Thrombocytopenia is a common problem with diverse congenital and acquired causes. Several factors have been identified to be important for the production of platelets and platelet counts, including stem cell factor, thrombopoietin (THPO), and the THPO receptor, MPL.[ 1 ] Additionally, the findings from genome-wide association studies (GWAS) suggest that additional factors encoded by genes located on chromosomes 6p21.3, 7q22.3, 9p24.1–p24.3, and 12q24 influence platelet counts in humans.[ 2 ] [ 3 ] This issue of Seminars in Thrombosis and Hemostasis provides an update on the causes, consequences, and management of a variety of congenital and acquired thrombocytopenias. Together, the articles illustrate how a low platelet count can reflect defects in platelet birth or a reduced life span, and that some disorders uniquely alter the phenotype of circulating platelets.[ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ] The issue also reviews important acquired, immune thrombocytopenic disorders, including two fascinating but quite distinct immune-mediated thrombocytopenic disorders: immune thrombocytopenia (ITP)[ 4 ] [ 5 ] [ 6 ] and heparin-induced thrombocytopenia (HIT).[ 7 ] The article by Pels is focused on ITP diagnosis (including how to categorize ITP as newly diagnosed, persistent, or chronic) and treatment.[ 4 ] The article discusses recent evidence, in addition to expert and consensus recommendations, including when to consider first-line therapies (such as corticosteroids, intravenous immunoglobulin, and anti-D) and second- and third-line therapies (such as immunosuppressants, splenectomy, and newer, thrombopoietic agents).[ 4 ] In their article on ITP, Toltl and colleagues provide an overview on ITP pathophysiology and discuss the factors influencing self-tolerance (cell deletion, receptor editing, induction of anergy, and extrinsic cellular suppression) and current concepts on how the loss of tolerance for host platelet antigens in ITP can occur.[ 5 ] The article by Kadir and McLintock provides a helpful review and guidance on diagnosing and managing thrombocytopenia in pregnancy, and how to distinguish ITP from gestational thrombocytopenia and other thrombocytopenic conditions that may present for the first time during the pregnancy.[ 6 ] The article also discusses how thrombocytopenic disorders affect mothers, fetuses, and newborns and how to manage preexisting platelet function defects during pregnancy and delivery.[ 6 ] It also provides helpful guidance on how to manage pregnant women with thrombocytopenia during labor and delivery.[ 6 ] In their article on HIT, Linkins and Warkentin give perspectives on the “real-world” issues for this important, immune-mediated, prothrombotic thrombocytopenic disorder, using a retrospective cohort of oncology patients and orthopedic surgery patients.[ 7 ] Their article provides expert and evidence-based insights on patients at risk for developing HIT and the typical diagnostic and management challenges.[ 7 ] The remaining articles of this issue provide an update on several congenital disorders associated with reduced platelet numbers (Table [ 1 ]).[ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ] These inherited platelet disorders include rare, autosomal recessive conditions,[ 9 ] [ 10 ] [ 12 ] [ 13 ] autosomal dominant conditions,[ 8 ] [ 12 ] [ 14 ] and X-linked disorders (Table [ 1 ]). While gain-of-function defects are uncommon among platelet disorders, two conditions discussed in this issue, thrombocytopenia Cargeeg[ 8 ] and Quebec platelet disorder (QPD)[ 14 ] are due to unique, gain-of-function problems. Table 1 Features of the Congenital Thrombocytopenia Disorders Reviewed in This Issue Condition Affected Gene or Locus Mode of Inheritance Unique Manifestation Reference Thrombocytopenia Cargeeg CYCS Autosomal dominant Thrombocytopenia due to a gain-of-function defect in apoptosis, leading to intramedullary platelet apoptosis but normal survival of circulating platelets Bordé et al8 CAMT MPL (majority of cases) Autosomal recessive or compound heterozygous Thrombocytopenia and bone marrow failure due to defects in the receptor for thrombopoietin Ballmaier and Germeshausen9 Glanzmann-like syndromes associated with macrothrombasthenia ITGA2B or ITGB3 Autosomal dominant or compound heterozygous Variation in platelet size and impaired platelet aggregation due to activating mutations in αIIbβ3 Nurden et al10 XLT with or without thalassemia GATA-1 X-linked Thrombocytopenia and anemia Millikan et al11 GPS NBEAL2 Autosomal recessive (majority of cases) Thrombocytopenia and gray platelets Di Paola and Johnson12 and recent publications22 23 24 Thrombocytopenia linked to the THC2 locus 10p11–12 Autosomal dominant Thrombocytopenia and a lack of mature megakaryocytes in the bone marrow Di Paola and Johnson12 TAR syndrome 1q21.1 microdeletion Possibly autosomal recessive Thrombocytopenia associated with the absence of radii and the presence of thumbs Toriello13 QPD PLAU Autosomal dominant Bleeding due to a gain of function defect in fibrinolysis. Normal or reduced platelet counts (reduced by ∼50%) Blavignac et al14 CAMT, Congenital amegakaryocytic thrombocytopenia; XLT, X-linked thrombocytopenia; GPS, gray platelet syndrome; TAR, Thrombocytopenia-absent radius; QPD, Quebec platelet disorder. Bordé and colleagues provide an expert review on thrombocytopenia Cargeeg.[ 8 ] This intriguing thrombocytopenic disorder is associated with a point mutation in cytochrome c and the premature release and destruction of platelets in the bone marrow of affected heterozygous individuals.[ 8 ] The authors discuss the clinical manifestations and pathogenesis and also summarize current knowledge about the processes of megakaryopoiesis and platelet release. The disorder provides an interesting illustration of how an enhanced apoptotic pathway alters the timing and location of...