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The bleeding newborn: A review of presentation, diagnosis, and management
Seminars in Fetal & Neonatal Medicine xxx (2015) 1e6
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Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Review
The bleeding newborn: A review of presentation, diagnosis, and management Julie Jaffray a, b, Guy Young a, b, Richard H. Ko a, b, * a b
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA, USA Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
s u m m a r y Keywords: Hemorrhage Hemostasis Infant Newborn
The neonatal hemostatic system is continuously developing with rapidly changing concentrations of many coagulation proteins. Thus, determining the etiology of bleeding in a newborn has additional challenges beyond those seen in older children or adults. Bleeding can be seen in both well and sick newborns due to congenital causes, such as hemophilia or von Willebrand disease, and acquired causes, such as liver failure or disseminated intravascular coagulation. Traditional coagulation testing should be interpreted with caution and with the help of a hematologist, if possible, due to the greatly different normal ranges between neonates as compared with older children and adults. However, despite these challenges, both clinical and laboratory clues can guide physicians appropriately to diagnose and treat the bleeding newborn. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction Bleeding in healthy neonates is rare, but in sick neonates, it is often serious and can be fatal. The clinical presentation of bleeding in neonates includes intracranial hemorrhage (ICH), cephalohematoma, bleeding after a procedure or venepuncture, or mucocutaneous bleeding such as bruising or gastrointestinal bleeding [1]. The etiology of such bleeding may arise from congenital issues, such as hemophilia, or from acquired issues including liver failure. Determining the cause of bleeding is a clinical challenge for both primary treating practitioners as well as hematology consultants due to the continuously evolving coagulation system in neonates. The coagulation system is comprised of cellular elements (platelets being the most important) and plasma proteins, all of which work in concert to protect from both hemorrhage and thrombosis. The concentrations of the plasma proteins are different in neonates when compared to older children and adults, and undergo rapid maturation over the first six months of life in a process
* Corresponding author. Address: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Mailstop #54, Los Angeles, CA 90027, USA. Tel.: þ1 (323) 361 5600; fax: þ1 (323) 361 7128. E-mail address: [email protected] (R.H. Ko).
known as developmental hemostasis [2]. Figure 1 illustrates the fetal development of the pro- and anticoagulant proteins [3e5]. Procoagulants present at adult levels at birth include fibrinogen, factor V (FV), factor VIII (FVIII) and von Willebrand factor (VWF), whereas factors II (FII), VII (FVII), IX (FIX) and X (FX) (vitamin Kdependent factors), and factors XI (FXI), XII (FXII), prekallikrein and high-molecular-weight kininogen (contact factors) are present at about 50% of adult levels at birth [6,7]. To balance lower levels of procoagulants, most of the anticoagulants (antithrombin, heparin cofactor II, protein C and protein S) are also lower at birth, though as a compensatory mechanism, the anticoagulant a-2-macroglobulin is actually higher at birth than adult levels [6,7]. As a result of lower levels of the procoagulant proteins, the activated partial thromboplastin time (aPTT) and prothrombin time (PT) are prolonged in neonates when compared to the adult range. Previous studies reported reference ranges for the aPTT, PT and the pro- and anticoagulant protein levels, in term and premature neonates [6e8]. Unfortunately these reference ranges must be interpreted with caution due to the significant laboratory variability of reagents and instruments used. The Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (ISTH) recommends creating pediatric reference ranges in each hospital, although this is quite time-consuming and costly [9]. This review discusses the various causes of bleeding in neonates and provides guidance on how to arrive at the appropriate diagnosis and suggest different treatment options. Bleeding disorders
http://dx.doi.org/10.1016/j.siny.2015.12.002 1744-165X/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Jaffray J, et al., The bleeding newborn: A review of presentation, diagnosis, and management, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.12.002
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Fig. 1. Fetal development of the coagulation system. FV, factor V; FVII, factor VII; FVIII, factor VIII; FIX, factor X; AT, antithrombin; HCII, heparin cofactor II. Reproduced with permission from Jaffray J, Young G. Developmental hemostasis clinical implications from the fetus to the adolescent. Pediatr Clin N Am 2013; 60:1407e17.
caused by thrombocytopenia or platelet dysfunction will be addressed in another article.
