Plerixafor as preemptive strategy results in high success rates in autologous stem cell mobilization failure.

Plerixafor in combination with granulocyte-colony stimulating factor (G-CSF) is approved for autologous stem cell mobilization in poor mobilizing patients with multiple myeloma or malignant lymphoma. The purpose of this study was to evaluate efficacy and safety of plerixafor in an immediate rescue approach, administrated subsequently to G-CSF alone or chemotherapy and G-CSF in patients at risk for mobilization failure. Eighty-five patients mobilized with G-CSF alone or chemotherapy were included. Primary endpoint was the efficacy of the immediate rescue approach of plerixafor to achieve ≥2.0 × 106 CD34+ cells/kg for a single or ≥5 × 106 CD34+ cells/kg for a double transplantation and potential differences between G-CSF and chemotherapy-based mobilization. Secondary objectives included comparison of stem cell graft composition including CD34+ cell and lymphocyte subsets with regard to the mobilization regimen applied. No significant adverse events were recorded. A median 3.9-fold increase in CD34+ cells following plerixafor was observed, resulting in 97% patients achieving at least ≥2 × 106 CD34+ cells/kg. Significantly more differentiated granulocyte and monocyte forming myeloid progenitors were collected after chemomobilization whereas more CD19+ and natural killer cells were collected after G-CSF. Fifty-two patients underwent transplantation showing rapid and durable engraftment, irrespectively of the stem cell mobilization regimen used. The addition of plerixafor in an immediate rescue model is efficient and safe after both, G-CSF and chemomobilization and results in extremely high success rates. Whether the differences in graft composition have a clinical impact on engraftment kinetics, immunologic recovery, and graft durability have to be analysed in larger prospective studies.

Increased mortality in patients with the lupus anticoagulant: the Vienna Lupus Anticoagulant and Thrombosis Study (LATS).

Data on the clinical course of lupus anticoagulant (LA)-positive individuals with or without thrombotic manifestations or pregnancy complications are limited. To investigate mortality rates and factors that might influence mortality, we conducted a prospective observational study of LA-positive individuals. In total, 151 patients (82% female) were followed for a median of 8.2 years; 30 of the patients (20%) developed 32 thromboembolic events (15 arterial and 17 venous events) and 20 patients (13%) died. In univariable analysis, new onset of thrombosis (hazard ratio [HR] = 8.76; 95% confidence interval [CI], 3.46-22.16) was associated with adverse survival. Thrombosis remained a strong adverse prognostic factor after multivariable adjustment for age and hypertension (HR = 5.95; 95% CI, 2.43-14.95). Concomitant autoimmune diseases, anticoagulant treatment at baseline, or positivity for anticardiolipin- or anti-ß2-glycoprotein I antibodies were not associated with mortality. In a relative survival analysis, our cohort of LA positives showed a persistently worse survival in comparison with an age-, sex-, and study-inclusion-year-matched Austrian reference population. The cumulative relative survival was 95.0% (95% CI, 88.5-98.8) after 5 years and 87.7% (95% CI, 76.3-95.6) after 10 years. We conclude that occurrence of a thrombotic event is associated with higher mortality in patients with LA. Consequently, the prevention of thromboembolic events in LA positives might improve survival.

The clinical significance of anti-prothrombin antibodies for risk assessment of thromboembolism in patients with lupus anticoagulant.

INTRODUCTION: Thromboembolism is a common manifestation of lupus anticoagulant (LA), however only a subgroup of LA-patients is affected by thrombosis. Study objective was to investigate whether anti-prothrombin antibodies can identify LA-patients at increased risk for thrombosis. MATERIALS AND METHODS: In total 79 patients, 50 with (42 men/8 women) and 29 without thrombosis (21 men/8 women), were investigated for their presence of anti-prothrombin IgG and IgM antibodies using assays from two different manufacturers (Aeskulisa=assay I, CoaChrom=assay II). RESULTS: The prevalence of elevated levels of anti-prothrombin IgG, IgM as well as IgG and/or IgM antibodies was 66% [assayI] (36% [assayII]), 38% (24%) and 72% (50%) in patients with thrombosis and 55% (24%), 28% (28%) and 66% (41%) in patients without thrombosis, respectively. Neither anti-prothrombin IgG or IgM nor IgG and/or IgM antibodies were found to indicate an increased risk for thrombosis. In the subgroup of patients with arterial or venous thrombosis there was also no association between anti-prothrombin antibodies and thrombosis. The comparison of median levels of IgG and IgM anti-prothrombin antibodies between patients with and without thrombosis yielded a borderline statistically significant difference only for anti-prothrombin IgG antibodies by using assay II (p=0.033), all other comparisons were not statistically significant. CONCLUSIONS: In conclusion, presence of anti-prothrombin antibodies was not associated with thromboembolism in LA-patients.

