Bleeding Disorders in Congenital Syndromes Susmita N. Sarangi, MD, Suchitra S. Acharya, MD Pediatricians provide a medical home for children with congenital abstract syndromes who often need complex multidisciplinary care. There are some syndromes associated with thrombocytopenia, inherited platelet disorders, factor deficiencies, connective tissue disorders, and vascular abnormalities, which pose a real risk of bleeding in affected children associated with trauma or surgeries. The risk of bleeding is not often an obvious feature of the syndrome and not well documented in the literature. This makes it especially hard for pediatricians who may care for a handful of children with these rare congenital syndromes in their lifetime. This review provides an overview of the etiology of bleeding in the different congenital syndromes along with a concise review of the hematologic and nonhematologic clinical manifestations. It also highlights the need and timing of diagnostic evaluation to uncover the bleeding risk in these syndromes emphasizing a primary care approach. Bleeding Disorders and Thrombosis Program, Cohen Children with congenital syndromes these patients as part of surveillance Children’s Medical Center of New York, New Hyde Park, with multiple anomalies need a or before scheduled procedures New York multidisciplinary approach to and recommends guidelines for Drs Sarangi and Acharya contributed to the their care, along with continued appropriate and timely referral to the conceptualization, content, and composition of the surveillance for rare manifestations hematologist. manuscript and approved the fi nal manuscript as such as a bleeding diathesis, which submitted. may not be evident at diagnosis. This Achieving hemostasis is a complex DOI: 10.1542/peds.2015-4360 accompanying bleeding diathesis process starting with endothelial Accepted for publication Aug 15, 2016 due to thrombocytopenia or other injury that results in platelet plug Address correspondence to Suchitra S. Acharya, coagulation defects may be a part of formation, which is then strengthened MD, Bleeding Disorders and Thrombosis Program, the syndrome that is not routinely by deposition of fibrin formed Cohen Children’s Medical Center of New York, 269- addressed. Consequently, this may go by the proteolytic coagulation 01 76th Ave, Suite 255, New Hyde Park, NY 11040. E-mail: [email protected] unrecognized in these children until cascade. Platelets initially attach they face hemostatic challenges, which to subendothelial collagen and PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). is not uncommon (given the number von Willebrand factor (vWF) via of corrective surgeries performed glycoproteins VI and 1bα (GPVI, Copyright © 2017 by the American Academy of Pediatrics for the congenital defects) in this GPIbα). This leads to activation of population leading to unanticipated platelets releasing Thromboxane FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial relationships surgical bleeding. Counseling for these A2 (TxA2) and conforming the relevant to this article to disclose. families should include discussions glycoprotein IIb/IIIa (GPIIb/IIIa) FUNDING: No external funding. regarding potential spontaneous or receptor on the platelet surface into trauma-related bleeding associated its high affinity state, which now POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of with these syndromes that can binds to fibrinogen and vWF. This interest to disclose. evolve over time. This review aims further leads to release of platelet to highlight congenital syndromes granule contents (fibrinogen, Factor where hemostatic defects have been V, platelet factor 4, Calcium, ADP, To cite: Sarangi SN and Acharya SS. Bleeding reported, aid the treating primary care ATP, serotonin, vWF) leading to an Disorders in Congenital Syndromes. Pediatrics. 2017;139(2):e20154360 physician (PCP) to adequately workup extremely procoagulant surface and Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 139 , number 2 , February 2017 :e 20154360 STATE-OF-THE-ART REVIEW ARTICLE platelet aggregation. The stage is of which 17% (43 samples) were made soon after birth. Although now set for the cascade of serine due to chromosomal anomalies. The survival beyond infancy is rare, life proteases (factors V, VII, VIII, IX, X, prevalence was 54% in Trisomy expectancy is improving. Recognizing XI, XII, XIII) activated by the release 13, 86% in Trisomy 18, 31% in thrombocytopenia is important of tissue factor, which culminate in Turner syndrome, and 6% in because these conditions have the cleaving of thrombin to form Trisomy 21–Down syndrome (DS). associated cardiac, respiratory, and an insoluble fibrin mesh leading However, Hord et