Case report: Decreased hemoglobin and multiple organ failure caused by ceftizoxime-induced immune hemolytic anemia in a Chinese patient with malignant rectal cancer.

Background: Drug-induced immune hemolytic anemia (DIIHA) is a rare but serious condition, with an estimated incidence of one in 100,000 cases, associated with various antibiotics. This study reports on a case of ceftizoxime-induced hemolysis observed in a patient in China. Case description: A Chinese patient diagnosed with malignant rectal cancer underwent antimicrobial therapy after laparoscopic partial recto-sigmoid resection (L-Dixon). After receiving four doses of ceftizoxime, the patient developed symptoms including rash, itchy skin, and chest distress, followed by a rapid decline in hemoglobin levels, the presence of hemoglobin in the urine (hemoglobinuria), renal failure, and disseminated intravascular coagulation. Laboratory analysis revealed high-titer antibodies against ceftizoxime and red blood cells (RBCs) in the patient's serum, including immunoglobulin M (IgM) (1:128) antibodies and immunoglobulin G (IgG) (1:8) antibodies, with noted crossreactivity to ceftriaxone. Significant improvement in the patient's hemolytic symptoms was observed following immediate discontinuation of the drug, two plasma exchanges, and extensive RBC transfusion. Conclusion: This case, together with previous reports, underscores the importance of considering DIIHA in patients who exhibit unexplained decreases in hemoglobin levels following antibiotic therapy. A thorough examination of the patient's medical history can provide crucial insights for diagnosing DIIHA. The effective management of DIIHA includes immediate cessation of the implicated drug, plasma exchange, and transfusion support based on the identification of specific drug-dependent antibodies through serological testing.

Disseminated Human Parvovirus B19 Infection Induced Multiple Organ Dysfunction Syndrome in an Adult Patient With Alcoholic Hepatitis Complicated by Hemolytic Anemia: A Case Report and Literature Review.

Background: Human parvovirus B19 (B19) can cause acute hepatitis and is attributed to the high mortality of alcoholic hepatitis (AH). B19 infection is generally self-healing in previously healthy people, but it can cause fatal effects in some high-risk groups and increase its virulence and infectivity. Disseminated B19 infection-induced multiple organ dysfunction syndrome (MODS) in patients with AH has not been reported yet. Here, we described B19 viremia in an adult patient with AH accompanied by hemolytic anemia (HA), leading to disseminated infection and secondary MODS, as well as self-limiting B19 infections in seven nurses caring for him. Meanwhile, we reviewed the literature on AH and B19 infection. Case Presentation: A 43-year-old male patient with AH accompanied by HA was transferred to the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, on March 31, 2021. After supportive treatment, his transaminase and bilirubin levels were reduced, but his anemia worsened. He received a red blood cell (RBC) infusion on April 9 for hemoglobin (Hb) lower than 6 g/dl. On April 13, he suddenly had a high fever. Under empirical anti-infection, his high fever dropped and maintained at a low fever level; however, his anemia worsened. On April 25, he was transferred to the medical intensive care unit (MICU) due to severe pneumonia, acute respiratory distress syndrome (ARDS), acute aplastic crisis (AAC), and hemophagocytic syndrome (HPS), which were subsequently confirmed to be related to B19 infection. After methylprednisolone, intravenous immunoglobulin (IVIG), empirical anti-infection, and supportive treatment, the lung infection improved, but hematopoietic and liver abnormalities aggravated, and systemic B19 infection occurred. Finally, the patient developed a refractory arrhythmia, heart failure, and shock and was referred to a local hospital by his family on May 8, 2021. Unfortunately, he died the next day. Fourteen days after he was transferred to MICU, seven nurses caring for him in his first two days in the MICU developed self-limiting erythema infectiosum (EI). Conclusions: B19 infection is self-limiting in healthy people, with low virulence and infectivity; however, in AH patients with HA, it can lead to fatal consequences and high contagion.

Hemolytic disease and reticulocytopenia of the newborn attributable to maternal immunoglobulin G anti-M reacting optimally at cold temperatures.

