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Home , Bleeding diathesis, GP1BB, Thrombocytopenia

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 , inherited disorders, factor deficiencies, connective tissue disorders, and vascular abnormalities, which pose a real risk of bleeding in affected children associated with trauma or . 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 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 , 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, 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 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. initially attach they face hemostatic challenges, which to subendothelial collagen and (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). is not uncommon (given the number (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 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 (PCP) to adequately workup extremely procoagulant surface and

Downloaded from www.aappublications.org/news by guest on September 27, 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 (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 , which culminate in Turner syndrome, and 6% in because these conditions have the cleaving of 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 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 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, , 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 , 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 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 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 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 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 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 . 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), is a relatively (platelet counts <150 000/μL), out and the diagnosis is usually common autosomal dominant

Downloaded from www.aappublications.org/news by guest on September 27, 2021 2 SARANGI and ACHARYA TABLE 1 Features of Congenital Syndromes Associated With Thrombocytopenia Disorder Incidence Clinical Features Incidence of Thrombocytopenia When to Refer to Hematology Trisomy 21 1 in 660 Cognitive impairment, hearing 7–28%a All patients with any hematologic issues, thyroid issues, heart abnormalities defects, gastroenteral atresias, cataracts Trisomy 13 1 in 5000 Cleft lip and palate, polydactyly, 54%a (All patients had platelet counts Platelet count <150 000/μL rocker bottom feet, cutis aplasia, >100 000/μL) omphalocele, VSD, PDA, neural tube defects Trisomy 18 1 in 5000 Dolichocephaly, micrognathia, 86%a (20% with platelet counts 50 000– Platelet count <150 000/μL overriding fi ngers, cardiac septal 100 000/μL) defects, horse shoe kidney, psychomotor retardation, feeding issues Turner 1 in 2500 Coarctation of aorta, aortic stenosis, 31%a (18% with platelet counts 50 000– Platelet count <100 000/μL or between syndrome short stature, ovarian failure, 100 000/μL) 100 000 and 150 000/μL and needs horseshoe kidney, cubitus valgus, surgery low posterior hairline, webbed neck DiGeorge 1 in 4000 Typical facies, thymic abnormalities, 30%1 (Usually mild Platelet count <150 000/μL and/or syndrome hypocalcemia, velopharyngeal macrothrombocytopenia) rapidly falling platelet counts in the insuffi ciency, conotruncal cardiac context of viral illness should be defects, tetralogy of Fallot, referred to rule out ITP truncus arteriosus, aortic arch anomalies Noonan 1 in 1000–2500 Facial dysmorphism, cardiac 6.2% 2 (27% have platelet function defects) Any patient with thrombocytopenia syndrome anomalies, short stature, bony and all patients before surgery to and genital anomalies. evaluate platelet function and other components of clotting cascade. Wiskott–Aldrich 1 in 4 million Microthrombocytopenia, eczema, Microthrombocytopenia is universal Refer all patients. Also refer to syndrome immune defects feature (platelet counts 5000–50 000/ . μL) 3 Cornelia de 1 in 10 000 Growth retardation, synophrys, 35% (15/43 patients) with platelet counts Check platelet count at diagnosis Lange limb abnormalities and cognitive <100 0004 (16% had ITP with majority and every 5 years if asymptomatic. syndrome impairment progressing to chronic ITP; 11% had Platelet count <100 000 or rapidly transient