Neonatal thrombosis clinical features and diagnosis uptodate

15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate Official reprint from UpToDateđ www.uptodate.com â 2022 UpToDate, Inc and/or its affiliates All Rights Reserved Neonatal thrombosis: Clinical features and diagnosis Authors: Anthony KC Chan, MBBS, FRCPC, FRCPath, Mihir D Bhatt, MD, FRCPC Section Editors: Sarah O'Brien, MD, MSc, Joseph A Garcia-Prats, MD Deputy Editor: Carrie Armsby, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete Literature review current through: Dec 2021. | This topic last updated: Sep 21, 2021 INTRODUCTION Thrombotic disease is uncommon in newborns; however, it is increasingly recognized as a complication of contemporary neonatal care Thrombosis contributes to neonatal morbidity and mortality The pathogenesis, clinical features, and diagnosis of neonatal thrombosis, excluding the central nervous system, are reviewed here Central nervous system thromboembolic disease and the management of neonatal thrombosis are discussed separately (See "Stroke in the newborn: Classification, manifestations, and diagnosis" and "Neonatal thrombosis: Management and outcome".) COAGULATION IN NEWBORNS Plasma concentrations of the components of the coagulation cascade ( figure 1) and fibrinolytic pathway ( figure 2) in newborns differ markedly from older children and adults Concentrations of these factors change from birth through infancy ( table 1) [1-4] (See "Overview of hemostasis".) In newborns, the following procoagulant, anticoagulant, and fibrinolytic factors differ considerably compared with adult levels: https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_res… 1/31 15:58, 03/01/2022 ● Neonatal thrombosis: Clinical features and diagnosis - UpToDate Vitamin K-dependent coagulation factors (II, VII, IX, X) and contact factors (XI, XII, prekallikrein, high molecular weight kininogen) are 50 to 70 percent of adult levels [5] These factors increase rapidly after birth, reaching adult levels of most components by six months of age [1] ● Factors V, VIII, and XIII; von Willebrand factor; and fibrinogen are at least 70 percent of adult levels [1] ● Coagulation inhibitors (antithrombin, heparin cofactor II, protein C, protein S) are approximately 50 percent of adult levels [1] However, the concentration of alpha-2-macroglobulin is greater in newborns than in adults ● The rate of thrombin generation in newborn plasma is 30 to 50 percent of adult values [6] ● Fibrinolytic factors plasminogen and alpha-1 antiplasmin are lower than adult values [1] However, levels of tissue plasminogen activator and plasminogen activator inhibitor-1 are higher ● Infants born preterm have even lower levels of vitamin K-dependent clotting factors as compared with those born at term ( table 2) and also lower values for inhibitors of coagulation including antithrombin and protein C [2,7] Because of their immature coagulation system, preterm infants are particularly at risk for developing bleeding or thrombotic complications in response to perinatal risk factors or iatrogenic events Due to the altered levels of procoagulant, anticoagulant, and fibrinolytic factors, newborns are at increased risk of bleeding or thrombotic complications compared with older children, especially in the presence of other hemostatic challenges such as indwelling catheters EPIDEMIOLOGY Incidence — Reported estimates of the incidence of neonatal thrombosis range from to cases per 100,000 live births [8-10] In studies performed in the neonatal intensive care unit (NICU) setting, rates of thrombosis range from 0.7 to 1.5 percent of NICU admissions [11-14] Reported incidence rates of neonatal thrombosis in the contemporary era are higher than in studies from the 1990s to early 2000s Improved detection and advances in management and survival of very preterm neonates likely explain the increase https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_res… 2/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate In a large multicenter observational study involving nearly 40,000 neonates cared for at 30 NICUs in Canada from 2014 to 2016, 1.5 percent of patients had at least one documented thrombosis during their NICU stay [14] Among patients with thrombosis, 75 percent of cases were venous (most commonly involving the portal vein), 19 percent were arterial (most commonly arterial stroke), and percent were mixed Risk factors — Important risk factors for thrombosis in newborns include: ● Central venous or arterial catheter – Thrombosis occurs in up to 10 percent of neonates with central venous catheters; however, most of these are asymptomatic [15] Arterial thrombosis occurs in up to 20 percent of neonates with umbilical arterial catheters (UACs) [16] The risk of thrombosis is influenced by location of the catheter (femoral location has the greatest risk) and how long the catheter remains in place [13,14,17-19] (See 'Catheter-associated thrombosis' below.) ● Polycythemia [20] (See "Neonatal polycythemia".) ● Infections [13] ● Major surgery ● Other underlying conditions (eg, metabolic disorders, congenital heart disease, congenital nephrotic syndrome) [21,22] ● Inherited thrombophilia– The inherited