BACKGROUND: Hemolytic disease of the fetus and newborn (HDFN) attributable to anti-M is rare, although case reports implicate anti-M in varying severities of HDFN, including fetal hydrops and intrauterine death. CASE DESCRIPTION: We describe the case of a newborn with HDFN associated with an atypical immunoglobulin (Ig) G anti-M that reacted best at cold temperatures. The maternal antibody detected in pregnancy was not reactive at 37°C, and a direct antiglobulin test (DAT) on red blood cells (RBCs) from the newborn was negative, suggesting an anti-M that should not have been clinically relevant. However, the infant developed hyperbilirubinemia (bilirubin level, 17.6 mg/dL), hemolytic anemia (hemoglobin nadir, 5.5 g/dL), and reticulocytopenia. Laboratory testing demonstrated the presence of an IgG anti-M in maternal and neonatal samples reacting best at 4°C. This passively acquired IgG anti-M provoked hemolytic anemia in the infant and likely suppressed erythropoiesis, resulting in reticulocytopenia with prolonged anemia. He was treated for IgG anti-M HDFN with 10 intravenous Ig infusions and 10 days of oral prednisone followed by a taper. He required seven transfusions with M- RBCs. His hemoglobin level normalized at 3 months of age. Follow-up at 2 years revealed no hematologic or neuro-developmental concerns. CONCLUSION: To our knowledge, this is the second report of HDFN attributable to an IgG anti-M reacting preferentially at cold temperature with no 37°C reactivity. Clinically relevant IgG anti-M may elude standard testing. Early recognition and testing for cold-reacting IgG anti-M should be considered for newborns with hemolysis, a negative DAT, and prolonged anemia.

Properdin Is a Key Player in Lysis of Red Blood Cells and Complement Activation on Endothelial Cells in Hemolytic Anemias Caused by Complement Dysregulation.

The complement system alternative pathway (AP) can be activated excessively in inflammatory diseases, particularly when there is defective complement regulation. For instance, deficiency in complement regulators CD55 and CD59, leads to paroxysmal nocturnal hemoglobinuria (PNH), whereas Factor H mutations predispose to atypical hemolytic uremic syndrome (aHUS), both causing severe thrombohemolysis. Despite eculizumab being the treatment for these diseases, benefits vary considerably among patients. Understanding the molecular mechanisms involved in complement regulation is essential for developing new treatments. Properdin, the positive AP regulator, is essential for complement amplification by stabilizing enzymatic convertases. In this study, the role of properdin in red blood cell (RBC) lysis and endothelial cell opsonization in these AP-mediated diseases was addressed by developing in vitro assays using PNH patient RBCs and human primary endothelial cells, where the effects of inhibiting properdin, using novel monoclonal antibodies (MoAbs) that we generated and characterized, were compared to other complement inhibitors. In in vitro models of PNH, properdin inhibition prevented hemolysis of patient PNH type II and III RBCs more than inhibition of Factor B, C3, and C5 (>17-fold, or >81-fold, or >12-fold lower molar IC90 values, respectively). When tested in an in vitro aHUS hemolysis model, the anti-properdin MoAbs had 11-fold, and 86-fold lower molar IC90 values than inhibition of Factor B, or C3, respectively (P < 0.0001). When comparing target/inhibitor ratios in all hemolysis assays, inhibiting properdin was at least as efficient as the other complement inhibitors in most cases. In addition, using in vitro endothelial cell assays, the data indicate a critical novel role for properdin in promoting complement activation on human endothelial cells exposed to heme (a hemolysis by-product) and rH19-20 (to inhibit Factor H cell-surface protection), as occurs in aHUS. Inhibition of properdin or C3 in this system significantly reduced C3 fragment deposition by 75%. Altogether, the data indicate properdin is key in promoting RBC lysis and complement activation on human endothelial cells, contributing to the understanding of PNH and aHUS pathogenesis. Further studies to determine therapeutic values of inhibiting properdin in complement-mediated diseases, in particular those that are characterized by AP dysregulation, are warranted.

Complement and Renal Thrombotic Microangiopathy Associated With Hypertension and Scleroderma.

