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Summary: Few studies have reported the real‐world use of both romiplostim and eltrombopag in immune thrombocytopenia (ITP). TRAIT was a retrospective observational study aimed to evaluate the platelet responses and adverse effects associated with the use of these thrombopoietin receptor agonists (TPO‐RAs) in adult patients with ITP in the United Kingdom. Of 267 patients (median age at diagnosis, 48 years) with ITP (primary ITP [n = 218], secondary ITP [n = 49]) included in the study, 112 (42%) received eltrombopag and 155 (58%) received romiplostim as the first prescribed TPO‐RA. A platelet count ≥30 × 109/L was achieved in 89% of patients with the first TPO‐RA treatments, while 68% achieved a platelet count ≥100 × 109/L. Treatment‐free response (TFR; platelet count ≥30 × 109/L, 3 months after discontinuing treatment) was achieved by 18% of the total patients. Overall, 61 patients (23%) switched TPO‐RAs, most of whom achieved platelet counts ≥30 × 109/L with the second TPO‐RA (23/25 who switched from eltrombopag to romiplostim [92%]; 28/36 who switched from romiplostim to eltrombopag [78%]). TFR was associated with secondary ITP, early TPO‐RA initiation after diagnosis, the presence of comorbidity and no prior splenectomy or treatment with steroids or mycophenolate mofetil. Both TPO‐RAs had similar efficacy and safety profiles to those reported in clinical studies. [ABSTRACT FROM AUTHOR]

Summary: Multiple studies have reported immune thrombocytopenia (ITP) relapse following SARS‐CoV‐2 vaccination, however baseline ITP relapse rate and antibody response to vaccination are not known. Patients with ITP who received at least one of the first three SARS‐CoV‐2 vaccination doses were included in the study. One hundred and twenty‐four patients met the inclusion criteria. Relapse rate was 4.2% following a first vaccine dose, 9.1% after a second and 2.9% after a third; baseline relapse rate was 7.6%. Ninety‐four per cent of patients who received three vaccine doses developed a clinical antibody response. SARS‐CoV‐2 vaccination appears to be safe and effective in patients with ITP. [ABSTRACT FROM AUTHOR]

The absence of reliable biomarkers in immune thrombocytopenia (ITP) complicates treatment choice, necessitating a trial‐and‐error approach. Machine learning (ML) holds promise for transforming ITP treatment by analysing complex data to identify predictive factors, as demonstrated by Xu et al.'s study which developed ML‐based models to predict responses to corticosteroids, rituximab and thrombopoietin receptor agonists. However, these models require external validation before can be adopted in clinical practice. Commentary on: Xu et al. A novel scoring model for predicting efficacy and guiding individualised treatment in immune thrombocytopenia. Br J Haematol 2024; 205:1108‐1120. [ABSTRACT FROM AUTHOR]

COVID-19 causes significant thrombosis and coagulopathy, with elevated D-dimer a predictor of adverse outcome. The precise mechanism of this coagulopathy remains unclear; one hypothesis is that loss of angiotensin-converting enzyme 2 activity during viral endocytosis leads to pro-inflammatory angiotensin-II accumulation, loss of angiotensin-1-7 and subsequent vascular endothelial activation. We undertook a double-blind randomized, placebo-controlled experimental medicine study to assess the effect of TRV027, a synthetic angiotensin-1-7 analogue on D-dimer in 30 patients admitted to hospital with COVID-19. The study showed a similar rate of adverse events in TRV027 and control groups. There was a numerical decrease in D-dimer in the TRV027 group and increase in D-dimer in the placebo group; however, this did not reach statistical significance (P = .15). A Bayesian analysis demonstrated that there was a 92% probability that this change represented a true drug effect. [ABSTRACT FROM AUTHOR]

Summary: Patients with refractory immune thrombocytopenia (rITP) have increased morbidity and mortality. Currently, there is limited understanding of the cause of refractoriness and no markers to help direct novel treatment options. Understanding the reason(s) for refractoriness is crucial to determining novel treatment options. The pathogenesis underlying rITP has generally been thought to be an underlying genetic predisposition with an environmental trigger. Familial ITP remains rare, and there are few twin studies, suggesting that a simple genetic cause is unlikely. However, genetic mutations provide the background for several autoimmune diseases. In this review, we explore the evidence of either an inherited genetic cause of rITP or an acquired mutation, in particular one resulting in clonal expansion of cytotoxic T cells. [ABSTRACT FROM AUTHOR]