thrombocytopenia) falling platelet count refer to hematology to rule out ITP Jacobsen 1 in 100 000 Dysmorphogenesis of hands and Macrothrombocytopenia (88.5%) Any patient with thrombocytopenia syndrome feet, frequent cardiac defects and with varying degrees of platelet and all patients before surgery to cognitive impairment function defects (platelets with evaluate platelet function. giant α granules, storage pool defects and delayed maturation of )5 PDA, patent ductus arteriosus; VSD, ventricular septal defect. a Prevalence data from fetal samples (Hohlfeld et al6 ). multisystem disorder with history and laboratory values are partial time (aPTT), a prevalence of 1 in 1000 to considered.17 – 22 Thrombocytopenia and Factor XI levels at a minimum 2500 individuals. Patients with is not reported as commonly; even in the absence of bleeding Noonan syndrome with germ-line however, platelet function defects symptoms and if there is a significant mutations in PTPN11 need to be are frequent with a prevalence of bleeding history to include platelet monitored for the development 27%.2 Up to 37% of these patients function testing and testing for other of myeloproliferative disorder or can have factor XI deficiency while components of the clotting cascade in juvenile myelomonocytic leukemia. 16 and mixed consultation with the hematologist. Prevalence of bleeding disorders factor deficiencies are also reported. 2 in Noonan syndrome has been well Due to the complex phenotype, Connective Tissue Disorders described (ranging between 50% a significant proportion of these and 89%) if positive bleeding history patients need surgical procedures. Easy bruising and bleeding are or abnormal hemostatic laboratory A reasonable screening process can prominent manifestations of values are considered, whereas it begin with obtaining a platelet count, heritable collagen disorders ranges between 10% and 42% if both (PT), activated with Ehlers-Danlos syndrome

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 139 , number 2 , February 2017 3 (EDS) being the most prevalent. Although collagen are an integral part of capillary scaffolding, they also contribute to platelet activation, adhesion, and aggregation. EDS is a clinically and genetically heterogeneous group of conditions with varying degrees of skin hyperextensibility, joint hypermobility, delayed , and atrophic skin scarring. There are 5 subtypes with a combined prevalence rate of 1 in 5000 individuals. Type IV EDS (vascular type) carries the gravest prognosis affecting medium and large sized vessels. It can initially present as easy bruising and gum bleeding, but depending on the vessels affected can have bleeding from every possible site of the body, including fatal intraabdominal bleeding. 23 The other subtypes of EDS manifest with soft, fragile hyperextensible skin along with joint dislocations and bony abnormalities. 23 The diagnosis is often challenging in children, especially when there is no family history and can lead to extensive hemostasis-related bleeding workups, which are often normal. In the office setting, clinicians can use the Beighton scoring system (Fig 1) for evaluation of joint hypermobility and refer patients FIGURE 1 with high scores to the geneticist The Beighton Scoring system for joint hypermobility. Degree of mobility assessed by passive for further evaluation and maneuvers in 5 joints. Total score: 0–9. Hypermobility score: ≥5. (Figure reproduced with permission confirmatory genetic testing. 24, 25 from Research UK; http:// www. arthritisresearch uk. org) Capillary fragility is common among all subtypes with variable degrees Abnormalities in Vasculature (telangiectasias) without intervening of platelet function defects and capillaries, which have a higher coagulation factor deficiencies Hereditary hemorrhagic propensity to bleed due to inherently (factors VIII, IX, XI, XII, and XIII) telangiectasia (HHT) or Osler– elevated perfusion pressures. In HHT, being reported. 