thrombophilias for which the pathogenic link is most clearly established include [23-25]: • Antithrombin deficiency • Protein C deficiency • Protein S deficiency • Factor V Leiden mutation • Prothrombin G20210A However, the incidence of these disorders in newborns with thrombosis is not known and the contribution of the prothrombotic state to the pathogenesis of neonatal thrombosis is uncertain [26] The approach to testing for https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_res… 3/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate thrombophilia in a newborn with clinically significant thrombosis is discussed below (See 'Coagulation studies' below.) CLINICAL FEATURES The clinical presentation of thrombosis is variable Signs and symptoms depend upon the location and size of the thrombus The most common predisposing factor for thrombosis is the presence of a central venous or arterial catheter [8,9] In thrombosis unrelated to a catheter, renal vein thrombosis (RVT) is the most common [9] Catheter-associated thrombosis — Central venous catheters are usually placed through the umbilical vein or major vessels such as the jugular vein Peripherally inserted central catheters are placed through peripheral veins in the arms, legs, or scalp Central venous catheters are widely used to provide intravenous fluids, parenteral nutrition, and medications to term and preterm infants who require intensive care In a series of 193 infants with central venous catheters, central venous or intracardiac thrombosis occurred in 13 percent [27] The location of the tip of the catheter may have an effect on the incidence of thrombosis Venous thrombosis — Many cases of venous thrombosis are asymptomatic and detected incidentally [23,28] Most are associated with central venous catheters [8,22,24] The presenting sign may be loss of patency of the catheter Other signs may include swelling and/or color changes in the affected extremity Symptomatic thrombosis in the inferior vena cava typically presents as swelling of the lower limbs and lower body [29] Superior vena cava thrombosis typically presents as swelling of the arm, neck, and head The severity of the swelling depends upon the size of the thrombus Chylothorax may be the presenting sign of superior vena cava thrombosis [30-32] The long-term outcome of venous thromboembolic disease in newborns depends upon the location Portal vein thrombosis (PVT) related to umbilical venous catheterization may result in portal hypertension [33-35] Long-term sequelae of RVT include systemic hypertension, renal insufficiency, and renal tubular dysfunction [36,37] A potential complication is post-thrombotic syndrome, a disorder characterized by edema and impaired viability of subcutaneous tissue in an extremity [24] The condition is caused by incompetent perforating valves, resulting in blood flow directed from deep to peripheral veins This disorder is increasingly recognized in older infants and children, but it appears to https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_res… 4/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate be less common following neonatal thrombosis Clinically relevant post-thrombotic syndrome only occurs in percent of the neonates [16,38] (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Post-thrombotic syndrome'.) Right atrial thrombosis — Right atrial thrombosis is associated with central venous catheter placement In one report, this disorder was detected by prospective echocardiography in the first few days after birth in of 76 (5 percent) very low birth weight infants who had umbilical catheters [39] Symptomatic intracardiac thrombosis can present as a new murmur or heart failure, as well as malfunction of the catheter [24] Arterial thrombosis — Nearly all cases of arterial thrombosis in neonates are associated with arterial catheters [24] Umbilical arterial catheters (UACs) and peripheral arterial catheters (radial, posterior tibial) are typically used for monitoring of blood pressure and blood gases; the femoral artery is often used for cardiac catheterization The incidence of arterial thrombosis associated with arterial catheters in neonates is variable and depends in part upon the method of detection used Prophylactic heparin infusion may reduce the risk of thrombosis, as discussed separately (See "Neonatal thrombosis: Management and outcome", section on 'Prevention of catheter-associated thrombosis'.) Umbilical artery catheter — The reported incidence of arterial thrombosis in neonates with UACs in place is approximately to 20 percent [16,40,41] Most UAC-associated thromboses are asymptomatic However, some present with signs of severe ischemia or organ dysfunction Depending upon the location of the thrombus, signs can include coolness; poor perfusion; and blanching of a toe, one or both limbs, or the buttocks Hypertension may also be noted In some cases, the presentation can mimic that of severe aortic coarctation (See "Clinical manifestations and diagnosis of coarctation of the aorta".) Renal failure, necrotizing enterocolitis, and spinal cord infarction are rare complications of UAC-associated thrombosis that can occur if the thrombosis extends into the