This increase generally occurs within several weeks of initiating treatment, and is not sustained after treatment cessation.

Servais (2001) conducted a longitudinal study of 92 HIV-infected people on highly active antiretroviral therapy (HAART) with blood abnormalities prior to commencement of HAART. 27 had platelets below 150,000 cells/microlitre. Half had viral load below 500 copies/ml after 2 years of treatment and blood disorders also improved. Mean platelet count rose from 110,000 to 180,000 at 6 months. 53% had improved a platelet count.

Miguez (2002) disputed that suggestion by Servais et al that treatment with HAART leads to an improvement in thrombocytopenia. Miguez reported that low platelets persisted in 70% of 37 people, most of whom were taking HAART, at 2 years follow-up. Half of the group were injecting drug users. This study included only people with persistent thrombocytopenia which could not be attributed to other infections or medications. Thrombocytopenia improved in 11 people, of whom only 6 were on HAART. From the same team, Burbano (2001) reported that risk of thrombocytopenia was associated with: use of heroin; low selenium levels; and abnormal liver enzymes. Comparing 26 HIV-infected drug users with thrombocytopenia and 54 age-matched, HIV-infected controls, Miguez and Burbano argue that several factors predict thrombocytopenia and that thrombocytopenia may be associated with more rapid HIV disease progression in drug users, despite antiretroviral therapy.

Carbonara (2001) reported a retrospective study of 15 people with HIV-associated severe thrombocytopenia who commenced HAART. Platelet count rose significantly by months 3. Among a sub-group followed for an average of 27 months, no relapse in platelet count occurred.

Gomez (2002) treated 28 HIV-infected people with thrombocytopenia with megestrol acetate. In total, 22 had a complete response which was sustained at 2 months in 12 cases.

Rarick (1991) treated 14 adults with HIV-related thrombocytopenia with IVIG (1g/kg on days 1, 2 and 15). The median platelet count increased from 17,000 at baseline to a maximum of 220,000. All patients had responded by day eight, but the effect was transient, with the median platelet count declining to 40,000 by day 15. The investigators suggested that IVIG may be used in patients with HIV-related thrombocytopenia who required an immediate increase in platelet count.

Ellis (1987) and Stellini (1992) each reported encouraging results treating thrombocytopenia with interferon alfa. Vianelli (1993) reported that interferon alfa may increase the platelet count by prolonging platelet survival.

HIV-related thrombocytopenia has also been reported to respond to dapsone, oral steroids, splenectomy and intravenous vincristine.

Kemeny (1993) reported the results of a retrospective chart review of 22 HIV-infected patients who underwent splenectomy. The patients were classified as having ITP (n=13) or a splenic infiltrative process (MAI, KS, or lymphoma, n=9). The investigators defined a complete response to the surgery to be a platelet count above 150,000 one month post-operatively. Complete responses were observed in 11/13 patients with ITP and 6/9 with splenic infiltrative processes.

References

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