23 Desmopressin Weber–Rendu syndrome is a telangiectasias can develop in the has been shown to reduce bleeding common autosomal inherited nasal mucosa within the first decade risk and postoperative bleeding disorder with altered defects in and worsen with age, presenting with in pediatric patients with EDS, vascular integrity with an incidence severe and recurrent . suggesting that a weakened platelet of 1 in 5000 individuals. The While evaluating significant and collagen interaction underlies underlying genes ENG, ACVRL1, prolonged epistaxis in a pediatric the bleeding tendency in EDS. 26 SMAD4 encode proteins leading patient, the PCP should inquire Therefore, individuals with suspected to elevated expression of vascular about bleeding from other sites, or confirmed diagnosis of EDS with endothelial growth factor. 27 This presence of anemia and gastro- any bleeding symptoms or planned leads to characteristic clinical enteral bleeding, and related surgical procedures should be manifestations of dilated and to arterio venous malformations referred to a hematologist. tortuous postcapillary venules among close family members. It

Downloaded from www.aappublications.org/news by guest on September 27, 2021 4 SARANGI and ACHARYA might be difficult to make a diagnosis TABLE 2 The Curacao Diagnostic Criteria for proteins of the coagulation in childhood as characteristic HHT cascade), specimen handling, telangiectasias are often not present Criteria Defi nition and interpretation and should be until later or present as benign- Epistaxis Spontaneous, recurrent carried out in conjunction with an looking mucocutaneous red spots nosebleeds experienced hematologist who can that go unnoticed by providers. Telangiectasias Multiple, at characteristic accurately interpret the clinical and The Curacao Criteria ( Table 2) is a sites (lips, oral cavity, laboratory findings. Although validated scoring system developed fi ngers, nose) transmission aggregometry and Visceral Pulmonary, , cerebral, to help elucidate a diagnosis of HHT involvement spinal, or gastrointestinal its modification lumiaggregometry as nosebleeds and telangiectasias are vascular malformations are used for initial screening for common in the general population. 28, 29 Family history A fi rst-degree relative with platelet function defects, there are Otorhinolaryngologists should be defi nite HHT limitations of standardization and consulted early on in a child with Diagnostic criteria reproducibility. However, it can Defi nite HHT 3 or 4 criteria are present prolonged recurrent nose bleeds to Probable HHT 2 criteria are present help identify platelet adhesion or look for these telangiectasias without HHT unlikely Only 1 criterion is present aggregation defects, platelet granule which the diagnosis may be missed release defects on the basis of which until a later encounter with a life- further confirmatory testing can be threatening bleeding episode. with known inherited platelet carried out. 32 disorders. Wiskott–Aldrich syndrome is a rare autosomal recessive disorder RARE CONGENITAL SYNDROMES Supplemental Table 5 outlines due to defects in the WASP gene ASSOCIATED WITH A BLEEDING the various features of inherited (Xp 11.22) with an incidence of 4 DIATHESIS thrombocytopenic syndromes. The per million live births. 3 The clinical underlying molecular defect can be Inherited Platelet Disorders features classically include the restricted to platelets alone, or in triad of microthrombocytopenia Many of the inherited some cases can involve other cells (platelet counts 5000–50 000/ thrombocytopenias are clinically thereby resulting in multisystem μL) presenting as bruising and mild and may go unrecognized dysfunction. Evaluation of the purpura in the neonatal period, unless faced with hemostatic patient and the family for presence eczema that develops around stressors such as menses, surgery, of , hearing loss, infancy and immune defects with trauma, or childbirth. 30 A thorough albinism, and renal findings will point recurrent sinopulmonary infections bleeding history is a crucial to an underlying syndromic cause of in midchildhood. A high index of component in the evaluation of thrombocytopenia. This is further suspicion should prompt referral to these patients, including obtaining complicated by the fact that all a hematologist who may recommend previous blood counts if available. components of the syndrome may not to ameliorate Particularly, time should be devoted be present in affected individuals and bleeding symptoms associated with to eliciting the family history with therefore a high index of suspicion is thrombocytopenia or bone marrow special attention to hemostatic key to their diagnoses. While working transplantation, which