Thrombotic microangiopathy is characterized by the presence of thrombocytopenia and microangiopathic hemolytic anemia and can occur in up to 50% of patients with hypertensive emergency and 10-15% with scleroderma. This review discusses the emerging role of complement in these 2 clinical entities. Specifically, we evaluate the evidence linking complement dysregulation with the manifestation of thrombotic microangiopathy and its clinical course in these settings. We also explore the rationale for complement blockade in these complex clinical scenarios that often have poor outcomes.

Neutrophil-Extracellular Traps, Cell-Free DNA, and Immunothrombosis in Companion Animals: A Review.

Immunothrombosis is a potentially beneficial physiological process that aids innate immunity and host defense against pathogen invasion. However, this process can also be damaging when it occurs to excess or in critical blood vessels. Formation of extracellular traps by leukocytes, particularly neutrophils, is central to our understanding of immunothrombosis. In addition to degranulation and phagocytosis, extracellular traps are the third mechanism by which neutrophils combat potential pathogens. These traps consist of extracellular DNA decorated with bactericidal cellular proteins, including elastase, myeloperoxidase, and cathepsins. Neutrophils can release these structures as part of a controlled cell-death process or via a process termed vital NETosis that enables the cells to extrude DNA but remain viable. There is accumulating evidence that NETosis occurs in companion animals, including dogs, horses, and cats, and that it actively contributes to pathogenesis. Numerous studies have been published detailing various methods for identification and quantification of extracellular trap formation, including cell-free DNA, measurements of histones and proteins such as high-mobility group box-1, and techniques involving microscopy and flow cytometry. Here, we outline the present understanding of these phenomena and the mechanisms of extracellular trap formation. We critically review the data regarding measurement of NETosis in companion animals, summarize the existing literature on NETosis in veterinary species, and speculate on what therapeutic options these insights might present to clinicians in the future.

Intraperitoneal transfusion for severe, early-onset rhesus disease requiring treatment before 20 weeks of gestation: A consecutive case series.

OBJECTIVE: To describe the management and perinatal outcomes of pregnancies affected by severe, early onset Rhesus isoimmunization treated with fetal intraperitoneal transfusions (IPTs). STUDY DESIGN: A ten-year consecutive case series of fetuses undergoing IPTs before 20 weeks gestation at Wessex Fetal Medicine Unit, Southampton, UK. Women with fetuses at risk of early onset fetal anaemia (before 20 weeks gestation) were identified from their obstetric history and maternal antibody levels at the time of booking. They were referred to our tertiary referral center. The decision to initiate transfusion was aided by middle cerebral artery peak systolic velocity as an indicator of fetal anaemia. No fetus was hydropic at the first transfusion. IPTs were commenced from as early as 15 weeks gestation in fetuses with difficult vascular access and performed regularly using this method until the cord could be successfully entered for intravascular transfusions. The main outcome measures were procedure and non procedure-related perinatal losses. RESULTS: 11 fetuses underwent 45 IPTs. 10/11 (91%) were delivered after 33 weeks gestation. There was one perinatal loss 1/11 (9%: 95% C.I 1.6-38%) from a cord accident during intravascular transfusion at 26 weeks gestation. There were no procedure related fetal losses or complications at the time of early IPTs. CONCLUSIONS: Previous studies report a perinatal loss rate with early intrauterine transfusion of 24% in gestations below 20 weeks using the intravascular route. This series suggests that intraperitoneal transfusion can be a safe and effective treatment for severe fetal anaemia at early gestations where vascular access is difficult.

The role of Complement in Post-Transfusion Hemolysis and Hyperhemolysis Reaction.

Transfusion-related hemolysis is classically the result of an interaction between antibodies produced by the recipient and blood group antigens carried by the donor red blood cells. This reaction may be life threatening, especially in sickle cell patients when they develop hyperhemolysis with concomitant accelerated clearance of their own red blood cells. The complement system is a key participant in the pathophysiology of post-transfusion hemolysis. Complement can trigger the hemolytic reaction, amplify the inflammatory response and increase tissue damage. Complement is activated by the classical pathway but may also be activated by the alternative pathway in sickle cell disease. The hemolysis-derived products permanently released by sickle cell patients with chronic hemolytic anemia may affect the potency of complement activation. All the observations in sickle cell patients as well as in vitro experiments and in vivo data in animal models support the conclusion that complement is key disease driver and a promising therapeutic target in the context of transfusion-related hemolysis and hyperhemolysis.

