Clinical outcomes in a cohort of patients with heparin-induced thrombocytopenia.

Background: Heparin-induced thrombocytopenia (HIT) is a thrombotic disorder usually prompting treatment with non-heparin anticoagulants. The benefits and risks of such treatments have not been fully assessed.

Methods: We analyzed data for 442 patients having a positive heparin-platelet factor 4 antibody test and recent heparin exposure.

Blood group A mothers are more likely to develop anemia during antenatal intravenous immunoglobulin treatment of fetal and neonatal alloimmune thrombocytopenia.

Background: Incompatibility between parental platelet (PLT) antigens may lead to sensitization of mother and development of fetal and neonatal alloimmune thrombocytopenia (FNAIT) resulting in fetal thrombocytopenia. Intravenous immunoglobulin (IVIG) with or without prednisone is the most effective, evidence-based antenatal treatment for subsequent FNAIT-affected pregnancies. IVIG infusion causes hemolysis in other settings, the degree depending upon patient blood groups (BGs).

Omission of fetal sampling in treatment of subsequent pregnancies in fetal-neonatal alloimmune thrombocytopenia.

Background: Fetal-neonatal alloimmune thrombocytopenia affects approximately 1 of 1000 live births, most of which are not severely thrombocytopenic. Despite effective treatment with intravenous gammaglobulin and/or prednisone, antenatal management of a subsequent affected pregnancy is complicated by the risks associated with fetal blood sampling. Furthermore, there are no biomarker(s) of high risk other than the occurrence of intracranial hemorrhage in a previous sibling.

A Novel PF4-Dependent Platelet Activation Assay Identifies Patients Likely to Have Heparin-Induced Thrombocytopenia/Thrombosis.

Background: Almost without exception, patients with heparin-induced thrombocytopenia/thrombosis (HIT) have antibodies that recognize platelet factor 4 (PF4) in a complex with heparin; however, many heparin-treated patients without HIT are also antibody-positive. A platelet activation test, the serotonin release assay (SRA), is useful for identifying a subset of antibodies that are platelet-activating and most likely to cause HIT. However, this "gold standard" assay for HIT diagnosis is technically demanding and is routinely available only through referral laboratories, limiting its availability for timely diagnosis and management.

Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection.

High-dose granulocyte transfusion therapy has been available for 20 years, yet its clinical efficacy has never been conclusively demonstrated. We report here the results of RING (Resolving Infection in Neutropenia with Granulocytes), a multicenter randomized controlled trial designed to address this question. Eligible subjects were those with neutropenia (absolute neutrophil count <500/μL) and proven/probable/presumed infection.

Suppression of in vitro megakaryopoiesis by maternal sera containing anti-HPA-1a antibodies.

Incompatibility of the human platelet antigen-1 (HPA-1) system is the most common cause of fetal/neonatal alloimmune thrombocytopenia (F/NAIT) and is thought to be mediated by accelerated clearance of antibody-opsonized fetal platelets. We evaluated the effect of maternal sera containing anti-HPA-1a antibodies (F/NAIT sera) on in vitro megakaryopoiesis. Compared with control maternal sera, 14 out of 17 F/NAIT sera significantly reduced megakaryocyte (MK) number.

Effects of red-cell storage duration on patients undergoing cardiac surgery.

Background: Some observational studies have reported that transfusion of red-cell units that have been stored for more than 2 to 3 weeks is associated with serious, even fatal, adverse events. Patients undergoing cardiac surgery may be especially vulnerable to the adverse effects of transfusion.

Methods: We conducted a randomized trial at multiple sites from 2010 to 2014.

Heparin-independent, PF4-dependent binding of HIT antibodies to platelets: implications for HIT pathogenesis.

Antibodies specific for platelet factor 4 (PF4)/heparin complexes are the hallmark of heparin-induced thrombocytopenia and thrombosis (HIT), but many antibody-positive patients have normal platelet counts. The basis for this is not fully understood, but it is believed that antibodies testing positive in the serotonin release assay (SRA) are the most likely to cause disease. We addressed this issue by characterizing PF4-dependent binding of HIT antibodies to intact platelets and found that most antibodies testing positive in the SRA, but none of those testing negative, bind to and activate platelets when PF4 is present without any requirement for heparin (P < .

Low-frequency human platelet antigens as triggers for neonatal alloimmune thrombocytopenia.

Background: Twenty-four low-frequency human platelet antigens (LFHPAs) have been implicated as immunogens in neonatal alloimmune thrombocytopenia (NAIT). We performed studies to define more fully how often these antigens trigger maternal immunization leading to NAIT.

Study Design And Methods: In a Phase 1 study, fathers of selected NAIT cases not resolved by serologic testing but thought to have a high likelihood of NAIT on clinical and serologic grounds were typed for LFHPAs by DNA sequencing.

Modified antibody in fetal alloimmunization.

In this issue of Blood, Ghevaert et al propose to develop a therapeutic antibody for fetal and neonatal alloimmune thrombocytopenia (FNAIT) that would block the actual antibody in sensitized mothers from binding and therefore prevent, or at least ameliorate, fetal and neonatal thrombocytopenia in fetuses who would otherwise be affected.1 The goal of the group is to engineer an antibody reagent that would on the one hand not engage conventional activating Fc receptors and on the other hand interact normally with FcRn, allowing transplacental passage.

Neonatal alloimmune thrombocytopenia: pathogenesis, diagnosis and management.