is usually stressors, such as menorrhagia, up these patients, it is important curative ( Table 1 and Supplemental bleeding after teeth extractions, to collect fresh blood samples Table 6). blood transfusions after surgery, or with citrate as the unexplained anemia. Platelet counts to eliminate the phenomenon Bone Marrow Failure Syndromes should be determined in family of pseudothrombocytopenia. members with bleeding symptoms. Automated platelet counters are not Thrombocytopenia in inherited The pattern of bruising and bleeding accurate in the presence of macro bone marrow failure syndromes disproportionate to trauma should or micro thrombocytopenia and (IBMFS) presents as a component of raise suspicion for nonaccidental manual inspection of peripheral progressive marrow failure, which trauma even in patients in whom smears under Giemsa or Wright is the hallmark of these syndromes. congenital platelet disorders are stain provide important information Thrombocytopenia may present in suspected. 31 The use of standardized regarding platelet number, size, and the neonatal period in congenital bleeding assessment tools is very granularity. After recognition of amegakaryocytic thrombocytopenia useful in this setting. The Pediatric these syndromes, further diagnostic and thrombocytopenia with Bleeding Questionnaire identified evaluation of platelet disorders needs absent radii (TAR) manifesting high bleeding scores (>96% of careful preparation (a nontraumatic as petechial bleeding and rarely patients) in a cohort of 23 patients blood draw to preserve component leading to catastrophic intracranial

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 139 , number 2 , February 2017 5 hemorrhage. Unlike other IBMFS, syndrome and a number of other should be based on the gestational the thrombocytopenia in TAR platelet abnormalities described, age, onset of thrombocytopenia (<72 improves after infancy and may rise including platelet function defects hours indicating likely placental, to levels safe to perform surgery, (Table 1). 36 – 38 It is important to perinatal factors; >72 hours suggesting that nonlife-threatening recognize that abnormal platelet indicating postnatally acquired procedures could be delayed until function usually persists despite infections), and the clinical status after infancy. resolution of thrombocytopenia in of the newborn (sick versus well presents with thrombocytopenia as some patients. Therefore, formal appearing). Karyotype testing should the first hematologic manifestation platelet function testing with a plan be done in all obviously dysmorphic during midchildhood, whereas in for platelet transfusions are indicated infants with thrombocytopenia. Shwachman–Diamond syndrome it before major procedures despite Inherited causes of thrombocytopenia appears later, having been preceded normal platelet counts.5 are in general rare and rarely by neutropenia for variable amounts present in the newborn period. If a 33 of time. Supplemental Table 6 Other Congenital Disorders clear family history is present, the outlines the various IBMFS that hematologist should be consulted have thrombocytopenia as part of Storage disorders such as Gaucher to guide appropriate timing of the syndrome. The pathognomonic disease and Niemann–Pick disease confirmatory testing and help physical features can aid in present with either manage thrombocytopenia in recognizing the underlying IBMFS, due to direct splenic infiltration or the neonatal period. This should but it is important to realize that . While caring include a comprehensive delivery half of these patients may not be for these patients, it is important plan with contraindication for recognized until adulthood. 34 to keep in mind that platelets can instrumental delivery, vacuum, pool and sequester inside the or use of fetal scalp monitoring. Chromosomal Disorders abnormally enlarged spleen, which Early onset thrombocytopenia <72 hours, presence of macro- Cornelia De Lange syndrome can lead to acute life-threatening thrombocytes in the smear, limb (heterozygous mutation of NIPBL thrombocytopenia. Von Gierke abnormalities, and platelet counts gene) is an autosomal dominant disease (glycogen storage disease 1) usually >50 000/ μL are good rare inherited disorder that can has been shown to have associated 39 clues pointing to an underlying have transient thrombocytopenia platelet function defects. Once inherited defect. In the setting of a at birth. 