Heparin-induced thrombocytopenia (HIT) is a syndrome of antibody-mediated activation of platelets and coagulation that confers increased risk for thrombosis. This article reviews recent studies of the pathogenesis, laboratory testing, frequency, and clinical presentation of HIT. Topics discussed include the nature of the neoepitopes on platelet factor 4 recognized by HIT antibodies, the nonspecific nature of the polyanions that support neoepitope formation, activation of monocytes and endothelium, and the development of new animal models. The transient "autoimmune" nature of HIT is highlighted in relation to new data concerning the rapid decline in HIT antibodies, as well as the recent recognition of a syndrome of "delayed-onset HIT" in which thrombocytopenia and thrombosis begin several days after stopping heparin. Detecting only HIT antibodies of the immunoglobulin G class is suggested as one way to increase diagnostic specificity of laboratory testing. Recent reports suggest that HIT could explain approximately 5% of cases of acute adrenal failure caused by bilateral adrenal hemorrhagic infarction.
Background: Primary immunodeficiencies (PID) are a group of inherited diseases that affect the development or activity of the immune system. In severe cases allogeneic haematopoietic stem cell transplantation has proved to be a successful curative modality but it is limited by toxicity and reduced efficacy in mismatched donor settings. Objective: Gene therapy for PID has been developed as an alternative strategy and has entered the clinical arena. In this review we discuss the outcomes of recent gene therapy trials and some of the problems that remain to be tackled. Methods: Results from clinical trials for X-linked severe combined immunodeficiency (SCID-X1), adenosine deaminase deficient SCID (ADA-SCID), and X-linked chronic granulomatous disease (X-CGD) are discussed. In addition, other conditions are highlighted such as the Wiskott Aldrich Syndrome (WAS) for which gene therapy has shown considerable promise in preclinical studies, and are currently being translated into novel clinical approaches. Results/conclusion: Whilst these encouraging results demonstrate that gene therapy can be used successfully to treat monogenic PID, the occurrence of vector-related side effects has highlighted the need for accurate assessment of the associated risks and a requirement for improvements in vector design.
Congenital forms of sideroblastic anemia constitute a subset of uncommon disorders within the wider spectrum of sideroblastic anemias, all of which are diagnosed by the presence of pathologic iron deposits in erythroblast mitochondria. The congenital sideroblastic anemias are heterogeneous disorders; some arise from known molecular defects but others are diagnosed only by their clinical features. Elucidation of several of the underlying defects has advanced our understanding of heme biosynthesis and iron metabolism in the erythroid cell. With the details of the porphyrin synthetic pathway clarified, now the important frontier of research is investigation of the mechanisms of mitochondrial and cellular iron homeostasis and their relationship to the regulation of heme biosynthesis. Knowledge gained from efforts in this area of study may also provide new approaches to treatments, which remain largely supportive for most types of congenital sideroblastic anemia.
Neonatal thrombocytopenia is a common clinical problem. The majority of episodes are early-onset thrombocytopenias due to impaired fetal megakaryocytopoiesis associated with placental insufficiency; the commonest causes of severe early-onset thrombocytopenia are immune thrombocytopenias, congenital infections, and asphyxia. By contrast, about 90% of cases of severe thrombocytopenia presenting after the first few days of life are due to late-onset bacterial sepsis, necrotizing enterocolitis, or both. Although clinically stable neonates tolerate relatively low platelet counts without significant risk of hemorrhage, ill or clinically unstable neonates with profound thrombocytopenia often have a poor outcome. Currently, the only therapy is platelet transfusion. Despite many published guidelines for platelet transfusion in the newborn, however, there have been no randomized trials to define the safe lower limit for platelet counts in sick neonates. The platelet threshold at which the benefits of transfusion outweigh the risks in neonates remains unclear. Well-designed trials are urgently needed.
Argatroban is a synthetic direct thrombin inhibitor. It is indicated for use in patients with heparin-induced thrombocytopenia (HIT). The greatest experience is in prevention and treatment of the disorder, but argatroban is also indicated for percutaneous coronary interventions in patients with HIT. There is somewhat limited experience with its use in a number of other clinical scenarios in these patients. The current data on the use of argatroban in patients with HIT are reviewed.
Overt strokes occur in about 11% of children with sickle cell disease, and many more develop silent infarcts. Until recently, the only available management intervention was the use of chronic transfusions to prevent stroke recurrence. The stroke prevention trial in sickle cell anemia (STOP) demonstrated that children at risk for strokes can be identified by transcranial Doppler (TCD) ultrasonography. In high-risk patients, the risk of first stroke can be decreased by 90% if patients are placed on chronic transfusion regimens. However, transfusing all patients with abnormal TCD is also problematic; as many as 60% do not seem to develop a stroke. At this time, a more precise stratification of stroke risk based on imaging studies, genetic studies, and neuropsychological testing is needed. Moreover, the development of alternatives to chronic transfusions, such as hydroxyurea and other pharmacologic therapies, may also improve the outlook for patients at high risk for stroke.
