Allogeneic Hematopoietic Stem Cell Transplantation in Glanzmann Thrombasthenia Complicated by Platelet Alloimmunization

Wiegering, Verena; Winkler, Beate; Langhammer, F.; Wölfl, Matthias; Wirbelauer, Johannes; Sauer, Karsten; Kobsar, Anna; Meyer, Todd; Strauss, Armin; Bakchoul, Tamam; Eyrich, Matthias; Schlegel, Paul G.

doi:10.1055/s-0031-1273726

Cited by 10 publications

(5 citation statements)

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“…38 Allogenic bone marrow transplant has been used successfully to correct dogs and humans with GT, 39,40 although transplant-related complications (eg, graft-versus-host disease, graft failure) has limited the use of this treatment. 41,42 Gene transfer into cytokine-mobilized CD34…”

Section: Gene Therapy Targeting the Megakaryocyte Lineagementioning

confidence: 99%

Megakaryocyte- and megakaryocyte precursor–related gene therapies

Wilcox

2016

Blood

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Hematopoietic stem cells (HSCs) can be safely collected from the body, genetically modified, and re-infused into a patient with the goal to express the transgene product for an individual’s lifetime. Hematologic defects that can be corrected with an allogeneic bone marrow transplant can theoretically also be treated with gene replacement therapy. Because some genetic disorders affect distinct cell lineages, researchers are utilizing HSC gene transfer techniques using lineage-specific endogenous gene promoters to confine transgene expression to individual cell types (eg, ITGA2B for inherited platelet defects). HSCs appear to be an ideal target for platelet gene therapy because they can differentiate into megakaryocytes which are capable of forming several thousand anucleate platelets that circulate within blood vessels to establish hemostasis by repairing vascular injury. Platelets play an essential role in other biological processes (immune response, angiogenesis) as well as diseased states (atherosclerosis, cancer, thrombosis). Thus, recent advances in genetic manipulation of megakaryocytes could lead to new and improved therapies for treating a variety of disorders. In summary, genetic manipulation of megakaryocytes has progressed to the point where clinically relevant strategies are being developed for human trials for genetic disorders affecting platelets. Nevertheless, challenges still need to be overcome to perfect this field; therefore, strategies to increase the safety and benefit of megakaryocyte gene therapy will be discussed.

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Section: Gene Therapy Targeting the Megakaryocyte Lineagementioning

confidence: 99%

Megakaryocyte- and megakaryocyte precursor–related gene therapies

Wilcox

2016

Blood

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“…Early HSCT for GT patients with severe life treating bleeding complications is recommended, because it avoids HLA-and αIIbβ3-alloimmunization and the accompanying risk for non-engraftment (29)(30).…”

Section: Stem Cell Transplantation Indications Choice Of Time Pointmentioning

confidence: 99%

“…All patients showed severe bleedings signs, one patient had to be admitted to the intensive care unit (30).…”

Section: First Author Yearmentioning

confidence: 99%

“…Regarding HSCT, pre-existing anti-platelet antibodies do not automatically predict an ongoing platelet destruction or platelet non-engraftment after transplantation (13,17,25,30,(33)(34)(35), but represent a high risk for complications before and during transplantation. This may result in platelet refractoriness and bleeding events, which may require intensive care treatment, multiple transfusions, intensive haemostatic treatment (e. g. rVIIa, antifibinolytics), high dose intravenous immunoglobulins (IVIG), rituximab (36)(37) and/or immuno absorption.…”

Section: First Author Yearmentioning

confidence: 99%

“…This fact may be of particular importance in GT and allo-sensitized patients. In the ten GT patients with alloimmunization against platelets, which received conditioning with busulfan and cyclophosphamid, alloantibodies disappeared after HSCT, they are still alive without significant morbidity and with resolved bleeding phenotype (13,30,(33)(34)(35)(36), whereas in one case with TAI and CPM conditioning engraftment failure and persistence of alloantibodies were documented (17). In the last years optimal responses to rituximab therapy in case of alloantibodies have been reported in GT patients, even during conditioning (36)(37) as well as in autoimmune thrombocytopenia and several other antibody formations prior to HSCT (63)(64).…”

Section: Myeloablative Conditioning Regimesmentioning

confidence: 99%

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Indication for allogeneic stem cell transplantation in Glanzmann’s thrombasthenia

Wiegering¹,

Sauer²,

Winkler³

et al. 2013

Hamostaseologie

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SummaryGlanzmann’s thrombasthenia (GT) is an autosomal recessive disorder characterized by a lack of thrombocyte aggregation due to the absence of thrombocyte glycoproteins IIb and αIIbβ3. The role of haematopoietic stem cell transplantation (HSCT) in GT remains controversial. However, HSCT offers the only curative approach for patients with a severe clinical phenotype.In this review, we will discuss the limitation of current status evidence and the specific risk of GT, in particular the alloimmunization and refractoriness to thrombocyte infusions. 19 successful HSCT in 18 GT type I patients have been reported. Mean age at transplantation was 5 years. All patients are still alive. The majority received sibling bone marrow transplant with busulfan and cyclophosphamid conditioning. GvHD incidence was within the normal range, but 10 patients showed alloimmunization of thrombocytes. Median follow up is 25 months.

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