35 More recently a higher these disorders are diagnosed, it well appearing infant with isolated incidence of chronic immune would be important to obtain a thrombocytopenia and absence of thrombocytopenia (ITP) in these baseline platelet count and refer to a any other features, it is reasonable patients has also been described hematologist for bleeding symptoms to treat for immune-mediated causes (see Table 1). 4 Self-injurious or before a surgical procedure of thrombocytopenia (neonatal behavior is often a component of for a comprehensive evaluation alloimmune thrombocytopenia) the syndrome that compounded of the bleeding phenotype and until platelet antigen incompatibility with thrombocytopenia can lead recommendations for surgery. can be demonstrated between to an increased risk of intracranial mother and infant serologically. bleeding. It has been proposed to GENERAL GUIDELINES FOR HEALTH Most allo or auto against get platelet counts for these patients MAINTENANCE AND MANAGEMENT OF neonatal platelets clear from the at diagnosis, with any unusual BLEEDING SYMPTOMS circulation over time with platelet bleeding symptoms and at 5 yearly counts normalizing within 1 to 2 intervals if asymptomatic and refer Newborn Period weeks in most infants. Persistence to hematology for severe bleeding Thrombocytopenia is encountered of thrombocytopenia beyond 8 to 12 symptoms. 4 fairly commonly (up to 25% weeks 42 after birth should warrant a (11q of admitted newborns) in the hematology consult especially in the syndrome) is perhaps the most well NICUs with rates increasing with absence of any immunologic factors described congenital syndrome prematurity. 40 The challenge lies or genetic syndromes. with thrombocytopenia that in identifying which of these can poses significant morbidity to stem from an underlying inherited Infancy and Beyond affected children. The clinical disorder. Fetal platelets are found in The reader is referred to health phenotype is variable with circulation by ∼5 weeks of gestation supervision guidelines for various macrothrombocytopenia a frequent and start reaching adult values by genetic syndromes, which are a (88.5% of patients) feature of the 22 weeks. 41 The diagnostic approach useful resource for

Downloaded from www.aappublications.org/news by guest on September 27, 2021 6 SARANGI and ACHARYA TABLE 3 Management of Common Bleeding Symptoms With Identifi ed Platelet/Coagulation Defects Symptom General and Preventive Associated With Platelet Associated With Coagulation Interventions Useful for Severe Symptoms Measures Defect Factor Defi ciency Epistaxis Place patient in sitting Local application of Local application of Bleeding lasting >10 min despite hemostatic position with neck forward. hydrophilic powder such hydrophilic powder such measures, >5 episodes per year: refer Firmly compress tip of nose as NasalCeasea as NasalCeasea to ENT for electrocauterization, nasal for 20 min. packing for persistent or profuse bleeding. Daily saline nasal lubrication Aminocaproic acid 50–100 Aminocaproic acid 100 mg/ HHT patients may need laser ablation or and humidifi cation of room mg/kg/dose every 6 h kg/dose every 6 h × 7 d embolization air. × 7 d Do not: Stick toilet paper, Desmopressinb intranasal rVIIa (used in Glanzmann thrombasthenia cotton balls in nose as can spray 150 μg/dose: 2 refractory to platelet transfusions)— dislodge clot sprays for adult, and 1 referral to hematology dose: 90 μg/kg Do not: squeeze bony part of spray for <50 kg child with dose repeated every 2–6 h3 nose as no blood vessels here Oral mucosal Ensure good dental hygiene Oral and/or systemic Oral and/or systemic Platelet and/or blood transfusions as bleeding and periodic dental aminocaproic acid. Can aminocaproic acid. Can indicated for platelet defect (spontaneous) cleanings use oral swish for 2 use oral swish for 2 min and spit but not as min and spit but not as effective effective Compression with gelatin Compression with gelatin For : Factor concentrates (FI, sponge sponge II, VII, VIII, IX, XIII defi ciencies) or FFP or cryoprecipitat (rich in FVIII, FI, VWF, and FXIII) FFP only choice for FV, FXI defi ciencies in the United States. Menorrhagia Hormonal regulation Tranexamic acid orally