renal, mesenteric, or branches of the spinal arteries [42-44] Peripheral artery occlusion — There are limited data on thrombosis associated with peripheral artery catheterization in neonates In the available reports, incidence rates ranged from to 63 percent [16] Clinical signs include decreased or absent https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_res… 5/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate peripheral pulses; diminished perfusion with a prolonged capillary refill time; and a cool, pale extremity The diagnosis can be confirmed by Doppler ultrasound Severe thrombosis in an extremity can result in long-term arterial insufficiency This may impair growth of the affected limb [45] Portal vein thrombosis — In the neonate, umbilical venous catheterization is associated with an increased risk of PVT [33,34,46,47] Most cases are asymptomatic and regress spontaneously Reported rates of PVT in studies using routine ultrasound surveillance for all patients with umbilical venous catheters range from 22 to 75 percent [40,48,49] In these studies, spontaneous resolution at one year was >95 percent among patients who underwent serial ultrasound monitoring [48,49] The majority of PVTs in neonates are asymptomatic However, a small minority of patients may develop long-term complications such as hepatic lobar atrophy and/or portal hypertension [33,47,50-52] The precise incidence of and risk factors for these complications are unknown In a retrospective study of 74 patients with neonatal PVT, 60 percent had complete resolution demonstrated on sequential ultrasound imaging over an average follow-up of 16 months; the remaining 40 percent had either partial resolution or stable appearance on follow-up ultrasound [52] In this study, only percent of patients experienced complications of PVT (hepatomegaly in two patients, splenomegaly in one patient); no patients in this series developed lobar atrophy or portal hypertension By contrast, an earlier study of 133 patients with neonatal PVT reported higher rates of hepatic lobar atrophy (23 percent) and portal hypertension (4.5 percent) [47] Renal vein thrombosis — RVT accounts for approximately 10 percent of venous thrombosis in newborns and is the most common form of thrombosis not associated with a vascular catheter [8,37] The proposed mechanisms resulting in RVT include reduced renal blood flow, hyperosmolality, hypercoagulability, and increased blood viscosity [53,54] Risk factors associated with RVT include prematurity, perinatal asphyxia, shock, dehydration, sepsis, polycythemia, cyanotic congenital heart disease, respiratory distress syndrome, and maternal diabetes [37,53,55,56] In addition, the prevalence of inherited thrombophilia (eg, antithrombin deficiency, protein C or S deficiency, factor V Leiden mutation, and prothrombin G20210A) is higher in infants with RVT compared with the general population [53,56] https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_res… 6/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate RVT, which may occur as an extension of inferior vena cava thrombosis, typically presents with one of the following cardinal features of RVT: flank mass, hematuria, or thrombocytopenia However, in one series of 23 cases of which 83 percent were diagnosed in the first month after birth, the complete triad was seen in only 13 percent [36] The clinical presentation of neonatal RVT was demonstrated by a systematic review of the literature from 1992 to 2006 that identified 271 patients from 13 case series [57] The following findings were noted: ● The time of presentation varied and occurred in utero (7 percent), by three days of life (67 percent), and after three days of life but before one month of age (26 percent) Most of the patients were born full term (71 percent), and there was a male predominance (67 percent) ● Patients had one or more of the following findings at presentation: gross hematuria (56 percent), thrombocytopenia (48 percent), and/or a palpable abdominal mass (45 percent) ● Approximately 70 percent of cases were unilateral, which involved the left kidney in two-thirds of these patients ● The thrombus extended into the inferior vena cava in approximately 44 percent of patients, and adrenal hemorrhage occurred in 15 percent ● Perinatal risk factors including asphyxia were identified in 32 percent of cases Other reported risk factors included maternal diabetes mellitus (8 percent) and dehydration (2 percent) ● Among the 149 patients in whom prothrombotic factors were investigated, 53 percent had at least one risk factor identified Purpura fulminans — Purpura fulminans in newborns is a rare, life-threatening condition characterized by disseminated intravascular coagulation and hemorrhagic skin necrosis [58] It usually is caused by homozygous or compound heterozygous deficiency in protein C or S, a mechanism that is consistent with the observation of consanguinity in some affected families [5864] The heterozygous parents of these infants have type protein C deficiency but infrequently have a history of thrombosis https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_res… 7/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate Purpura fulminans also can result from acquired protein C deficiency due to consumptive coagulopathy, as in meningococcemia [58] (See "Clinical manifestations of meningococcal infection", section on 'Purpura fulminans' and "Protein C deficiency", section on 'Control of protein C levels'.) Clinical presentation — Neonatal purpura fulminans usually occurs on the first day of life Affected infants present with ecchymoses, extensive venous and arterial thromboses (initially at sites of trauma), laboratory evidence of disseminated intravascular coagulation (thrombocytopenia, hypofibrinogenemia, and increased prothrombin time and activated partial thromboplastin time times), and extremely low levels of protein C or protein S antigen (less than percent of normal) [59-61,6570] Delayed presentation of the disorder (after six months of age) has been reported [71] Diagnosis — The diagnosis of protein C or S deficiency is made by testing a citrated plasma sample for protein C and S activity [58] The sample must be collected prior to initiation of treatment, but treatment should not be delayed while awaiting the results Results should be compared with age-specific reference ranges because protein C and S activity in healthy neonates is substantially lower than in older children or adults [1,2] Ideally, the diagnosis is confirmed with genetic testing; a list of clinical laboratories that perform genetic testing for this disorder is available at the GeneTests website LABORATORY FINDINGS Neonatal thrombosis is often associated with thrombocytopenia Thus, the diagnosis of thrombosis should be considered in neonates with thrombocytopenia who lack an alternative explanation for the low platelet count Other causes of neonatal thrombosis are summarized in the table ( table 3) and discussed separately (See "Neonatal thrombocytopenia: Etiology".) DIAGNOSIS Imaging ● Doppler ultrasound – Doppler ultrasound examination is the imaging test of choice to confirm thrombosis in most cases The advantages of this technique are that it is noninvasive, does not require exposure to ionizing radiation, and can be https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_res… 8/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate performed at the bedside Contrast angiography is considered the gold standard However, it is rarely used because of its invasive nature The accuracy of ultrasound may be reduced by the presence of a catheter because reduced compressibility of the vessel lumen by the ultrasound probe (a sign of thrombosis) is difficult to assess [24] Interpretation may also be limited by the low pulse pressure in preterm and sick newborns In one series of 47 infants with umbilical venous catheters, the accuracy of Doppler ultrasonography was poor compared with contrast venography in detecting asymptomatic thrombus [28] Thrombi were detected by venogram in 14 patients (30 percent) The sensitivity and specificity of echocardiographic diagnosis for the three cardiologists who interpreted the studies ranged from 21 to 43 and 76 to 94 percent, respectively However, the relative accuracy of these techniques to detect symptomatic thrombosis is not known ● Renal vein thrombosis (RVT) imaging – Doppler ultrasound is the most commonly used imaging technique to confirm the diagnosis of RVT The ultrasound features depend upon the timing of the examination [72-74] During the first few days, echogenic streaks appear in a peripheral focal segment of the affected kidney During the first week, the kidney appears swollen and echogenic, with prominent and less echogenic medullary pyramids As the swelling decreases, the kidney appears heterogeneous with loss of corticomedullary differentiation The kidney may subsequently atrophy with focal scarring or recover Color Doppler ultrasonography may show absent intrarenal and renal venous flow in the early stages of RVT [72] Indeed, the sonographic findings can be used to predict outcome [75] ● Pretreatment cranial ultrasound – If anticoagulation therapy is planned, we suggest performing a baseline pretreatment cranial ultrasound to rule out intracranial or intraventricular hemorrhage This is especially important for preterm infants (See "Neonatal thrombosis: Management and outcome", section on 'Pretreatment evaluation'.) Coagulation studies ● Testing for thrombophilia – Decisions regarding testing for thrombophilia in newborns with clinically significant thrombosis are made on a case-by-case basis The utility of testing newborns with catheter-related thrombosis is minimal [76] However, patients with thrombosis that is not catheter related and those with recurrent thrombosis generally should https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_res… 9/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate be evaluated Because it is difficult to interpret values of coagulation and fibrinolytic factors in the neonatal period and in the setting of acute thrombosis, we prefer to delay testing for prothrombotic disorders in most cases until the child is older, except when the thrombosis is severe or recurrent The benefits of testing are uncertain Inherited thrombophilias are associated with a risk of recurrence