Summary: Although modern clinical management strategies have improved the outcome of paediatric patients with severe autoimmune and inflammatory diseases over recent decades, a proportion will experience ongoing or recurrent/relapsing disease activity despite multiple therapies often leading to irreversible organ damage, and compromised quality of life, growth/development and long‐term survival. Autologous and allogeneic haematopoietic stem cell transplantation (HSCT) have been used successfully to induce disease control and often apparent cure of severe treatment‐refractory autoimmune diseases (ADs) in children. However, transplant‐related outcomes are disease‐dependent and long‐term outcome data are limited in respect to efficacy and safety. Moreover, balancing risks of HSCT against AD prognosis with continually evolving non‐transplant options is challenging. This review appraises published literature on HSCT strategies and outcomes in individual paediatric ADs. We also provide a summary of the European Society for Blood and Marrow Transplantation (EBMT) Registry, where 343 HSCT procedures (176 autologous and 167 allogeneic) have been reported in 326 children (<18 years) for a range of AD indications. HSCT is a promising treatment modality, with potential long‐term disease control or cure, but therapy‐related morbidity and mortality need to be reduced. Further research is warranted to establish the position of HSCT in paediatric ADs via registries and prospective clinical studies to support evidence‐based interspeciality guidelines and recommendations. [ABSTRACT FROM AUTHOR]

Registries are essential tools for a better comprehension of rare disease epidemiology and management.1 Immune thrombocytopenia (ITP) is a rare disease with an annual incidence rate of about three per 100 000 individuals.2 Knowledge has been generated in ITP epidemiology during the last decade thanks to large cohorts of patients with ITP, including the recognition of factors related to variations in incidence, clinical course, predictors of chronicity, risk factors for bleeding, infection and thrombosis, as well as the determination of real-world treatment strategies.3 Nevertheless, many issues remain unknown in ITP (Table S1). In the Nordic chronic ITP registry, also called Nordic Country Patient Registry for Romiplostim (NCPRR), the diagnosis of ITP has been further validated by medical chart review of all included patients. [Extracted from the article]

Summary: Autoimmune haemolytic anaemia (AIHA) is a rare complication of allogeneic haematopoietic stem cell transplantation (HSCT), observed with an incidence of 1–5%. Paediatric age, diagnosis of non‐malignant disease, lympho‐depleting agents in the conditioning regimen, use of unrelated donor, graft versus host disease and infections have been associated with a higher risk of AIHA post HSCT. Post‐HSCT AIHA is associated with high mortality and morbidity, and it is often very difficult to treat. Steroids and rituximab are used with a response rate around 30–50%. These and other therapeutic strategies are mainly derived from data on primary AIHA, although response rates in post‐HSCT AIHA have been generally lower. Here we review the currently available data on risk factors and therapeutic options. There is a need for prospective studies in post‐HSCT AIHA to guide clinicians in managing these complex patients. [ABSTRACT FROM AUTHOR]

Summary: Immune thrombocytopenia (ITP) is an acquired immune‐mediated disorder. Bleeding is the primary symptom that presents in varying severities. ITP has a negative impact on health‐related quality of life (HRQoL). The ITP Life Quality Index (ILQI) was developed as a 10‐item patient‐reported outcome measure to assess impact on HRQoL in ITP. The objective of the present study was to confirm the content validity of the ILQI with a qualitative interview study in the UK involving 15 adult participants with ITP. Combined concept elicitation (CE) and cognitive debriefing (CD) interviews were conducted to explore the symptoms and impacts associated with ITP and confirm content validity of the draft ILQI. The CE phase elicited 14 ITP symptom concepts, including: bruising (all 15 patients, 100%), fatigue (14, 93·3%) and bleeding gums/blood blisters (13, 86·7%). Impacts included decreased ability to participate in sport (all 15 patients, 100%) and anxiety (12, 80%). The CD phase resulted in an adjustment to the ILQI recall period from 1 week to 'the past month'. Updates were made to improve relevance and response options. The qualitative interviews support the content validity of the ILQI and confirm that the concepts assessed are relevant and consistently understood and interpreted by adult patients with ITP. [ABSTRACT FROM AUTHOR]