2. Congenital causes of bleeding 2.1. Hemophilia Deficiencies of FVIII and FIX are known as hemophilia A and B, respectively, and are inherited in an X-linked recessive pattern. Female relatives are known as hemophilia carriers. The incidence of hemophilia is 1 per 5000 males (FVIII) and 1 in 20,000 males (FIX) [10]. Persons with hemophilia are classified based on their plasma factor activity [severe (<1%), moderate (1e5%) or mild (>5 to 40%)]. Bleeding in hemophilia (mostly the severe type) may present in neonates as either post-procedural bleeding (e.g. circumcision or heel sticks) or even as ICH. Newborns with hemophilia are 44 times more likely to have symptomatic ICH compared to normal newborns, and it is more likely to occur after an assisted vaginal delivery [11,12]. The mean age of patients with hemophilia having their first bleed is 28.5 days [13]. Although diagnosing hemophilia in neonates is usually straightforward, issues of developmental hemostasis can make it more challenging than in older children. Up to 70% of patients are diagnosed in the first month of life [14]. Any newborn with unexpected or excessive bleeding should have an aPTT, and, though many normal infants have a prolonged aPTT, this should not preclude an evaluation of factor levels in the above situation. As the FVIII activity in neonates approximates that of a normal adult, making the diagnosis of severe or moderate hemophilia A is straightforward. The diagnosis of mild hemophilia can be more difficult due to increased FVIII activity resulting from the stress of delivery, thus levels should be repeated at six to 12 months of age if mild FVIII deficiency is suspected [15]. When evaluating FIX levels, however, as stated previously, FIX activity is about 50% of adult levels at birth, which overlaps with the range of mild hemophilia, making the diagnosis of mild hemophilia B difficult, and, as above, testing should be repeated at six to 12 months. Treatment of hemophilia is based on replacing the missing protein with factor concentrates; if needed, consultation with a pediatric hematologist is suggested to assist in management.
2.2. von Willebrand disease von Willebrand Disease (VWD) is the most frequently inherited bleeding disorder, affecting ~1% of the population, and is transmitted in autosomal dominant or recessive patterns [16,17]. There are three main categories of VWD based on the quantitative level or function of von Willebrand factor (VWF): type 1, 2, or 3. Most patients with VWD have type I, which is due to a partial quantitative deficiency of VWF and is usually associated with a mild phenotypic bleeding presentation [18]. Type 2 VWD is a qualitative dysfunction of VWF and is typically associated with a more severe bleeding phenotype. Type 2 is further divided into four separate subtypes, 2A, 2B, 2M, and 2N, which are based on the functional and structural interactions between VWF and platelets or FVIII. Type 3 is the rarest form of VWD in which patients have complete or almost complete deficiency of VWF and have the most severe bleeding phenotype [18,19]. Typically only patients with type 3 or some type 2 VWD present with bleeding as neonates [20]. Mucocutaneous bleeding is the hallmark of VWD; patients can have epistaxis, bruising, gum bleeding, and gastrointestinal bleeding, but also bleeding after trauma or surgery. The diagnosis of VWD is based on three main laboratory assays: (i) a quantitative measure of VWF in the plasma, (ii) the activity of VWF and its ability to bind platelets (iii) and FVIII activity [21]. High molecular weight multimer analysis can also be performed to help differentiate type 2 varieties. Table 1 shows the laboratory values that are consistent with each type of VWD. At birth, neonates have normal to increased levels of VWF activity and high-molecular weight VWF multimers compared to adult levels, which is why most patients with type 1 and 2 VWD do not present with bleeding until later in life [7,8]. The management of bleeding in a neonate with VWD is typically with plasma-derived FVIII (pdFVIII) products that contain VWF, and consultation with a pediatric hematologist is suggested to assist in management.
2.3. Rare inherited bleeding disorders Patients with rare factor deficiencies represent 3e5% of all coagulation disorders, with an incidence of 1:500,000 to
Please cite this article in press as: Jaffray J, et al., The bleeding newborn: A review of presentation, diagnosis, and management, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.12.002
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Table 1 Typical laboratory values for the main types of von Willebrand disease.
VWF antigen VWF activity FVIII activity Platelet count VWF multimers
Type 1
Type 2A
Type 2B
Type 2M
Type 2N
Type3
Low Low Low Normal Normal or mildly decreased expression in all sizes
Low Very low Normal or low Normal Loss of high and intermediate weight multimers
Low Very low Normal or low Low Decreased high molecular weight multimers
Low Very low Normal or low Normal Normal
Low Normal or low Very low Normal Normal
Absent Absent Extremely low Normal Absent
VWF, von Willebrand factor; FVIII, factor VIII.
