ALLOIMMUNE THROMBOCYTOPENIA

The subcommittee continues efforts toward providing a consensus statement on the management of alloimmune thrombocytopenia caused by maternal alloimmunization against fetal platelets. In previous meetings the laboratory evaluation of suspected cases has been discussed. The name for this syndrome has been proposed to be "alloimmune thrombocytopenia" ("AIT"), rather than "neonatal" alloimmune thrombocytopenia ("NATP"). The proposed nomenclature is appropriate because thrombocytopenia usually is present during gestation in affected pregnancies and because an affected fetus can suffer from serious hemorrhage antenatally as well as during the perinatal period.

This year’s meeting focussed on the clinical management of families affected with alloimmune thrombocytopenia. Presentations by Drs. Bussel and Kaplan were followed by a focussed discussion among the members present at the meeting. The first affected infant in a family is usually diagnosed based upon the clinical presentation of isolated thrombocytopenia in an otherwise healthy full term neonate. The suspected condition often requires therapy before serologic confirmation can be obtained. Transfusion with antigen negative platelets is appropriate if there is severe thrombocytopenia or serious hemorrhage. Diagnostic imaging (ultrasound or CT scan) should be performed to determine whether there is intracranial bleeding. The mother is usually the donor for the antigen negative platelets. However, alternative therapy may need to be started if there will be a delay in obtaining, processing, and testing maternal platelets. Maternal platelets must be 1) washed or plasma depleted to minimize the transfer of antiplatelet alloantibody, 2) irradiated to prevent graft versus host disease, and 3) filtered to reduce the risk of embolization of platelet aggregates. Alternative treatments (e.g., IV IgG, steroids, exchange transfusion, and transfusion with random donor platelets) may be initiated while preparing the antigen negative platelets.

After the diagnosis of AIT is confirmed, the family must be informed about the risk of this syndrome in subsequent pregnancies. Paternal genotyping for the platelet allotype implicated is appropriate. Subsequent pregnancies should be managed with the consultation of a high risk perinatal center. There is currently no antenatal intervention that can prevent thrombocytopenia and hemorrhage in all cases, but IV IgG infusions (with or without steroids) and fetal platelet transfusions during pregnancy have been reported to be efficacious in some cases. Several intervention protocols are under evaluation in North America and Europe. Affected families should be informed about these protocols and be offered referral to a specialty center. The subcommittee will prepare a manuscript to summarize the areas of consensus in this field.

AUTOIMMUNE THROMBOCYTOPENIA

Dr. Bussel presented a summary of current therapies used to treat autoimmune thrombocytopenia (ITP). First line treatments include steroids (oral or intravenous), IV IgG, and anti-D. Dr. Bussel cautioned that the time to achieve a platelet response with anti-D is longer than with IgG (72 hours, compared to 24-48 hours). However, preliminary results with a higher dose of anti-D (75mcg/kg, rather than 50mcg/kg) indicate a more rapid response.

Dr. Warrier presented results of her retrospective review of 16 pediatric patients with Evan's Syndrome. This group of patients was distinguished by the presence of multi- system aspects of the disease such as lymphoproliferation. These patients had an extremely poor outcome with 36% mortality from hemorrhage and post-splenectomy sepsis. Discussion indicated that the prognosis for adults with Evan's Syndrome tends to be better than for the pediatric patients reported.

AUTOIMMUNE THROMBOCYTOPENIA: WHICH PATIENTS ARE APPROPRIATE CANDIDATES FOR STEM CELL TRANSPLANTATION?

Stem cell transplantation (autologous and allogeneic) has been reported to be effective therapy for autoimmune diseases. Dr. Ertem reviewed the published reports and European Bone Marrow Transplant data base experience with this therapy. For serious autoimmune disease overall the long term results are promising; remissions resulted in 87% of cases after allogeneic stem cell transplantation and in 33% of cases after autologous transplantation. The European League Against Rheumatologic Diseases has recommended specific guidelines for severity of rheumatologic diseases that might warrant transplantation therapy. The Platelet Immunology Subcommittee set a goal to prepare analogous recommendations for patients with immune thrombocytopenia.

The clinical results of stem cell transplantation to date for patients with ITP and Evan's Syndrome are not encouraging. After a 1997 publication reporting complete response of two ITP patients after autologous stem cell transplantation, both of the reported patients relapsed (12 and 18 months post transplant). In only eight ITP patients have autologous stem cell transplantation results been reported. Results are as follows: three patients - complete responses (two relapsed at 12 and 18 months; third patient in remission but currently only eight months post transplant), one patient - partial response at eight months post transplant, and four patients - no response. One Evan's Syndrome patient is in complete remission eight months after autologous transplantation.

Allogeneic stem cell transplantation has been effective in correcting autoimmune thrombocytopenia in an animal model. The risk of standard allogeneic transplantation may be too high to warrant this therapy for most patients with immune cytopenias although non-myeloablative preparative regimens might provide better options by decreasing the procedure-related mortality rate.

Only those patients who are refractory to available therapies should currently be considered candidates for stem cell transplantation. Data are needed on long-term outcomes of subsets of ITP patients to allow assessment of current mortality rates for refractory patients. There presently is an ongoing international registry of pediatric ITP patients, but a registry of adult patients is also needed. It was recommended that at the present time stem cell transplantation for patients with immune cytopenias only take place as part of a clinical investigation protocol. Dr. Ertem will lead the subcommittee in preparing a consensus statement in this area.

DRUG RELATED IMMUNE THROMBOCYTOPENIA

A proposal by Dr. Chong to organize an international wet workshop to assess results of laboratory testing for heparin-dependent antibodies was enthusiastically approved. Interested laboratory directors will communicate with Dr. Chong. He will also invite participation from laboratories active in this area that may not have been represented at this meeting. The goal will be to present the results at the 2000 meeting in the Netherlands.

NOMENCLATURE

The subcommittee chair will circulate proposals for platelet alloantigen nomenclature to interested members. Proposals will also be shared with the ISBT working party on platelet antigens. The goal is to achieve consensus with the ISBT by the time of the 2000 SSC meeting. The WHO liaison representatives will be encouraged to participate in this consensus activity.