However, among patients who present with thrombosis as a neonate, the recurrence risk is low (3 to percent) and often a distant event, occurring at the earliest in the teenage years [25,77] (See "Thrombophilia testing in children and adolescents", section on 'Children with venous thromboembolism'.) When the decision is made to perform thrombophilia testing in a neonate, the results should be interpreted using reference values for the appropriate postnatal and gestational age [78] Abnormal results should be repeated in four to six weeks, and parents should be counseled about the results Consultation with a pediatric hematologist is advised Tests to perform to evaluate for thrombophilia in neonates are generally the same as for older children, as summarized in the table ( table 4) The one difference is that testing for antiphospholipid antibodies should be performed on a maternal blood sample rather than testing the neonate Thrombophilia testing in infants and children is discussed in greater detail separately (See "Thrombophilia testing in children and adolescents".) ● Pretreatment coagulation tests – If anticoagulation therapy is planned, we suggest performing baseline pretreatment laboratory testing, including the following: • Prothrombin time and international normalized ratio • Activated partial thromboplastin time • Platelet count • Fibrinogen level SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately (See "Society guideline links: Thrombotic diseases in infants and children".) https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_re… 10/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate 54 Marks SD, Massicotte MP, Steele BT, et al Neonatal renal venous thrombosis: clinical outcomes and prevalence of prothrombotic disorders J Pediatr 2005; 146:811 55 Kuhle S, Massicotte P, Chan A, Mitchell L A case series of 72 neonates with renal vein thrombosis Data from the 1-800-NOCLOTS Registry Thromb Haemost 2004; 92:729 56 Winyard PJ, Bharucha T, De Bruyn R, et al Perinatal renal venous thrombosis: presenting renal length predicts outcome Arch Dis Child Fetal Neonatal Ed 2006; 91:F273 57 Lau KK, Stoffman JM, Williams S, et al Neonatal renal vein thrombosis: review of the English-language literature between 1992 and 2006 Pediatrics 2007; 120:e1278 58 Price VE, Ledingham DL, Krümpel A, Chan AK Diagnosis and management of neonatal purpura fulminans Semin Fetal Neonatal Med 2011; 16:318 59 Seligsohn U, Berger A, Abend M, et al Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn N Engl J Med 1984; 310:559 60 Marciniak E, Wilson HD, Marlar RA Neonatal purpura fulminans: a genetic disorder related to the absence of protein C in blood Blood 1985; 65:15 61 Peters C, Casella JF, Marlar RA, et al Homozygous protein C deficiency: observations on the nature of the molecular abnormality and the effectiveness of warfarin therapy Pediatrics 1988; 81:272 62 Sugahara Y, Miura O, Yuen P, Aoki N Protein C deficiency Hong Kong and 2: hereditary protein C deficiency caused by two mutant alleles, a 5-nucleotide deletion and a missense mutation Blood 1992; 80:126 63 Mahasandana C, Suvatte V, Marlar RA, et al Neonatal purpura fulminans associated with homozygous protein S deficiency Lancet 1990; 335:61 64 Pung-amritt P, Poort SR, Vos HL, et al Compound heterozygosity for one novel and one recurrent mutation in a Thai patient with severe protein S deficiency Thromb Haemost 1999; 81:189 65 Yuen P, Cheung A, Lin HJ, et al Purpura fulminans in a Chinese boy with congenital protein C deficiency Pediatrics 1986; 77:670 https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_re… 17/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate 66 Branson HE, Katz J, Marble R, Griffin JH Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant Lancet 1983; 2:1165 67 Estellés A, Garcia-Plaza I, Dasí A, et al Severe inherited "homozygous" protein C deficiency in a newborn infant Thromb Haemost 1984; 52:53 68 Sills RH, Marlar RA, Montgomery RR, et al Severe homozygous protein C deficiency J Pediatr 1984; 105:409 69 Rappaport ES, Speights VO, Helbert B, et al Protein C deficiency South Med J 1987; 80:240 70 Limperger V, Klostermeier UC, Kenet G, et al Clinical and laboratory characteristics of children with venous thromboembolism and protein C-deficiency: an observational Israeli-German cohort study Br J Haematol 2014; 167:385 71 Tuddenham EG, Takase T, Thomas AE, et al Homozygous protein C deficiency with delayed onset of symptoms at to 10 months Thromb Res 1989; 53:475 72 Hibbert J, Howlett DC, Greenwood KL, et al The ultrasound appearances of neonatal renal vein thrombosis Br J Radiol 1997; 70:1191 73 Cremin BJ, Davey H, Oleszczuk-Raszke K Neonatal renal venous thrombosis: sequential ultrasonic appearances Clin Radiol 1991; 44:52 74 Wright NB, Blanch G, Walkinshaw S, Pilling DW Antenatal and neonatal renal vein thrombosis: new ultrasonic features with high frequency transducers Pediatr Radiol 1996; 26:686 75 Kraft JK, Brandão LR, Navarro OM Sonography of renal venous thrombosis in neonates and infants: can we predict outcome? Pediatr Radiol 2011; 41:299 76 Turebylu R, Salis R, Erbe R, et al Genetic prothrombotic mutations are common in neonates but are not