Factor concentrates (FI, II, Co-manage with gynecology 15–25 mg/kg TID or 10 VII, VIII, IX, XIII defi ciencies) mg/kg IV TID for serious or FFP or cryoprecipitate bleedingc (rich in FVIII, FI, VWF, and FXIII) Platelet and/or blood FFP only choice for FV, FXI High dose estrogen therapyc until bleeding transfusions defi ciencies in the United ceases followed by taper and oral States contraception Progesterone impregnated intrauterine devices (eg, Mirenad) Bruising/minor Protective cushions/pads Use of tropical thrombin for oozing and lacerations as indicated. Rarely if minor lacerations. compromising may need specifi c treatment Life-threatening Avoid contact sports, wear Platelet and/or blood Factor concentrates (FI, II, Refer to hematology to help guide use bleeding (CNS, GI helmets/protective devices transfusions VII, VIII, IX, XIII defi ciencies) of various products like rVIIa and bleeding) as indicated in conditions or FFP or cryoprecipitate concentrates with severe defi ciencies. (rich in FVIII, FI, VWF, and FXIII) Immediate evaluation to rule FFP only choice for FV, FXI out intracerebral bleeding. defi ciencies in the United Treat fi rst, image once States stabilized. Blood transfusion CNS, central nervous system; GI, gastrointestinal; IV, intravenously; TID, 3 times per day. a Catalina Healthcare, Mendon, NY. b Also useful in connective tissue disorders. c Concomitant use of estrogen and tranexamic acid carries a black box warning due to increased risk of thrombosis and if used should be separated by 4 hours. d Bayer Healthcare Pharmaceuticals, Whippany, NJ. involved in the care of these The comprehensive care of children bleeding, and avoidance of children. 43 – 46 Periodic hematologic and adolescents with syndromes medications such as and screening has been recommended mentioned in this review should nonsteroidal anti-inflammatory in Noonan syndrome, DS, Turner include careful attention to oral analgesics. Dental procedures should syndrome, and Jacobsen syndrome as hygiene to prevent gum bleeding, ensure good local hemostasis with outlined in previous sections. hormonal control of menstrual fibrillar collagen products along

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 139 , number 2 , February 2017 7 with other indicated systemic hemostatic because of abundance of in the mouth. Children with a high risk of bleeding should avoid contact sports, heavy exercise, or isometric exercise and wear protective pads to avoid deep and bruising. 26 Nonweight bearing exercises such as aqua therapy should be encouraged to promote a healthy lifestyle. Some of these children can have restrictive diets and K and vitamin C may need to be supplemented, the deficiencies of which can aggravate the underlying bleeding disorder. Common bleeding symptoms and their management are addressed in Table 3.

Antifibrinolytic agents (ε amino caproic acid and tranexamic acid) inhibit activity, thereby strengthening clot formation and can be used for prevention of minor FIGURE 2 trauma-induced or minor surgical Suggested approach to sequential presurgical evaluation for children with congenital syndromes bleeding especially involving mucosal with known or suspected bleeding diathesis. The laboratory workup should start with an initial surfaces that are rich in fibrinolytic screen and a more exhaustive workup can be done in conjunction with the hematologist on the basis of known hemostatic defects for the specifi c congenital syndrome and the bleeding phenotype enzymes in areas such as the mouth, of the individual patient. aBleeding phenotype: prolonged (>10 min), persistent (>5 episodes/year) nose, uterus, and gastrointestinal nose bleeds, petechiae with minor trauma, bleeding while brushing teeth, heavy menstrual bleeding, tract. Desmopressin (1-deamino- prolonged bleeding after tooth eruption or extractions; prolonged bleeding after a procedure 8-D arginine vasopressin) increases requiring a red cell transfusion, >1 cm especially palpable in nature after minor trauma. bHigh risk procedures: craniosynostosis surgery, multiple teeth extraction especially wisdom teeth, platelet aggregation by increasing plastic or vascular procedures, cardiac procedures, scoliosis surgery, , liver or kidney plasma levels of vWF and factor VIII, biopsy. cLow risk procedures: simple dental extraction, bronchoscopy, central venous catheter thus improving platelet adhesion removal, cutaneous biopsy, GI endoscopy with biopsy, laparoscopic abdominal surgery. dInclude and function. It has been shown factor XI levels in patients with Noonan syndrome. to be useful in various platelet secretion and granule defects, EDS and therefore should be reserved studies are needed to evaluate and Noonan syndromes, where it for serious bleeding symptoms. the impact of thromboelastogram can improve platelet function and In some cases, judicious and to improve patient outcomes in promote hemostasis. 