This patient has chronic ITP which warrants initiation of treatment, since the current platelet counts are < 30 × 10 SP 9 sp /L. The second line of treatment will be either azathioprine (2-3 mg/kg/day) or dapsone (1-2 mg/kg/day). We occasionally find a patient who is unresponsive to any medical therapy and maintains platelet counts of only 10-20 × 10 SP 9 sp /l. In such patients, if a caesarean section is planned for an obstetric indication, we would consider performing a splenectomy at the same time.16 I The patient once more has an uneventful birth, but at a follow-up with you 30 days post-partum, platelets are now on two consecutive occasions 20-30 × 109/l i . As haematologists, we always seek to follow standardized guidelines for practice and apply the best treatment within our means for our patients with blood diseases. I would use a therapy with a robust evidence of activity, (i.e., splenectomy or a TPO-RA or rituximab), according to the patient's previous treatment history and the patient's characteristics and expectations.1 Conclusions (N Cooper) The management of ITP, particularly during pregnancy, is not straightforward. [Extracted from the article]

Fostamatinib demonstrated efficacy in phase 3 trials of adults with immune thrombocytopenia (ITP). Post hoc analysis compared patients who received fostamatinib as second‐line therapy (after steroids ± immunoglobulins) versus third‐or‐later‐line therapy (after ≥2 prior lines of therapy including a second‐line agent). Platelet responses ≥50 000/µl were observed in 25/32 (78%) second‐line and 54/113 (48%) third‐or‐later‐line patients. Bleeding events were less frequent in second‐line (28%) versus third‐or‐later‐line (45%) patients. Responses once achieved tended to be durable in both groups. The safety profile was similar in both groups. In this post hoc analysis, fostamatinib was more effective as second‐line than third‐or‐later‐line therapy for ITP. [ABSTRACT FROM AUTHOR]

The article offers a study on detection of anti-platelet antibodies (APabs) in immune thrombocytopenia, an autoimmune disorder characterized by low platelet count through flow cytometry, resulting from platelet destruction or platelet production. Topics include diagnosis and detection of patients for immunoglobulin g bound to platelet surfaces. Longitudinal analysis of APabs positivity/negativity in identifying patients whose APAbs are pathogenic, and those whose disease is manifest.

The article discusses the United Kingdom (UK) immune thrombocytopenia (ITP) forum to assess several aspects of prescribing practice for the use of thrombopoietin receptor agonists (TPO-RA). Topics discussed include preference for TPO-RA than splenectomy, the National Institute for Health and Care Excellence's (NICE) recommendations for the uses of TPO-RA, efficacy and side effect profiles of romiplostim and eltrombopag and marrow fibrosis in a subset of patients on TPO-RA.

The management of patients with immune thrombocytopenia ( ITP) is rapidly evolving. Over the last 15 years, a number of novel treatments have improved practice, with many steroid-sparing agents and a reduction in the progression to splenectomy. Although this has improved clinical care, many therapeutic challenges remain. There is no diagnostic test, no biomarkers to direct treatment and few comparative studies to help management decisions. Development of up to date guidelines is difficult with little high-grade evidence. First line treatment continues to be steroids and intravenous immunoglobulins ( IVIG) although both are often poorly tolerated and not curative. Common second line treatments include rituximab, immunosuppressive agents, such as azathioprine and mycophenolate mofetil, and the thrombopoietin receptor agonists romiplostim and eltrombopag. There are no comparative studies to decide between these agents and treatment is generally individualized, depending on comorbidity. Use of splenectomy has declined and is generally reserved for patients with chronic disease, although the exact position of splenectomy is subject to debate. Further understanding of the cause of disease in individual patients may help guide treatment. Randomized controlled studies of common treatments and novel treatments for refractory patients are urgently needed. [ABSTRACT FROM AUTHOR]

In order to investigate the I FAS, TNFRSF13B WAS i mutation spectrum in ITP, we sequenced coding regions and exon/intron boundaries of the I FAS i and I WAS i genes in 130 adults with persistent or chronic primary ITP. Furthermore, in view of the association of I FAS i mutations with ITP as part of Evans syndrome, we deliberately included a total of 10 such patients, none of whom had I FAS i mutations. [Extracted from the article]