Prevention of delayed hemolytic transfusion reaction.

Post-transfusion hemolysis is the most frequent immune reaction to transfusion in sickle cell disease. Its frequency is underestimated due to its biological and clinical characteristics. It results principally from the high incidence of alloimmunization in these patients, but no antibodies are detectable in 30% of cases. Prevention is based on the prevention of alloimmunization through the use of matched RBCs for highly immunogenic blood groups, taking into account the patient's transfusion history, particularly in patients undergoing occasional transfusion, which is associated with a higher risk of DHTR development than chronic transfusion. In addition to the use of matched RBCs, the prevention of alloimmunization through immunotherapy should be considered.

Clinical presentation of delayed hemolytic transfusion reactions and hyperhemolysis in sickle cell disease.

Red blood cell (RBC) transfusion therapy is a key component in the comprehensive management of patients with sickle cell disease (SCD). Consequently, most adult SCD patients will receive at least one, and many will receive more than a hundred RBC transfusions in their lifetime. SCD patients develop RBC alloantibodies much more frequently than non-SCD transfused patients, which often make the selection of compatible RBCs extremely difficult, in addition to placing patients at significantly higher risk of suffering from delayed hemolytic transfusion reactions (DHTRs). Similar to alloimunization, DHTRs are much more common in patients with SCD compared to other heavily transfused populations, and are particularly consequential due to their propensity to cause hyperhemolysis, a life-threatening phenomenon in which both transfused RBCs in addition to the patient's own sickle-erythrocytes are destroyed. In this review, we highlight the incidence and pathophysiology of DHTRs; illustrate common presentations, appropriate evaluations and outcomes of DHTRs in patients with SCD; and discuss strategies for preventing or reducing the likelihood of DHTRs from occurring.

Red blood cell alloimmunization and delayed hemolytic transfusion reactions in patients with sickle cell disease.

Red blood cell (RBC) alloimmunization is more common in patients with sickle cell disease (SCD) than in any other studied patient population. The high prevalence of RBC alloimmunization is multi-factorial, likely involving the chronic hemolysis and inflammatory status of SCD itself, the transfusion burden of patients, and the RH genetic diversity of patients and blood donors, among other reasons. Antibody evanescence, or the decrease of RBC alloantibodies below levels detectable by blood bank testing, occurs frequently with fewer than 30% of alloantibodies estimated to be detected by current screening practices. Evanescence increases the likelihood that a patient with SCD will have a delayed hemolytic transfusion reaction upon future RBC exposure, with previously undetected alloantibodies coming roaring back in an anamnestic manner after exposure to the cognate RBC antigen. A subset of patients having delayed hemolytic transfusion reactions go on to experience hyperhemolysis; some but not all cases of hyperhemolysis are associated with previously evanescent RBC alloantibodies. There is an increasing appreciation of the association between RBC alloantibodies and RBC autoantibodies, as well as involvement of the alternative complement pathway in some instances of hyperhemolysis. A case report in this manuscript describes a highly alloimmunized patient with SCD who experiences a delayed hemolytic transfusion reaction with bystander hemolysis due to a previously evanescent, complement binding anti-M RBC alloantibody. Additional studies, including those involving multiple centers and countries, are needed to further understand RBC alloimmunization in patients with SCD and to develop strategies to prevent or mitigate potentially life-threatening hemolytic transfusion reactions.

Immuno-hematological findings in Delayed Hemolytic Transfusion Reaction (DHTR).

Sickle cell disease (SCD) is the most prevalent genetic disorder in France. Many other countries are also affected. Transfusion is still a key treatment for patients suffering from this condition. As a result, SCD patients are much more exposed to transfusions and their risks than the general population. The most feared situation is delayed hemolytic transfusion reaction (DHTR). In certain situations, defined as hyperhemolysis, autologous red blood cells (RBCs) are also targeted and destroyed. This can put the patient in a life-threating situation. Further transfusions worsen the hemolysis. As DHTR will mimic a new or resistant vaso-occlusive crisis, it can be easily underdiagnosed. SCD patients are more likely to be alloimmunized than the general population, due to discrepancies between the recipient's and donor's RBCs phenotypes. Furthermore, they are often transfused in an inflammatory state, and they also frequently harbor partial antigens in the RH system. SCD patients are more prone to develop a new alloantibody than the general population. As a result, patients with DHTR often have complex mixtures of allo and autoantibodies; RH antibodies and those considered as irregular natural antibodies are frequent. Nevertheless, about a third of DHTRs are reported in patients with no previous history of immunization. In addition, a third of SCD patients will not develop an antibody after a DHTR. The evanescence of the antibodies is important. In several studies, DHTRs were reported only in patients who were occasionally transfused. Identifying patients at risk of developing a DHTR is key to managing them properly.