26, 47 – 49 Both tailored use of fresh-frozen plasma bleeding disorders. 1-deamino-8-D arginine vasopressin (FFP), cryoprecipitate, and rVIIa and/or antifibrinolytic agents may be indicated. The use of can be used as monotherapy or rVIIa is approved in Glanzmann’s GUIDELINES FOR MANAGEMENT adjuvant to more definitive thrombasthenia where it improves BEFORE SURGICAL PROCEDURES treatment. Hemostasis therapy platelet aggregation and fibrin and Patients suspected to have a should be tailored on the basis of thrombin generation.50 Point of care congenital syndrome with a the underlying hemostatic defect, devices, such as thromboelastogram, bleeding diathesis (symptomatic severity of bleeding symptoms, or which can quantify global hemostasis or asymptomatic) must have a hemostatic challenge of planned and monitor response to therapeutic sequential evaluation at least 2 to 4 surgery and results of the bleeding agents, are increasingly being weeks before a scheduled surgical evaluation. Although platelet explored in clinical settings such as procedure as proposed in Fig 2. transfusion seems straightforward, trauma and surgery, 51 which can Bleeding assessment tools are useful the development of alloantibodies provide improved bleed management to get a standardized bleeding may cause platelet refractoriness and patient outcomes. Further history and calculate bleeding scores,

Downloaded from www.aappublications.org/news by guest on September 27, 2021 8 SARANGI and ACHARYA 4 — — — transfusion transfusion hysterectomy therapy, or desmopressin therapy, or desmopressin therapy, or desmopressin therapy, or desmopressin therapy, or desmopressin therapy, or desmopressin therapy, desmopressin, or surgical intervention or blood surgical intervention or blood surgical Blood transfusion, replacement Blood transfusion, replacement Blood transfusion, replacement Blood transfusion, replacement Blood transfusion, replacement Blood transfusion, replacement Spontaneous or traumatic requiring Spontaneous or traumatic requiring 3 — therapy desmopressin antifi brinolytics antifi antifi brinolytics antifi antifi brinolytics antifi brinolytics antifi antifi brinolytics antifi Blood transfusion, antifi brinolytics, blood brinolytics, antifi requiring replacement requiring replacement D&C or iron therapy Blood transfusion, replacement antifi brinolytics or iron antifi Surgical hemostasis, Surgical replacement therapy, or transfusion, replacement therapy or desmopressin therapy or desmopressin therapy or desmopressin Surgical hemostasis or Surgical Subdural, any intervention Intracerebral, any intervention 2 — strips spontaneous antifi brinolytics antifi Consultation or Consultation only hemostasis, Surgical Consultation only Packing, cauterization, or Antifi brinolytics or brinolytics Antifi contraceptive pill use D&C, iron therapy or Consultation only or steri- 1 only only — duration duration Reported Identifi ed cause Identifi >1 cm and on trauma Consultation only >5 per year or min Reported at least once Consultation only hemostasis or Surgical >5 per year or >10 min Posttrauma, no therapy Spontaneous, no therapy Spontaneous or traumatic, Posttrauma, no therapy Spontaneous, no therapy Spontaneous or traumatic, Reported or consultation Reported or consultation Reported, no consultation Consultation only hemostasis or Surgical Reported, no consultation Consultation only Resuturing, repacking, or in 1 0 No No No No Never Never Never in 1 extraction bleeding in 1 delivery No deliveries or no None done or no bleeding None done or no bleeding No or trivial ( ≤ 5 per year) No or trivial ( ≤ 5 per year) No or trivial ( ≤ 5 per year) –1 — — — — — — — — — — 2 surgeries 2 deliveries 2 extractions No bleeding in at least No bleeding in at least No bleeding in at least The Components and Scoring of the Pediatric Bleeding Questionnaire a Includes postcircumcision, umbilical stump, cephalhematoma, macroscopic hematuria, postvenipuncture, and conjunctival hemorrhage. Muscle Central nervous system Other Menorrhagia Postpartum Surgery Tooth extraction Oral cavity Gastrointestinal tract Minor wounds Epistaxis Cutaneous TABLE 4 Symptom/Score for von Willebrand disease of a pediatric bleeding questionnaire. J Thromb Haemost . 2009;7(8): Table S1. —, score not Reprinted with permission from Bowman M, Riddel J, Rand ML, Tosetto A, Silva James PD. Evaluation of the diagnostic utility available for this particular system. a