Severe immune thrombocytopenia purpura ( ITP) presents a clinical challenge. Second-line treatment options are variable without a precise protocol. We present 46 severe ITP patients treated with mycophenolate mofetil ( MMF), retrospectively identified from three London teaching hospitals. Data was collected on patient demographics, co-morbidities and previous treatment strategies. Our key interest was whether there was a sustained response in platelet count to MMF. Patients included 27 males and 19 females whose ages ranged from 19 to 93 years old (median 52·5 years). Twenty-nine had primary ITP and 17 had secondary ITP, a third of whom had viral-associated disease. The standard dose of MMF was 1 g/day. Twenty-four patients (52%) responded with 15 (33%) achieving a complete response. No active viral-associated ITP patients demonstrated a response to MMF, although numbers were small ( n = 4). We were not able to demonstrate a difference between responders and non-responders based on gender, age, previous therapies or time since diagnosis of ITP. Three of four previously splenectomized patients responded, two achieving complete response. We conclude that MMF is a useful steroid-sparing immunosuppressant to be considered in the second-line or later treatment of ITP. [ABSTRACT FROM AUTHOR]

An introduction is presented which discusses reports on topics including blood transfusion, use of imatinib to treat chronic myeloid leukaemia, and sickle cell disease.

Most children with immune thrombocytopenia ( ITP) have transiently low platelet counts and do not suffer from bleeding. Treatments with steroids, immunosuppression or splenectomy are not thought to be curative and may create more problems than the low platelet count. Consequently, many children do not receive treatment unless there is bleeding. However, although registry data looks promising, this approach outcome is not consistent between countries, or even between centres in the same country, leading to confusion for both physicians and families. Reaching a consensus for the management of paediatric ITP is further complicated by the lack of a diagnostic test and by the heterogeneity of the disease; for example, although most children remain relatively asymptomatic and go into an early remission, some patients have significant bleeding and others do not go into spontaneous remission. This review assesses the available evidence to guide physicians and families on making management decisions, showing the wide range of treatment choices, and the different approaches between countries and considers methods by which further information could be acquired to provide a more stratified approach to management. [ABSTRACT FROM AUTHOR]

Rituximab is widely used in autoimmune diseases including immune thrombocytopenia ( ITP), although the mechanism of effect remains unclear. This study describes the effects of rituximab on platelet-associated antibodies ( PA- APAs), B and T cell counts and clonality ( IGHV and TRG@ gene rearrangements), FCGR3A ( Fcγ RIIIa) and FCGR2A ( Fcγ RIIa) polymorphisms and correlation to anti- CD40 ligand (CD40L) response. PA- APA levels fell more frequently in responders (6/8) than in non-responders (2/10: P = 0·08-0·15). Two responders had no PA- APAs. Two non-responders with a fall in PA- APAs had very high CD8 levels. One non-responder had a B cell clone, one responder and one non-responder had a T cell clone. 15/16 patients had the same responses to rituximab and anti CD40 L. Patients with FCGR3A V/ V polymorphisms were more likely to respond to rituximab ( P = 0·03). In summary, the fall in PA- APAs in responders confirms the humoural effect of rituximab. Failure to respond in patients with very high CD8 levels, despite PA- APA fall indicates a role for T cell-mediated platelet/megakaryocyte destruction. Concordance of response to anti- CD40 L suggests autoantibody-producing cells are under T cell control. Finally, the effect of FCGR polymorphisms on response confirms the importance of FCGR-mediated depletion of B cells in autoimmunity. This has implications on the pathology of ITP as well as the immunological effect of B cell depletion. [ABSTRACT FROM AUTHOR]

Non-healing wounds cause considerable patient morbidity and represent a significant economic burden. Central to wound repair is re-epithelialization, a crucial process involving the modulation of cell adhesion to allow keratinocyte migration to cover the exposed underlying tissues. The cellular mechanisms regulating the earliest stages of re-epithelialization are unclear. We present the first direct evidence that protein kinase Cα (PKCα) plays an important role in regulating wound re-epithelialization. In PKCα−/− mice re-epithelialization is delayed, while in novel bitransgenic mice over-expressing constitutively active PKCα it is accelerated. These effects are not due to changes in keratinocyte proliferation, apoptosis or intrinsic cell motility. Instead, they correlate with changes in desmosomal adhesiveness, delay being preceded by retained desmosomal hyper-adhesiveness and acceleration with a rapid switch to desmosomal Ca2+-dependence. We demonstrate mechanistic conservation in acute human wounds where PKCα localizes to wound edge desmosomes, which become Ca2+-dependent. However, in chronic wounds PKCα remains cytoplasmic and desmosomes fail to switch from the hyper-adhesive state. These results throw new mechanistic light on the earliest stages of wound re-epithelialization and suggest activation of PKCα as a new therapeutic strategy for non-healing wounds. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Depletion of B lymphocytes using the anti-CD20 monoclonal antibody rituximab has wide-spread use in the treatment of patients with autoimmune disorders. As haematopoietic progenitor cells and only a fraction of differentiated plasma express CD20, the effect of rituximab on immune function appears to be minimal. However, hypogammagobulinaemia can occur with repeated doses and emerging data from large studies suggest a subtle increase in the risk of infection. Reactivation of latent JC virus, resulting in progressive multifocal leucoencephalopathy, and hepatitis B virus, resulting in hepatoxicity, have been documented in patients receiving rituximab; although confounding effects of concomitant immunosuppressive therapies and immune dysregulation due to the underlying disease make causal associations of infections problematic. This review discusses the efficacy of B cell depletion therapy in the treatment of autoimmune diseases, the effect of B cell depletion on infection and immunity including the role of the B cell in autoimmunity, and identifies areas of controversy. [ABSTRACT FROM AUTHOR]