associated with umbilical catheter-associated thrombosis J Perinatol 2007; 27:490 77 van Ommen CH, Heijboer H, Büller HR, et al Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands J Pediatr 2001; 139:676 78 Andrew M Developmental hemostasis: relevance to thromboembolic complications in pediatric patients Thromb Haemost 1995; 74:415 Topic 5912 Version 18.0 https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_re… 18/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_re… 19/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate GRAPHICS Coagulation cascade detailed/traditional view Schematic representation of the coagulation cascade including our improved understanding of the role of the tissue factor (TF) pathway in initiating clotting, interactions between pathways, and the role of https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_re… 20/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate thrombin in sustaining the cascade by feedback activation of coagulation factors PK: prekallikrein; HK: high molecular weight kininogen; PL: phospholipid Adapted from: Ferguson JD, Banning AP Spontaneous intramural aortic haematoma: incidence, prognosis and complications Eur Heart J 1998; Suppl 19:8 Graphic 69920 Version 10.0 https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_re… 21/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate Regulation of fibrinolysis by plasminogen activator inhibitor-1 (PAI-1), α2-antiplasmin, and thrombinactivatable fibrinolysis inhibitor (TAFI) PAI-1 inhibits plasmin formation by inhibiting t-PA α2-antiplasmin inhibits the activity of plasmin, thereby inhibiting fibrinolysis TAFI circulates in plasma as a zymogen It is activated by thrombin when thrombin is bound on to its endothelial cofactor TM, and therefore represents a link between blood coagulation and fibrinolysis During fibrinolysis, plasmin cleaves intact fibrin at lysine residues, initially yielding large, insoluble fibrin fragments with lysine residues at their carboxyl termini Plasminogen binds avidly to C-terminal lysine residues within the partially degraded fibrin clot and assumes a conformation that is susceptible to activation by t-PA, thereby promoting plasmin formation, continued fibrinolysis ("rapid fibrinolysis"), and generation of smaller, soluble fibrin fragments that are dispersed by flowing blood Activated TAFI (TAFIa) is a carboxypeptidase that removes lysine residues from the C-termini of https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_re… 22/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate partially degraded fibrin fragments By removing C-terminal lysine residues from large fibrin fragments in the partially degraded clot, TAFI inhibits recruitment of plasminogen to the clot, thereby slowing fibrinolysis ("slow fibrinolysis") PAI-1: plasminogen activator inhibitor-1; t-PA: tissue-type plasminogen activator; TAFI: thrombin-activatable fibrinolysis inhibitor; TAFIa: activated form of TAFI; TM: thrombomodulin Diagram supplied by William P Fay, MD Graphic 81428 Version 8.0 https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_re… 23/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate Normal range for coagulation tests by age Age Coagulation tests Day of life Day of life Mean (boundary) Mean (boundary) to 12 months Mean (boundary) to years to 10 years Mean (boundary) Mean (boundary) 11 to 16 years Mean (boundary) Adult Mean (boundary) PT(s)* 15.6 (14.416.4)¶ 14.9 (13.516.4)¶ 13.1 (11.5-15.3) 13.3 (12.114.5)¶ 13.4 (11.715.1)¶ 13.8 (12.716.1)¶ 13 (11.5-14.5) INR 1.26 (1.15- 1.2 (1.05- (0.86-1.22) 1.03 (0.92- 1.04 (0.87-1.2)¶ 1.08 (0.97-1.3)¶ (0.8-1.2) aPTT(s)* 38.7 (34.3- 36.3 (29.5- 39.3 (35.1- 37.7 (33.6- 37.3 (31.8- 39.5 (33.9- 33.2 (28.6-38.2) Fibrinogen (g/L) 2.8 (1.92-3.74) 3.3 (2.83-4.01) 2.42 (0.823.83)¶ 2.82 (1.624.01)¶ 3.04 (1.99-4.09) 3.15 (2.12-4.33) 3.1 (1.9-4.3) Factor II (U/mL) 0.54 (0.41- 0.62 (0.5- 0.9 (0.62- 0.89 (0.7-1.09)¶ 0.89 (0.67-1.1)¶ 0.9 (0.61-1.07)¶ 1.1 (0.78-1.38) Factor V (U/mL) 0.81 (0.64- 1.22 (0.92-1.54) 1.13 (0.94-1.41) 0.97 (0.67- 0.99 (0.56- 0.89 (0.67- 1.18 (0.78-1.52) Factor VII (U/mL) 0.7 (0.520.88)¶ 0.86 (0.671.07)¶ 1.28 (0.83-1.6) 1.11 (0.72-1.5)¶ 1.13 (0.7-1.56)¶ 1.18 (0.69-2) 1.29 (0.61-1.99) Factor VIII 1.82 (1.05-3.29) 1.59 (0.83-2.74) 0.94 (0.54- 1.1 (0.36-1.85)¶ 1.17 (0.52- 1.2 (0.59-2)¶ 1.6 (0.52-2.9) vWF (U/mL) n/a n/a n/a 0.82 (0.6-1.2) 0.95 (0.44-1.44) (0.46-1.53) 0.92 (0.5-1.58) Factor IX 0.48 (0.35- 0.72 (0.44- 0.71 (0.43- 0.85 (0.44- 0.96 (0.48- 1.11 (0.64- 1.3 (0.59-2.54) (U/mL) 0.56)¶ Factor X (U/mL) 0.55 (0.46- 0.6 (0.46- 0.95 (0.77- 0.98 (0.72- 0.97 (0.68- 0.91 (0.53- 1.24 (0.96-1.71) 1.35)¶ 44.8)¶ 0.69)¶ 1.03)¶ 1.35)¶ 42.2)¶ 0.73)¶ (U/mL) 0.97)¶ 46.3)¶ 1.03)¶ 1.45)¶ 1.21)¶ 1.14)¶ 46.3)¶ 1.27)¶ 1.27)¶ 43.7)¶ 1.41)¶ 1.82)¶ 1.45)¶ 46.1)¶ 1.41)¶ 2.16)¶ https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_re… 24/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate 0.67)¶ 0.75)¶ 1.22)¶ 1.25)¶ 1.25)¶ 1.22)¶ 0.3 (0.7-0.41)¶ 0.57 (0.24- 0.89 (0.62- 1.13 (0.65-1.62) 1.13 (0.65-1.62) 1.11 (0.65-1.39) 1.12 (0.67-1.96) 0.58 (0.43- 0.53 (0.14- 0.79 (0.2- 0.85 (0.36- 0.81 (0.26- 0.75 (0.14- 1.15 (0.35-2.07) (U/mL) 0.8)¶ XIIIa (U/mL) n/a n/a n/a 1.08 (0.721.43)¶ 1.09 (0.651.51)¶ 0.99 (0.57-1.4) 1.05 (0.55-1.55) XIIIs (U/mL) n/a n/a n/a 1.13 (0.69- 1.16 (0.77- 1.02 (0.6-1.43) 0.97 (0.57-1.37) Factor XI (U/mL) Factor XII 0.79)¶ 0.8)¶ 1.25)¶ 1.35)¶ 1.35)¶ 1.56)¶ 1.37)¶ 1.54)¶ 1.17)¶ All factors except fibrinogen are expressed as units per milliliter, where pooled plasma contains 1.0 U/mL All data are expressed as the mean, followed by the upper and lower boundary encompassing 95% of the population Between 20 and 67 samples were assayed for each value for each age group Some measurements were skewed due to a disproportionate number of high values The lower limit, which excludes the lower 2.5% of the population, is given PT: prothrombin time; INR: international normalized ratio; aPTT: activated partial thromboplastin time; VIII: factor VIII procoagulant; vWF: von Willebrand factor; n/a: data not available * Normal range for PT and aPTT should be based upon the standards set by individual clinical laboratories ¶ Denotes values that are significantly different from adults Data on vWF, XIIIa and XIIIs from: Andrew M, Vegh P, Johnston M, et al Maturation of the Hemostatic System During Childhood Blood 1992; 80:1999 Remaining data from: Monagle P, Barnes C, Ignjatovic V, et al Developmental Haemostasis Thrombosis and Haemostasis 2006; 95:362 Graphic 66999 Version 6.0 https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_re… 25/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate Reference values for coagulation tests in healthy premature infants (30 to 36 weeks gestation) during first months of life Tests Day M Day Day 30 B M B M B Day 90 M B Day 180 M B Adult M B PT (s) 13 (10.6-16.2)* 12.5 (10-15.3)*¶ 11.8 (10-13.6)* 12.3 (10-14.6)* 12.5 (10-15)* 12.4 (10.8-13.9) aPTT (s) 53.6 (27.5-79.4)Δ 50.5 (26.974.1)Δ 44.7 (26.9-62.5) 39.5 (28.3-50.7) 37.5 (21.7-53.3)* 33.5 (26.6-40.3) TCT (s) 24.8 (19.2-30.4)* 24.1 (18.8-29.4)* 24.4 (18.8-29.9)* 25.1 (19.4-30.8)* 25.2 (18.9-31.5)* 25 (19.7-30.3) Fibrinogen 2.43 (1.5- 2.80 (1.6- 2.54 (1.5- 2.46 (1.5- 2.28 (1.5-3.6)¶ 2.78 (1.56-4) 3.73)*¶Δ (g/L) II (units/mL) 0.45 (0.2-0.77)¶ 4.18)*¶Δ 0.57 (0.29-0.85)Δ 4.14)*¶ 0.57 (0.36- 3.52)*¶ 0.68 (0.3-1.06) 0.87 (0.51-1.23) 1.08 (0.7-1.46) 0.95)¶Δ V (units/mL) 0.88 (0.411.44)*¶Δ (0.46-1.54) 1.02 (0.48-1.56) 0.99 (0.59-1.39) 1.02 (0.58-1.46) 1.06 (0.62-1.5) VII 0.67 (0.21-1.13) 0.84 (0.3-1.38) 0.83 (0.21-1.45) 0.87 (0.31-1.43) 0.99 (0.47-1.51)* 1.05 (0.67-1.43) 1.11 (0.5-2.13)*¶ 1.15 (0.53- 1.11 (O.50- 1.06 (0.58- 0.99 (0.5- 0.99 (0.5-1.49) (units/mL) VIII 2.05)*¶Δ (units/mL) l.99)*¶Δ 1.88)*¶Δ 1.87)*¶Δ VWF (units/mL) 1.36 (0.78-2.1)¶ 1.33 (0.722.19)¶ 1.36 (0.662.16)¶ 1.12 (0.75-l.84)* 0.98 (0.541.58)*¶ 0.92 (0.5-1.58) IX (units/mL) 0.35 (0.19- 0.42 (0.14- 0.44 (0.13- 0.59 (0.25-0.93) 0.81 (0.5-1.2)¶ 1.09 (0.55-1.63) 0.65)¶Δ 0.74)¶Δ 0.80)¶ X (units/mL) 0.41 (0.11-0.71) 0.51 (0.19-0.83) 0.56 (0.2-0.92) 0.67 (0.35-0.99) 0.77 (0.35-1.19) 1.06 (0.7-1.52) XI (units/mL) 0.3 (0.08- 0.41 (0.13- 0.43 (0.15- 0.59 (0.25- 0.78 (0.46-1.1) 0.97 (0.67-1.27) 0.82 (0.22-1.42) 1.08 (0.52-1.64) 0.52)¶Δ XII 0.38 (0.1-0.66)Δ 0.69)Δ 0.39 (0.09- 0.71)Δ 0.43 (0.11-0.75) 0.93)Δ 0.61 (0.15-1.07) https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_re… 26/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate 0.69)Δ (units/mL) PK 0.33 (0.09-0.57) 0.45 (0.26- 0.59 (0.31-0.87) 0.79 (0.37-1.21) 0.78 (0.4-1.16) 1.12 (0.62-1.62) 0.75)¶ (units/mL) HMWK (units/mL) 0.49 (0.09-0.89) 0.62 (0.24-1)Δ 0.64 (0.161.12)Δ 0.78 (0.32-1.24) 0.83 (0.41-1.25)* 0.92 (0.5-1.36) XIIIa 0.7 (0.32-1.08) 1.01 (0.57-1.45)* 0.99 (0.51-1.47)* 1.13 (0.71-1.55)* 1.13 (0.65-1.61)* 1.05 (0.55-1.55) 0.81 (0.35-1.27) 1.1 (0.68-1.58)* 1.07 (0.57-1.57)* 1.21 (0.75-1.67) 1.15 (0.67-1.63) 0.97 (0.57-1.37) 1.7 (1.122.48)¶Δ 1.91 (1.212.61)Δ 1.81 (1.09-2.53) 2.38 (1.58-3.18) 2.75 (1.913.59)Δ 3.36 (2.48-4.24) (units/mL) XIIIb (units/mL) Plasminogen (CTA, units/mL) All factors except fibrinogen and plasminogen are expressed as units/mL, where pooled plasma contains 1.0 units/mL Plasminogen units are those recommended by the CTA All values are given as a mean (M), followed by lower and upper boundary encompassing 95% of the population (B) Between 40 and 96 samples were assayed for each value for newborns PT: prothrombin time; aPTT: activated partial thromboplastin time; TCT: thrombin clotting time; VWF: von Willebrand factor; PK: prekallikrein; HMWK: high molecular weight kininogen; CTA: Committee on Thrombolytic Agents * Values indistinguishable from those of adults ¶ Measurements are skewed, owing to a disproportionate number of high values Lower limit that excludes the lower 2.5% of the population is given (B) Δ Values different from those of full-term infants Reprinted from: Andrew M, Paes B, Milner R, et al Development of the Human Coagulation System in the Healthy Premature Infant Blood 1988; 72:1651 Copyright ©1988 The American Society of Hematology Graphic 65080 Version 5.0 https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_re… 27/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate Common causes of neonatal thrombocytopenia Increased destruction or consumption of platelets Immune thrombocytopenia Alloimmune