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 139 , number 2 , February 2017 9 which can help recognize individual contraindicated depending on the 4. Lambert MP, Jackson LG, Clark D, bleeding risk. The components of the level of thrombocytopenia and other Kaur M, Krantz ID, Deardorff MA. Pediatric Bleeding Questionnaire are hemostatic defects. The incidence of thrombocytopenia presented in Table 4 for review. 52 in children with Cornelia de Lange A thorough head to toe physical syndrome. Am J Med Genet A. CONCLUSIONS 2011;155A(1):33–37 examination to identify and uncover bleeding risk should focus on Abnormalities in hemostasis 5. Mattina T, Perrotta CS, Grossfeld P. hyperextensibility, telangiectasias, leading to clinical bleeding are an Jacobsen syndrome. Orphanet J Rare palpable bruises, splenomegaly, often unidentified component of Dis. 2009;4:9 ecchymoses, and petechiae. All many congenital syndromes. These 6. Hohlfeld P, Forestier F, Kaplan C, Tissot medications and alternative therapies abnormalities are important for the JD, Daffos F. Fetal thrombocytopenia: (including herbal preparations) PCP to recognize and anticipate, a retrospective survey of 5, 194 should be carefully reviewed, and thereby prompting timely referral fetal blood samplings. Blood. any medications known to affect to the hematologist to adequately 1994;84(6):1851–1856 hemostasis should be discontinued or manage these patients to prevent 7. Hord JD, Gay JC, Whitlock JA. substituted. A basic workup should catastrophic bleeding. Thrombocytopenia in neonates with include a , trisomy 21. Arch Pediatr Adolesc Med. PT, and aPTT with mixing studies 1995;149(7):824–825 (when PT/aPTT are prolonged), ABBREVIATIONS 8. Watts TL, Roberts IAG. Haematological which helps distinguish a clotting aPTT: activated partial thrombo- abnormalities in the growth-restricted factor deficiency from nonspecific plastin time infant. Semin Neonatol. 1999;4:41–54 coagulation inhibitors. In syndromes DS: Down syndrome 9. Webb D, Roberts I, Vyas P. Haematology with known qualitative platelet EDS: Ehlers-Danlos syndrome of Down syndrome. Arch Dis Child defects, platelet function analysis FFP: fresh-frozen plasma Fetal Neonatal Ed. 2007;92(6): (PFA-100), which has replaced the HHT: hereditary hemorrhagic F503–F507 , should be included as telangiectasia 10. Lange BJ, Kobrinsky N, Barnard part of the initial workup if available. IBMFS: inherited bone marrow DR, et al. Distinctive demography, Further testing should be guided by failure syndromes biology, and outcome of acute myeloid a pediatric hematologist who can ITP: immune thrombocytopenia leukemia and myelodysplastic then order confirmatory testing. ML-DS: myeloid leukemia associ- syndrome in children with Down Knowledge of the underlying platelet ated with Down syndrome: Children’s Cancer Group Blood abnormality can guide further syndrome Studies 2861 and 2891. . 1998;91(2):608–615 platelet function testing because the PCP: primary care physician use of specific platelet agonists can PT: prothrombin time 11. Rainis L, Bercovich D, Strehl S, et al. limit the amount of blood drawn in TAR: thrombocytopenia with Mutations in exon 2 of GATA1 are early pediatric patients. A multidisciplinary absent radii events in megakaryocytic malignancies associated with trisomy 21. Blood. team involving the surgeon, vWF: von Willebrand factor 2003;102(3):981–986 hematologist, and anesthesiologist should tailor a treatment plan before 12. Panarello C, Acquila M, Caprino D, Gimelli G, Pecorara M, Mori PG. surgery for these patients with the REFERENCES Concomitant Turner syndrome judicious use of platelets and other 1. 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