Immune thrombocytopaenic purpura (ITP) is an autoimmune bleeding disease that is rarely fatal. However, in many adults treatment is unsatisfactory, with as much morbidity from the immunosuppressive effects of treatment as from bleeding. Identifying the underlying disease process should help us to identify more targeted therapies and improve not only the treatment but also the quality of life of patients with this disorder. [ABSTRACT FROM AUTHOR]

Because of its B-cell depleting effect, rituximab has entered clinical trials in several autoimmune conditions. This study assesses the efficacy and safety of rituximab in 57 adults with chronic immune thrombocytopenic purpura (ITP). All patients had platelet counts <30 × 109/l, all had received two or more previous ITP treatments and 31 had undergone splenectomy. Patients received rituximab 375 mg/m2 weekly for 4 weeks. Thirty-one patients (54%) responded, achieving a platelet count >50 × 109/l: 18 achieved a complete response (CR: platelet count >150 × 109/l) and 13 a partial response (PR: platelet count 50–150 × 109/l). Twenty-nine responses occurred within 8 weeks of the first infusion. Sixteen of 18 CR patients (28% overall), including eight who had failed splenectomy, continued in CR after a median of 72·5 weeks; 15 of 16 are >1 year from the first infusion. Only two of 13 maintained a PR. Thirty-three patients experienced grade 1–2 adverse events and one a grade 3 event, but they all completed treatment. Circulating B cells fell to <0·03 × 109/l. No changes in immunoglobulin levels or infectious complications were seen. In summary, rituximab was well tolerated with no immediate complications and induced a lasting, substantial response in 32% of adults with chronic ITP. [ABSTRACT FROM AUTHOR]

Intravenous (IV) anti-D and IV immunoglobulin (IVIG) slow the Fc γ receptor (Fc γR)-mediated destruction of antibody-coated platelets in patients with immune thrombocytopenic purpura (ITP). This pilot study explored the mechanism of these immunoglobulin preparations by measuring interleukin-10 (IL-10), monocyte chemoattractant protein-1 (MCP-1), IL-6 and tumour necrosis factor  α (TNF α), before and after infusion and by assessing the effect of Fc γRIIa and Fc γRIIIa polymorphisms on both cytokine and haematologic responses to anti-D. Following IVIG, only IL-10 was increased at 2 h and MCP-1 on day 7 ( P < 0·05). In contrast, 2 h after anti-D infusion, plasma levels of all four cytokines were increased ( P < 0·01); five of six patients with the highest MCP-1, IL-6 and TNF α levels had chills. Higher IL-10 levels correlated with platelet increases at 24 h and haemoglobin decreases at day 7 ( P < 0·025). Patients with the Fc γRIIa-131HH genotype had significantly higher MCP-1, IL-6 and TNF α levels. Patients with the Fc γRIIIa-158VF genotype had higher platelet increments at day 7 ( P < 0·05). Soluble CD16 (sCD16) was increased 2 h after IV anti-D; day 7 levels correlated with day 7 haemoglobin decreases ( P < 0·01). In conclusion, the relationship of Fc γRIIa and Fc γRIIIa polymorphisms with both cytokine levels and platelet increments implicated these receptors in responses to anti-D and supported different mechanisms of Fc γR interaction to those seen with IVIG. [ABSTRACT FROM AUTHOR]

The article presents information on the diagnosis of autoimmune lymphoproliferative disorder type III with rituximab in a 10-year old boy. Due to repeated episodes of idiopathic thrombocytopenic purpura (ITP) and autoimmune neutropenia and following three courses of steroids, he received rituximab 375 mg weekly in July 2002. This lead to a complete resolution (CR) of both ITP and autoimmune neutropenia and virtual disappearance of lymphadenopathy.

