Thrombocytopenic Platelet Disorders

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 proplatelet formation and platelet release, and leads to reduced circulating platelet numbers without causing other clinical manifestations.[8]

The importance of the THPO receptor, MPL, in platelet production is discussed in the article on congenital amegakaryocytic thrombocytopenia (CAMT) by Ballmaier and Germeshausen.[9] This article comprehensively reviews a rare but important inherited bone marrow failure syndrome that typically presents with thrombocytopenia right after birth.[9] The article summarizes data for a cohort of patients diagnosed with CAMT in the past two decades,[9] with most but not all cases attributed to mutations within MPL.[9] The article provides guidance on how to distinguish CAMT from other syndromes associated with thrombocytopenia in infancy and childhood, and the outcomes from hematopoietic stem cell transplantation—the only known cure for CAMT.[9]

Traditionally, Glanzmann thrombasthenia has been classified and viewed as a nonthrombocytopenic platelet disorder, resulting from mutations that reduce expression or impair functions of the platelet integrins receptor αIIbβ3.[15] In their article, Nurden and colleagues review how some mutations in the genes encoding αIIbβ3 activate this receptor and manifest with thrombocytopenia due to altered platelet production and megakaryocytopoiesis.[10] The article also provides contemporary views on αIIbβ3 activation and its importance in platelet function.[10]

Transcription factors are important for the differentiation of hematopoietic stem cells along the megakaryocyte lineage for the production of platelets. In their article, Millikan and colleagues discuss the integral role of GATA-1 transcription factor in hematopoiesis and the association of GATA-1 mutations with three main disorders: X-linked thrombocytopenia, X-linked thrombocytopenia and thalassemia, and congenital erythropoietic porphyria.[11] The article also reviews the relationship between the trisomy 21 of Down syndrome and GATA-1 mutations that result in transient myeloproliferative disorders or acute megakaryoblastic leukemia.

Linkage analyses have been central to identify the causes of some thrombocytopenic platelet disorders. In their article, Di Paola and Johnson discuss two interesting but unrelated thrombocytopenic platelet disorders whose genetic cause has been investigated by linkage analyses: gray platelet syndrome (GPS) and thrombocytopenia linked to the THC2 locus at chromosome 10p11–12.[12] GPS, which is commonly autosomal recessive in inheritance, is characterized by an absence of platelet α-granules and it has been mapped to a 3p21 locus.[12] On the other hand, thrombocytopenia linked to the THC2 locus has an autosomal dominant pattern of inheritance and has been associated with mutations in several genes, including the microtubule-associated serine/threonine kinase-like (MASTL) gene, acyl-coenzyme A binding domain-containing protein 5 (ACBD5) gene, and a gene coding for ankyrin repeat domain-containing protein 26 (ANKRD26).[12]

Some congenital platelet disorders are associated with syndromic features that often suggest the diagnosis. The article by Toriello discusses the cause and features of thrombocytopenia-absent radius (TAR) syndrome, which is associated thrombocytopenia, absent radii, and the presence of thumbs.[13] The author reviews the range of anomalies that have been associated with this syndrome, and disorders to consider in the differential diagnosis. Toriello also discusses that the precise cause of thrombopenia in TAR syndrome remains unknown, although it has been associated with microdeletion of chromosome 1q21.1.

Platelet function disorders that increase fibrinolysis are rare. The article by Blavignac and colleagues provides an update on the features, pathogenesis, and treatment of a unique profibrinolytic platelet disorder, called QPD, which reduces platelet counts by ∼50% and causes a unique gain-of-function defect in fibrinolysis due to markedly increased expression and storage of urokinase plasminogen activator (uPA) in platelets.[14] The authors discuss how the disorder alters the platelet but not plasma levels of uPA, and the recent information on the genetic cause, which is a 78 kb tandem duplication that includes PLAU (the uPA gene) on chromosome 10q22.2.

Collectively this issue illustrates the spectrum symptoms and clinical manifestations associated with important thrombocytopenic disorders. Different algorithms for diagnosis of thrombocytopenic disorders have been proposed.[16] [17] At present, there are uncertainties about their broader applicability to different populations as founder effects have influenced the relative prevalence of different inherited thrombocytopenic disorders in regions of the world. We recognize that the mechanism of thrombocytopenia can be difficult to ascertain for individual patients, given the many genes and factors involved in megakaryopoiesis and platelet production.[8] [18] [19] Nonetheless, the new knowledge on the biology and pathology of thrombopoiesis (from in vitro and in vivo models)[19] has greatly advanced our understanding and has led to new treatments, such as thrombopoietic drugs for ITP (as discussed in this issue[4] [5]) and for some congenital thrombocytopenias, such as myosin heavy chain 9-related disorders[20] (a condition recently reviewed in Seminars in Thrombosis and Hemostasis).[21] The field is constantly changing and the genetic cause of GPS was recently reported to be mutations in the NBEAL2 gene.[22] [23] [24] We hope readers enjoy the collection of articles in this issue that covers the causes, consequences, and treatment of several important and fascinating thrombocytopenic disorders.

REFERENCES

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