Neonatal alloimmune thrombocytopenia, (NAIT) is caused by maternal antibodies raised against alloantigens carried on fetal platelets. Although many cases are mild, NAIT is a significant cause of morbidity and mortality in newborns and is the most common cause of intracranial haemorrhage in full-term infants. In this report, we review the pathogenesis, clinical presentation, laboratory diagnosis and prenatal and post-natal management of NAIT and highlight areas of controversy that deserve the attention of clinical and laboratory investigators.

Prevalence and clinical significance of low-avidity HPA-1a antibodies in women exposed to HPA-1a during pregnancy.

Background: Recent studies suggest that HPA-1a-specific, low-avidity maternal antibodies not detectable by conventional methods can cause neonatal alloimmune thrombocytopenia (NAIT). We performed studies to further define the incidence and clinical significance of this type of antibody.

Study Design And Methods: Surface plasmon resonance analysis was used to detect low-avidity antibodies in HPA-1a-negative, "antibody-negative" mothers of suspected NAIT cases.

Platelet-associated antibodies, cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia.

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 (FcγRIIIa) and FCGR2A (FcγRIIa) 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).

Improving the specificity of the PF4 ELISA in diagnosing heparin-induced thrombocytopenia.

Heparin induced thrombocytopenia (HIT) is a serious complication of heparin therapy. The PF4 ELISA is a serologic assay that provides laboratory support for the clinical diagnosis of HIT, but it is often positive in patients who do not have the syndrome. We examined whether the specificity of the PF4 ELISA can be improved by 1) taking antibody potency into consideration, 2) by measuring only IgG antibodies, and 3) by utilizing a high concentration heparin inhibition step.

New platelet glycoprotein polymorphisms causing maternal immunization and neonatal alloimmune thrombocytopenia.

Background: Maternal immunization against low-frequency, platelet (PLT)-specific antigens is being recognized with increasing frequency as a cause of neonatal alloimmune thrombocytopenia (NAIT).

Study Design And Methods: Serologic and molecular studies were performed on PLTs and DNA from two families in which an infant was born with severe thrombocytopenia not attributable to maternal immunization against known PLT-specific alloantigens.

Results: Antibodies reactive only with paternal PLTs were identified in each mother using flow cytometry and solid-phase assays.

Fetal and neonatal alloimmune thrombocytopenia: a management algorithm based on risk stratification.

Fetal and neonatal alloimmune thrombocytopenia constitutes the most common cause of severe thrombocytopenia in fetuses and neonates and of intracranial hemorrhage among term newborns. The cornerstone of therapy involves the use of steroids and intravenous immunoglobulins. Despite the risk of potentially devastating consequences to the fetus, fetal blood sampling has typically been used to document response to therapy.

Persistence of lymphocytotoxic antibodies in patients in the trial to reduce alloimmunization to platelets: implications for using modified blood products.

Patients with acute myelogenous leukemia undergoing induction chemotherapy have significant decreases in alloimmune platelet refractoriness if they receive filter-leukoreduced or UV-B-irradiated vs standard platelet transfusions (3%-5% vs 13%, respectively; P ≤ .03) with no differences among the treated platelet arms (Trial to Reduce Alloimmunization to Platelets). Therefore, measuring antibody persistence might identify the best platelets for transfusion.

Dose of prophylactic platelet transfusions and prevention of hemorrhage.

Background: We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia.

Methods: We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1x10(11), 2.

Clinicopathologic features of agranulocytosis in the setting of levamisole-tainted cocaine.

Levamisole is a known contaminant of cocaine and, via this route, has been associated with otherwise unexplained agranulocytosis. Levamisole is currently present in the majority of cocaine samples seized by the US Drug Enforcement Agency. We identified 20 cases of unexplained agranulocytosis in our practice locations of Albuquerque, NM, and Vancouver, Canada.

New low-frequency platelet glycoprotein polymorphisms associated with neonatal alloimmune thrombocytopenia.

Background: Recent reports suggest that maternal immunization against low-frequency, platelet (PLT)-specific glycoprotein (GP) polymorphisms is a more common cause of neonatal alloimmune thrombocytopenia (NATP) than previously thought.

Study Design And Methods: Serologic and molecular studies were performed on PLTs and DNA from three families in which an infant was born with apparent NATP not attributable to maternal immunization against known PLT-specific alloantigens.

Results: Antibodies reactive only with paternal PLTs were identified in each mother.

Neonatal alloimmune thrombocytopenia due to HPA-9b incompatibility.

Neonatal alloimmune thrombocytopenia (NAIT) is one of the most frequent causes of both severe thrombocytopenia and intracranial hemorrhage (ICH) in fetuses and term neonates. The diagnosis is established by demonstrating antibodies against human platelet antigens (HPA) and discordance in platelet antigen typing between parents or between the mother and neonate. We report a case of NAIT that was likely due to maternal sensitization to HPA-9b (Max(a)), a recently recognized, rare platelet-specific antigen.

Neonatal alloimmune thrombocytopenia associated with maternal-fetal incompatibility for blood group B.

Background: Blood group A and B antigens are expressed only weakly on platelets (PLTs) of most individuals but are very strongly expressed on PLTs from approximately 1 percent of normal subjects (Type II high expressers). The implications of this trait for transfusion medicine are undefined.

Study Design And Methods: A family was studied in which two Group B infants were born with neonatal thrombocytopenia, whereas a third infant whose blood group was A(2) had a normal PLT count at birth.