thrombocytopenia Autoimmune thrombocytopenia Drug-induced immune thrombocytopenia Sequestration and trapping Hypersplenism Kasabach-Merritt syndrome Platelet activation and consumption Disseminated intravascular coagulation Thrombosis Type 2B von Willebrand disease Decreased production of platelets Congenital thrombocytopenias Drug-associated marrow suppression Infiltrative bone marrow disorders Preeclampsia Miscellaneous causes Infection: Both destructive and decreased production (ie, bone marrow suppression) can cause neonatal thrombocytopenia Asphyxia: Mechanism uncertain Dilution https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_re… 28/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate Graphic 52668 Version 8.0 https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_re… 29/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate Laboratory evaluation for thrombophilias in children Thrombophilia Laboratory studies* Factor V Leiden mutation DNA-based PCR assay (or screen with functional assay for activated protein C resistance) Prothrombin 20210 mutation DNA-based PCR assay Antithrombin deficiency Antithrombin activity via chromogenic or clotting assay Protein C deficiency Protein C activity via chromogenic or clotting assay Protein S deficiency Free and total protein S levels measured via immunoassays Antiphospholipid antibodies¶ Immunoassays for IgG and IgM antibodies to cardiolipin and beta-2-glycoprotein-I and functional assay for the lupus anticoagulant phenomenon This table summarizes our suggested approach to testing for thrombophilia in children We suggest testing only for defects that are strongly associated with increased risk of VTE, which are listed in this table Other tests that may be included on a "thrombophilia panel" but that we suggest not routinely performing include factor VIII level, homocysteine level, MTHFR variant testing, and lipoprotein(a) level Refer to UpToDate topic on thrombophilia testing in children for further details of our approach PCR: polymerase chain reaction; IgG: immunoglobulin G; IgM: immunoglobulin M; VTE: venous thromboembolism; MTHFR: methylene tetrahydrofolate reductase gene * Refer to separate UpToDate content for details of laboratory testing for these disorders ¶ Testing for antiphospholipid antibodies is performed only when evaluating children who have had a VTE This testing is not part of the evaluation of asymptomatic children with a positive family history of VTE, because antiphospholipid antibody syndrome is an acquired rather than inherited thrombophilia Graphic 88804 Version 9.0 https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_re… 30/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and diagnosis - UpToDate Contributor Disclosures Anthony KC Chan, MBBS, FRCPC, FRCPath Patent Holder: ATTWILL [Anticoagulation] Grant/Research/Clinical Trial Support: Octopharma [Recombinant factor VIII]; CSL Plasma [Recombinant factor IX]; Novo Nordisk [Recombinant factor IX]; Bayer [Clinical trials]; Sanofi [Clinical trials]; Sobi [Clinical trials]; BMS [Clinical trials]; I-ACT [Neonatal thrombosis]; AceAge [Hemophilia, point-of-care ultrasound] Consultant/Advisory Boards: Bayer [Pediatric coagulation disorders]; Daiichi Sankyo [Steering committee for clinical trials]; CSL Behring [Hemophilia B] Other Financial Interest: Bayer [Honoraria]; Novo Nordisk [Honoraria]; Takeda [Honoraria] All of the relevant financial relationships listed have been mitigated Mihir D Bhatt, MD, FRCPC No relevant financial relationship(s) with ineligible companies to disclose Sarah O'Brien, MD, MSc Grant/Research/Clinical Trial Support: Bristol Myers Squibb [Anticoagulation] Consultant/Advisory Boards: Bristol Myers Squibb [Anticoagulation]; Anthos [Anticoagulation] All of the relevant financial relationships listed have been mitigated Joseph A Garcia-Prats, MD No relevant financial relationship(s) with ineligible companies to disclose Carrie Armsby, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose Contributor disclosures are reviewed for conflicts of interest by the editorial group When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence Conflict of interest policy  https://www-uptodate-com.ezproxy.library.unlv.edu/contents/neonatal-thrombosis-clinical-features-and-diagnosis/print?search=Neonatal thrombosis: Clinical features and diagnosis&source=search_re… 31/31 ... https://www -uptodate- com.ezproxy.library.unlv.edu/contents /neonatal- thrombosis- clinical- features- and- diagnosis/ print?search =Neonatal thrombosis: Clinical features and diagnosis& source=search_res… 3/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features. .. https://www -uptodate- com.ezproxy.library.unlv.edu/contents /neonatal- thrombosis- clinical- features- and- diagnosis/ print?search =Neonatal thrombosis: Clinical features and diagnosis& source=search_res… 8/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features. .. https://www -uptodate- com.ezproxy.library.unlv.edu/contents /neonatal- thrombosis- clinical- features- and- diagnosis/ print?search =Neonatal thrombosis: Clinical features and diagnosis& source=search_re… 10/31 15:58, 03/01/2022 Neonatal thrombosis: Clinical features and