al 7 reported mild craniofacial anomalies that may need to a stable clot at the site of injury. to moderate thrombocytopenia corrective or palliative surgeries. With the many players involved in (platelet counts 40 000–100 000/ Surgical planning in these patients coagulation, it can be seen how the μL) in 28% of neonates with DS. The needs a multidisciplinary team with clinical bleeding phenotype can be exact mechanism is not known, but screening blood work to identify modified by gene–gene interactions is thought to be due to decreased thrombocytopenia, which if present by improving or worsening the platelet production, from chronic will need platelet transfusions pre- integrity of clot formation directly fetal hypoxia, which also leads to and postoperatively depending upon or indirectly. Therefore, this review intrauterine growth retardation. 8 the complexity of the surgery guided will focus on congenital syndromes by the hematologist. DS (Trisomy 21) is also associated associated with quantitative with other hematologic findings, Turner syndrome (45, X) can (thrombocytopenia) and qualitative such as polycythemia, neutropenia, be associated with transient platelet function defects (ie, defects abnormal circulating blasts, thrombocytopenia (31% of patients 6) in platelet generation or defects at 1 erythroblastosis, and giant platelets. 9 in the newborn period. Due to the or more levels of platelet activation) Approximately 10% of neonates with single functional X chromosome, girls and coagulation factor deficiencies. DS have transient myeloproliferative can inherit X-linked conditions like It will also highlight congenital disorder, which can present with hemophilia, but this has only very syndromes where bleeding can isolated thrombocytopenia or rarely been described. 12 Therefore, result from defects in the underlying thrombocytosis, leukocytosis, or prolonged bleeding events warrants connective tissue or anatomic persistent peripheral blood blasts. referral to a hematologist for workup. malformations that increase These abnormal blood cells will self- Gastro-enteral bleeding can occur in predisposition to bleeding. It will resolve in most infants by 3 months Turner syndrome due to associated further discuss basic evaluation of after birth; however, 20% can have inflammatory bowel disease or these patients on the basis of a high more progressive disease. Both often unrecognized intestinal index of suspicion and highlight what transient myeloproliferative disorder telangiectasias (incidence of 7%). 13 phenotypes need specialist referral and myeloid leukemia associated for both health maintenance and DiGeorge syndrome (22q11.2 del) with DS (ML-DS), which presents prevention of surgical bleeding and is the most common micro deletion at 1 to 4 years of age, have somatic discuss general treatment principles. syndrome with associated mild mutations in the megakaryocyte Table 1 and Supplemental Tables 5 macrothrombocytopenia in 30% erythroid transcription factor and 6 summarize the key features of of patients resulting from deletion GATA-1. 10, 11 ML-DS has a preceding the congenital syndromes discussed of the contiguous GP1BB gene in myelodysplastic phase with patients in this review. the deleted Chromosome 22q11 presenting with progressive locus, which codes for the subunit anemia and thrombocytopenia, of the platelet adhesion receptor. 1 which then develops into leukemia. COMMON CONGENITAL SYNDROMES Immune dysfunction is common in ASSOCIATED WITH A BLEEDING DS-associated acute lymphoblastic these patients and it is estimated DIATHESIS leukemia develops after age 4 years, that immune thrombocytopenic presenting with cytopenias, and often purpura is 200 times more common in Chromosomal Syndromes lower platelet counts than ML-DS these patients as compared with the patients. Therefore, all DS patients 14, 15 A fault in chromosome distribution general population. These platelet should have a complete blood cell during cell division leads to abnormalities need to be identified count at birth and if found to have aneuploidy, which can be associated early on and specifically before any hematologic abnormalities with thrombocytopenia but is rarely corrective cardiac surgeries. Close should be referred to hematology. severe. Hohlfeld et al 6 in a study of collaboration with a hematologist 5194 fetal blood samples (17 to 41 Other trisomies such as Trisomy 13 before these surgeries will help avert weeks) reported 4.7% samples (247 and Trisomy 18 have very distinct bleeding complications. samples) with thrombocytopenia clinical patterns ( Table 1), Noonan syndrome is a relatively (platelet counts <150 000/μL), out and the diagnosis is usually common autosomal dominant Downloaded