Anti-beta2-glycoprotein I antibodies are associated with pregnancy loss in women with the lupus anticoagulant.

The presence of lupus anticoagulant (LA) predisposes to fetal loss and to venous and arterial thrombosis; however, a subgroup of women is unaffected by pregnancy loss. Currently, no predictive markers are available for the identification of women positive for LA at increased risk for pregnancy loss. It was the aim of our study to investigate whether increased anti-beta2-GPI-antibodies predict pregnancy loss in women positive for LA. We performed a cross-sectional study in a cohort of 39 women with persistent LA, who had in total 111 pregnancies. Fifteen women had exclusively normal pregnancies (30 pregnancies) and 24 women had pregnancy losses (81 pregnancies). Anti-beta2-GPI-antibodies were determined using a semiquantitative enzyme linked immunoassay (QUANTA Lite beta2 GPI IgG and IgM; Inova Diagnostics). Increased levels of anti-beta2-GPI antibodies were significantly associated with pregnancy loss [odds ratio (OR) 9.6, 95% confidence interval (CI) 1.6-56.4]. This risk was even higher in the subgroup of women (n = 16) with more than two miscarriages or fetal loss after the first trimester [OR 13.1, 95% CI 1.4-126.3]. There was no significant association between anticardiolipin antibodies and pregnancy loss [OR 3.5, 95% CI 0.7-17.6]. The co-existence of anti-beta2-GPI and anticardiolipin antibodies was also predictive for pregnancy loss [OR 6.1, 95% CI 1.3-29.7]. Interestingly, the prevalence of thrombosis was similar between women with normal pregnancy (87%) and those with pregnancy loss (75%). We conclude that increased levels of anti-beta2-GPI antibodies are predictive for pregnancy loss among women positive for LA, and that prophylactic treatment should be considered in these women even without a history of previous pregnancy loss.

The Fc gammaRIIa polymorphism R/H131, autoantibodies against the platelet receptors GPIb alpha and Fc gammaRIIa and a risk for thromboembolism in lupus anticoagulant patients.

There is a clear propensity of individuals with lupus anticoagulant (LA) for thromboembolic disease (TE). Yet, it is not clear how individuals at risk for TE can be differentiated from those who are not. The Fc gammaRIIa receptor is the only Fc receptor expressed by platelets. As platelets can be activated via this receptor, we have compared gene frequencies of the Fc gammaRIIa polymorphism R/H131 in 46 and 27 patients with (LA/TE+) and without TE (LA/TE-), respectively, in an exploratory study. Furthermore, we investigated the presence of autoantibodies against Fc gammaRIIa and/or GPIb alpha, which is in close proximity to the Fc gammaRIIa and interacts with it functionally, and a possible linkage of antibody formation to HLA class II alleles. The Fc gammaRIIa-R/R131 genotype was significantly less frequent in patients with LA compared to controls (p<0.025). These findings were due to an increased frequency of heterozygous patients in the LA/TE+ cohort (odds ratio 6.76, 95% confidence interval 1.55-62.03, p<0.008). For the first time, heterozygosity, rather than homozygosity, can be linked to disease, which may be explained by the dual function of the Fc gammaRIIa, namely binding of antibodies to platelets and thereby their activation, and, on the other hand, clearance of antibody coated platelets by the phagocyte system. There was no correlation between the presence of anti-Fc gammaRIIa or anti-GPIb alpha autoantibodies and the Fc gammaRIIa-R/H131 polymorphism, nor the incidence of TE, nor HLA class II alleles.

Mortality in severe, non aggressively treated adult autoimmune thrombocytopenia.

A total of 130 consecutive patients with severe autoimmune thrombocytopenia (AITP) who were diagnosed and treated in our institution between 1991 and 2001 were followed up. The patients were almost exclusively treated with prednisolone, immunoglobulin and/or splenectomy. The aim of the treatment was to keep the platelet count at least above 10,000 microL. None of the patients died from bleeding, two patients died from infection and seven from other unrelated causes. These data show that AITP is a relatively benign disease that does not require aggressive treatment. Bleeding can be prevented if the platelet count can be kept above 10,000 microL.