Severe thrombocytopenia (< 50 x 10(9)/L) frequently accompanies advanced necrotizing enterocolitis (NEC). In premature infants with severe thrombocytopenia, despite a paucity of evidence to support the practice, platelet transfusions are commonly used to maintain arbitrary levels of platelet counts in an effort to prevent hemorrhage. However, platelet transfusions contain a variety of bioactive factors, including platelet activating factor (PAF), which can augment systemic inflammatory processes. A growing body of evidence that incriminates PAF in the pathogenesis of NEC has emerged over the past few decades from both animal and human data. Both severe thrombocytopenia and multiple platelet transfusions have been associated with increased mortality, but it is admittedly difficult to differentiate between the effects of the underlying disease and the effects, if any, of the platelet transfusions. In this report, we review the roles of PAF and platelet transfusions in infants with severe NEC.
Accurate platelet counts in severe thrombocytopenia are critical in clinical practice to facilitate decisions at prophylactic platelet-transfusion thresholds. Until recent years, the accuracy of platelet counts has been limited by the reliance of hematology analyzers on calibration material values derived from the manual platelet counting method. The calibration of hematology analyzers in thrombocytopenia and the reduction of variation between instruments have been hindered by a lack of adequate quality control materials, making the accuracy of automated methodologies in routine practice difficult to assess. This situation could now be vastly improved by the use of the International Reference Method (IRM) to assign calibration materials and by further knowledge of the accuracy and limitations of the particular types of automated platelet count available to the clinician. These changes will improve clinical confidence in the accuracy of a platelet count and thus inform clinical decisions at the current level of prophylactic platelet transfusions.
Immune thrombocytopenic purpura (ITP) is an enigmatic, usually transient disorder in children, largely thought to be a self-limited, postinfectious, autoimmune phenomenon. The often strikingly low platelet count, coupled with the sometimes dramatic cutaneous manifestations of thrombocytopenia, compels most clinicians to prescribe drug therapy. However, closer scrutiny reveals that although most children with newly diagnosed ITP have platelet counts less than 10,000/microL, very few will experience severe or life-threatening hemorrhage, leading to perpetual controversy over whether to give drug therapy to minimally or moderately symptomatic children with ITP. This review focuses on when and how to use drug therapy to treat ITP in children.
Alpha thalassemia is a genetic disorder of hemoglobin production that typically is inherited in an autosomal co-dominant fashion. Rare forms of alpha-thalassemia, however, occur as de novo or acquired disorders. These disorders occur in two clinical situations: 1) alpha-thalassemia associated with mental retardation, and 2) acquired alpha-thalassemia (HbH disease) associated with myelodysplastic syndrome. Study of these rare disorders has led to the identification and characterization of a gene on the X chromosome (called ATRX) that encodes a trans-acting factor capable of influencing the expression of alpha-globin and other genes.
Hereditary hemochromatosis has been redefined over the past century, from a rare (but often fatal) disorder of iron overload known as "bronzed diabetes" to only biochemical evidence of altered iron metabolism, and recently to mere expression of the C282Y homozygous genotype of the HFE gene. The variable definitions of the disease, as well as the variable degree of penetrance of the C282Y homozygous genotype, have made it difficult to determine optimal screening strategies. Multiple studies performed since discovery of the C282Y mutation have led to the conclusion that overall penetrance of the genotype is low and that screening of asymptomatic general populations for hereditary hemochromatosis is not recommended. Screening for HFE mutations among certain patient groups, including patients with cirrhosis, however, may help target those who would benefit most from iron removal. For most patients, phlebotomy is the preferred treatment option; iron chelation therapies are available for patients unable to tolerate phlebotomy.
Major recent developments in cobalamin deficiency include issues such as the nature of food-cobalamin malabsorption, sensitivities and specificities of diagnostic tests, and emerging data on oral therapy. These have been heavily influenced by studies of subclinical deficiency, which has a much slower progression (which may be nonlinear), arises from different causes, and poses different, more public health-oriented management considerations than the less frequent but much more medically important entity of clinically expressed deficiency. Distinguishing carefully between the two deficiency states is helpful because clinical lessons and strategies derived from one may not apply equally to the other, as illustrated by controversial decisions about clinical issues such as the serum cobalamin level diagnostic of deficiency. Reassessment of diagnostic and management approaches, including improving our ability to diagnose cobalamin malabsorption, is required.
Volume-reduced platelet concentrates (PCs) can be a useful option for transfusing a high number of platelets in the smallest possible plasma volume, especially in neonatal and other pediatric patients. In addition to decreasing the risk of circulatory overload, volume-reduced PCs contain less plasma, which may reduce the likelihood of adverse plasma-related transfusion reactions. Volume reduction can be achieved either during collection and processing of apheresis PCs (primary volume reduction) or, subsequently, by recentrifugation of stored PCs (secondary volume reduction). There is no standard method for preparing volume-reduced PCs. Although in vitro data suggest impaired platelet function with some methods of volume-reducing PCs, in vivo studies show acceptable hemostatic function, posttransfusion recovery, and platelet count increments for both primary and secondary volume-reduced PCs. This review presents an overview of recent studies on functional characteristics of different types of volume-reduced PCs.