The emerging role of immunothrombosis in paediatric conditions.

BACKGROUND: Immunothrombosis is a physiological process based on the release of neutrophil extracellular traps (NETs) to immobilise, contain and kill bacteria. This is an innate immune response in which the local activation of blood coagulation exerts the critical protective function during microbial infection. In recent years, there has been much interest in the adult literature about the key role of immunothrombosis in pathologic states including thrombosis, cancer, sepsis and trauma. Currently, little research has been done into its role in paediatric conditions. METHODS: We conducted a literature search of the National Library of Medicine (MEDLINE/PubMed) from the years 2000 to May 2018 and qualitatively identified 24 relevant papers. References of articles included for full-text review were checked for relevant publications. RESULTS: Our aim is to summarise the most relevant evidences regarding an excessive production or defective removal of NETs in paediatric conditions. In particular, we have divided the role of immunothrombosis into acute (sepsis, necrotising enterocolitis, otitis media, neonatal arterial ischaemic stroke, haemolytic anaemic diseases) and chronic (systemic lupus erythematous, type 1 diabetes mellitus, respiratory diseases, graft-versus-host disease) conditions to find important similarities in their pathophysiology. CONCLUSION: The field of immunothrombosis in paediatric conditions is still in its infancy. We have presented multiple pathways of NET-induced disease together with possible areas of future research and treatments.

Presumptive Glucocorticoid-Induced Refractory Hypocalcemia in a Dog with Idiopathic Immune-Mediated Hypoparathyroidism, Thrombocytopenia, and Hemolytic Anemia.

Clinically relevant hypocalcemia is a well-documented complication of glucocorticoid administration in people with hypoparathyroidism. The current report describes the phenomenon in a dog. A 7 yr old neutered male Pomeranian was diagnosed with immune-mediated thrombocytopenia, immune-mediated hemolytic anemia, and primary hypoparathyroidism. This dog required long-term parenteral calcium gluconate to prevent clinical hypocalcemia despite appropriate doses of oral calcitriol and calcium carbonate. This is the first description of clinically significant presumptive glucocorticoid induced hypocalcemia in a dog with primary hypoparathyroidism.

Vaccination and Associated Adverse Events in Dogs Previously Treated for Primary Immune-Mediated Hemolytic Anemia.

This study described the rate of vaccine reactions in a population of dogs receiving vaccines after diagnosis of primary immune-mediated hemolytic anemia (IMHA). A secondary objective was to describe the time elapsed between vaccination and initial diagnosis of IMHA. A medical record search identified cases meeting criteria for primary IMHA. Owners and referring veterinarians were surveyed regarding vaccination of the dog following diagnosis. Referring veterinarians were surveyed regarding vaccination prior to diagnosis of IMHA. A completed survey was returned in 44 cases. Twenty-two dogs received vaccinations after diagnosis, and 22 dogs did not. The median time elapsed between vaccination and initial diagnosis was 280 days. No dog was vaccinated within 30 days of diagnosis. Two of the following possible reactions were noted out of 22 dogs vaccinated: vomiting and urticarial eruption in a dog administered a rabies and canine distemper vaccine, and recurrent anemia in a dog administered a rabies vaccine. The rate of vaccine reactions was higher than previously reported, although the time period evaluated was longer than in previous studies. The relationship between initial vaccination and development of IMHA, and between vaccination and vaccine reaction, in this population is uncertain and may reflect coincidence or differences in susceptibility.

Immune hemolysis secondary to injection of contrast medium.