An introduction is presented in which the editor discusses various reports within the issue that includes significance of Fas pathway among immune thrombocytopenia (ITP) patients; illustration of difference in proportion of several immune cells; and association of ITP with impaired apoptosis.

The article reflects on the functional aspects of megakaryocyte-platelet system. Topics discussed include use of genetics for the diagnosis of platelet function disorders, understanding of megakaryocytic development and platelet production, and platelet disorders linked with thrombocytopenic patients. Also investigated is the role of platelets in cancer, metastases and immunity.

The article presents a study on the addition of alpha interferon (IFN&#X03B1) to increase the graft-versus-leukaemia (GVL) for the children with leukaemia. It mentions that the there were 17 patients received an IFN&#X03B1 therapy with initial stem cell transplantation (SCT). It concludes that the early use of IFN&#X03B1 lessens the mortality from graft-versus-host disease (GVHD).

An introduction to the journal is presented in which the editor discusses an overview of current practices in cord blood transplantation (CBT) from the establishment of cord blood banks, an important review of the use of cord blood as an alternative to other haematopoietic stem cells and an article on the importance of human leucocyte antigen [HLA] matching and stem cell dose.

An introduction is presented in which the editor discusses various reports within the issue on topics including anaemia, malaria infection, and management of haematological conditions.

Because of its B-cell depleting effect, rituximab has entered clinical trials in several autoimmune conditions. This study assesses the efficacy and safety of rituximab in 57 adults with chronic immune thrombocytopenic purpura (ITP). All patients had platelet counts < 30 x 10(9)/l, all had received two or more previous ITP treatments and 31 had undergone splenectomy. Patients received rituximab 375 mg/m(2) weekly for 4 weeks. Thirty-one patients (54%) responded, achieving a platelet count >50 x 10(9)/l: 18 achieved a complete response (CR: platelet count >150 x 10(9)/l) and 13 a partial response (PR: platelet count 50-150 x 10(9)/l). Twenty-nine responses occurred within 8 weeks of the first infusion. Sixteen of 18 CR patients (28% overall), including eight who had failed splenectomy, continued in CR after a median of 72.5 weeks; 15 of 16 are >1 year from the first infusion. Only two of 13 maintained a PR. Thirty-three patients experienced grade 1-2 adverse events and one a grade 3 event, but they all completed treatment. Circulating B cells fell to < 0.03 x 10(9)/l. No changes in immunoglobulin levels or infectious complications were seen. In summary, rituximab was well tolerated with no immediate complications and induced a lasting, substantial response in 32% of adults with chronic ITP.

Intravenous (IV) anti-D and IV immunoglobulin (IVIG) slow the Fcgamma receptor (FcgammaR)-mediated destruction of antibody-coated platelets in patients with immune thrombocytopenic purpura (ITP). This pilot study explored the mechanism of these immunoglobulin preparations by measuring interleukin-10 (IL-10), monocyte chemoattractant protein-1 (MCP-1), IL-6 and tumour necrosis factor alpha (TNFalpha), before and after infusion and by assessing the effect of FcgammaRIIa and FcgammaRIIIa polymorphisms on both cytokine and haematologic responses to anti-D. Following IVIG, only IL-10 was increased at 2 h and MCP-1 on day 7 (P < 0.05). In contrast, 2 h after anti-D infusion, plasma levels of all four cytokines were increased (P < 0.01); five of six patients with the highest MCP-1, IL-6 and TNFalpha levels had chills. Higher IL-10 levels correlated with platelet increases at 24 h and haemoglobin decreases at day 7 (P < 0.025). Patients with the FcgammaRIIa-131HH genotype had significantly higher MCP-1, IL-6 and TNFalpha levels. Patients with the FcgammaRIIIa-158VF genotype had higher platelet increments at day 7 (P < 0.05). Soluble CD16 (sCD16) was increased 2 h after IV anti-D; day 7 levels correlated with day 7 haemoglobin decreases (P < 0.01). In conclusion, the relationship of FcgammaRIIa and FcgammaRIIIa polymorphisms with both cytokine levels and platelet increments implicated these receptors in responses to anti-D and supported different mechanisms of FcgammaR interaction to those seen with IVIG.