BACKGROUND: Drug-induced immune hemolytic anemia (DIIHA) is a rare but sometimes severe side effect. CASE REPORT: We describe the case of a 32-year-old patient who presented a cardiovascular collapse and a severe hemolysis secondary to the injection of iomeprol, a contrast medium, after a carcinologic surgery. RESULTS: The evolution was favorable after blood transfusion and short catecholamine support. The biology showed drug-dependent antibodies after incubation with iomeprol. CONCLUSION: This case is the second report of DIIHA with iomeprol.

Therapeutic potential of staphylococcal superantigen-like protein 7 for complement-mediated hemolysis.

Previous studies have demonstrated that staphylococcal superantigen-like protein 7 (SSL7), a protein produced by Staphylococcus aureus, potently inhibits the formation of the complement membrane attack complex by binding to complement component 5 (C5). However, because of the predicted immunogenicity of SSL7 as a foreign protein in humans, its potential as a new complement inhibitor for treating complement-mediated diseases is uncertain. In this study, we found that administration of SSL7 significantly prevented complement-mediated hemolysis and reduced hemoglobinuria in a mouse model of complement-mediated intravascular hemolysis. Interestingly, although repetitive administrations of SSL7 elicited anti-SSL7 antibody production, administration of SSL7 at a dose of 2 µg/mouse was still able to significantly attenuate complement-mediated intravascular hemolysis in vivo in the presence of the antibodies. In addition, even though anti-SSL7 antibodies were detectable in normal human donors, these antibodies did not significantly reduce the complement inhibitory activity of SSL7 in in vitro assays. Finally, inoculation of SSL7 in the anterior chamber of the eye suppressed the production of SSL7-reactive antibodies after repetitive SSL7 administration. These results suggest that SSL7 could be developed as an economical alternative to the existing C5-targeted drug, eculizumab, especially for controlling acute complement activation in catastrophic conditions such as drug-induced immune hemolytic anemia and ABO-incompatible erythrocyte transfusions. These data also suggest that approaches such as anterior chamber-associated immune deviation could be employed to establish an antigen-specific immune tolerance for long-term SSL7 administration. KEY MESSAGES: • SSL7 functions in the presence of anti-SSL7 antibodies both in vitro and in vivo. • SSL7 has the potential to be developed as a new and economical complement inhibitor for treating complement-mediated hemolysis.

A Rare Non-Hemolytic Case of Idiopathic Cold Agglutinin Disease.

BACKGROUND: Cold agglutinin disease is a very rare condition associated with agglutination of erythrocytes in cold environment usually due to IgM type antibodies. Other than hemolytic anemias, it may interfere with routine hemogram tests due to miscalculation of red blood cell count (RBC) and other hemogram parameters calculated with involvement of RBC. Awareness of the condition is important to overcome laboratory errors. METHODS: We studied a peripheral blood smear and repeated the hemogram test at 37°C to establish the diagnosis of cold agglutinin disease. RESULTS: Initial hemogram test results of the fifty-eight year-old man was as follows: RBC: 1.34 M/µL, hemoglobin (Hb): 12.4 g/dL, hematocrit (Htc): 11.8%, mean corpuscular hemoglobin (MCH): 92.4 pg, and mean corpuscular hemoglobin concentration (MCHC): 105 gr/dL. Despite the standard indirect Coombs test being negative, repeated tests at room temperature was 4+. We suspected cold agglutinin disease and repeated the hemogram test using the Bain-Marie method at 37°C and the test results showed RBC: 3.4 M/µL, hemoglobin: 12.6 g/dL, hematocrit: 30.2%, MCH: 31.7 pg, and MCHC: 41.8 g/dL. CONCLUSIONS: Inappropriate hemogram results may be a sign of underlying cold agglutinin disease. Hemolytic anemia not always accompanies the disease; however, cold exposure may trigger erythrocyte agglutination in vitro and may cause erratic laboratory results.

Increased number of tissue factor protein expressing thrombocytes in canine idiopathic immune mediated hemolytic anemia.

Dogs suffering from canine idiopathic immune mediated hemolytic anemia (cIIMHA) are at great risk of dying particularly in the first two weeks after the diagnosis is made. This high mortality risk may be associated with the development of thromboembolism (TE) and/or disseminated intravascular coagulation (DIC) resulting in organ failure. The exact mechanism of the development of TE and/or DIC in cIIMHA is still undetermined. Therefore, this study investigates the presence of tissue factor (TF) in thrombocytes of dogs suffering from cIIMHA, using OptiPrep™ for the isolation of blood cells and immunocytochemistry (ICC) to visualize TF on thrombocytes. The normalised TF quantity, acquired with 'colour deconvolution' (ImageJ plug in), revealed that in cIIMHA dogs the fraction TF positive thrombocytes was statistically significant higher (P < 0.001; mean 0.79; n = 7) compared to the fraction TF positive thrombocytes of the healthy dogs (mean 0.43; n = 9). We further have indications that the fraction of TF positive thrombocytes decreases with time and therapy, but that the progression rate differs individually. Since cIIMHA dogs have more thrombocytes that are TF-positive compared to healthy dogs, this may explain the increased risk to develop TE and DIC. Furthermore, it seems that the number of TF-positive thrombocytes in cIIMHA dogs remains high during the first two weeks of the disease, the time when the animals are at greatest health risk.

Immunoglobulin for alloimmune hemolytic disease in neonates.

BACKGROUND: Exchange transfusion and phototherapy have traditionally been used to treat jaundice and avoid the associated neurological complications. Because of the risks and burdens of exchange transfusion, intravenous immunoglobulin (IVIg) has been suggested as an alternative therapy for alloimmune hemolytic disease of the newborn (HDN) to reduce the need for exchange transfusion. OBJECTIVES: To assess the effect and complications of IVIg in newborn infants with alloimmune HDN on the need for and number of exchange transfusions. SEARCH METHODS: We performed electronic searches of CENTRAL, PubMed, Embase (Ovid), Web of Science, CINAHL (EBSCOhost), Academic Search Premier, and the trial registers ClinicalTrials.gov and controlled-trials.com in May 2017. We also searched reference lists of included and excluded trials and relevant reviews for further relevant studies. SELECTION CRITERIA: We considered all randomized and quasi-randomized controlled trials of IVIg in the treatment of alloimmune HDN. Trials must have used predefined criteria for the use of IVIg and exchange transfusion therapy to be included. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane and its Neonatal Review Group. We assessed studies for inclusion and two review authors independently assessed quality and extracted data. We discussed any differences of opinion to reach consensus. We contacted investigators for additional or missing information. We calculated risk ratio (RR), risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB) for categorical outcomes. We calculated mean difference (MD) for continuous variables. We used GRADE criteria to assess the risk of bias for major outcomes and to summarize the level of evidence. MAIN RESULTS: Nine studies with 658 infants fulfilled the inclusion criteria. Term and preterm infants with Rh or ABO (or both) incompatibility were included. The use of exchange transfusion decreased significantly in the immunoglobulin treated group (typical RR 0.35, 95% CI 0.25 to 0.49; typical RD -0.22, 95% CI -0.27 to -0.16; NNTB 5). The mean number of exchange transfusions per infant was also significantly lower in the immunoglobulin treated group (MD -0.34, 95% CI -0.50 to -0.17). However, sensitivity analysis by risk of bias showed that in the only two studies in which the treatment was masked by use of a placebo and outcome assessment was blinded, the results differed; there was no difference in the need for exchange transfusions (RR 0.98, 95% CI 0.48 to 1.98) or number of exchange transfusions (MD -0.04, 95% CI -0.18 to 0.10). Two studies assessed long-term outcomes and found no cases of kernicterus, deafness or cerebral palsy. AUTHORS' CONCLUSIONS: Although overall results show a significant reduction in the need for exchange transfusion in infants treated with IVIg, the applicability of the results is limited because of low to very low quality of evidence. Furthermore, the two studies at lowest risk of bias show no benefit of IVIg in reducing the need for and number of exchange transfusions. Based on these results, we have insufficient confidence in the effect estimate for benefit of IVIg to make even a weak recommendation for the use of IVIg for the treatment of alloimmune HDN. Further studies are needed before the use of IVIg for the treatment of alloimmune HDN can be recommended, and should include blinding of the intervention by use of a placebo as well as sufficient sample size to assess the potential for serious adverse effects.