1:2,000,000 [22,23]. Deficiencies in fibrinogen, FII, FV, FVII, FX, FXI, or FXIII may present in neonates, and each will be discussed briefly below. 2.3.1. Disorders of fibrinogen Fibrinogen is converted to fibrin and, along with platelets, forms the structure of blood clots. Patients with disorders of fibrinogen may have either decreased or complete absence of fibrinogen levels (hypofibrinogenemia, afibrinogenemia), or dysfunctional fibrinogen (dysfibrinogenemia). Afibrinogenemia is inherited in an autosomal recessive pattern, whereas the heterozygous form is hypofibrinogenemia. Neonates may present with prolonged bleeding from the umbilical cord stump, post circumcision, ICH, or mucocutaneous bleeding [24]. Patients with disorders of fibrinogen will have a prolonged PT and aPTT. Decreased functional or antigenic fibrinogen assays are the confirmatory tests. Normal term neonates have fibrinogen levels equal to adult normal values at birth [7,8]. Fibrinogen concentrates are the ideal treatment for bleeding episodes. Fresh frozen plasma (FFP) or cryoprecipitate may also be used for bleeding when fibrinogen concentrates are unavailable. 2.3.2. Prothrombin (FII), FV, FVII, FX, and FXI deficiency Patients with FII, FV, FVII, FX, and FXI deficiency are inherited in an autosomal recessive pattern, and there is a higher incidence of FXI deficiency in those of Ashkenazi Jewish descent [25]. Most factor deficiencies in neonates can lead to mucocutaneous bleeding, ICH, prolonged umbilical stump bleeding, or bleeding after procedures or trauma. FVII and FXI levels do not correlate well with bleeding phenotype; some patients with very low factor levels do not have any bleeding, and those with higher factor levels may have profuse bleeding [25,26]. Diagnosing rare factor deficiencies should begin with a PT and aPTT. Isolated prolongation of the PT is seen with FVII deficiency, and isolated prolongation of the aPTT is seen with FXI deficiency. Patients with FII, FV and FX deficiency will result in a prolongation of both the PT and aPTT. When a specific factor deficiency is suspected, confirmatory factor-specific assays should be performed. As above, diagnosing these factor deficiencies in a newborn is challenging due to the issues of developmental hemostasis [7,8]. Factor concentrates are available for the replacement of FVII (rFVIIa) and FII, FVII, FIX, and FX (prothrombin complex concentrates). FXI concentrate is available in some countries but not in the USA currently. FFP is the only treatment for patients with deficiencies of FV and FXI. 2.3.3. FXIII deficiency FXIII, composed of two A and two B subunits, cross-links fibrin and stabilizes clots. FXIII deficiency is inherited in an autosomal recessive pattern and clinical manifestations may occur in neonates, most commonly with umbilical cord stump bleeding
(50e70% of cases), ICH, and prolonged bleeding after procedures or trauma [27e29]. Low levels of FXIII do not prolong the PT or aPTT. Thus if both the PT and aPTT are within the normal range for age, and a bleeding disorder is suspected, then a quantitative FXIII assay should be performed. The clot solubility assay previously used to diagnose FXIII deficiency lacks sensitivity for very low levels of FXIII. Plasmaderived and recombinant FXIII products are available, although the recombinant form can only be used for A-subunit deletions. Cryoprecipitate should be used if FXIII concentrate is unavailable. 3. Acquired causes of bleeding 3.1. Liver failure The liver is responsible for the synthesis of most pro- and anticoagulant proteins (except FVIII and VWF) and thrombopoetin, which stimulates platelet production. A disruption in liver function may have a significant impact on the coagulation system, exacerbating the effects in neonates whose systems are already delicately balanced. Patients with liver failure may present with both bleeding and thrombosis, and the etiology, diagnosis, and treatment are all challenging. Neonates with liver disease may present with any manner of bleeding. Coagulation laboratory abnormalities seen in liver failure are elevated PT, aPTT and D-dimer, decreased fibrinogen activity, and decreased platelet count. The treatment for bleeding in liver failure is difficult due to the risks of fluid overload and thrombosis. FFP has historically been the first line of treatment for bleeding due to liver failure in neonates since it replaces all coagulation proteins. Studies have shown that large volumes of FFP are required to correct the coagulation abnormalities [30]. Off-label use of rFVIIa has been used and resulted in excellent control of bleeding due to liver disease in neonates; however, this medication carries with it a risk for thrombosis [31]. Cryoprecipitate to correct low fibrinogen, and prothrombin complex concentrates (PCCs) to correct deficiencies of factors II, VII, IX, and X can be used for bleeding due to liver disease. 3.2. Vitamin K deficiency bleeding Vitamin K is a crucial cofactor in the production of procoagulant proteins factors II, VII, IX and X, and of natural coagulation inhibitors, proteins C and S. Vitamin K is essential for the gcarboxylation of these clotting factors which is required for their functionality. Vitamin K deficiency bleeding (VKDB) is classified as early, classical, or late (see Table 2). Early onset VKDB is due to cross-placental transfer of compounds that interfere with vitamin K metabolism. Classical VKDB is due to a physiologic deficiency in vitamin K at birth combined with either a lack of vitamin K in breast milk or inadequate feeding. Late onset VKDB is again due to inadequate vitamin K content in breast milk and is thus found
Please cite this article in press as: Jaffray J, et al., The bleeding newborn: A review of presentation, diagnosis, and management, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.12.002
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Table 2 Vitamin K deficiency classification.a Early
Classical
Late
Age Risk factors
<24 h Maternal medications (vitamin K antagonists, anticonvulsants, antituberculin drugs)
1e7 days Lack of prophylactic vitamin K treatment, poor feeding (particularly if breastfed)
Sites of bleeding
Cephalohematoma, umbilical stump, intracranial
Frequency
Less than 5% in at-risk population
Treatment
Prothrombin complex concentrates, vitamin K (may not be effective)
Gastrointestinal, umbilicus, mucocutaneous, circumcision, intracranial With prophylactic vitamin K: extremely rare, Without prophylactic vitamin K (0.01e1%) Parenteral vitamin K (intravenous preferred) Prothrombin complex concentrates for active bleeding
2 weeks Exclusive breastfeeding, poor feeding, gastrointestinal disorders, liver disease, pancreatic disease, antibiotic therapy Intracranial, mucocutaneous, gastrointestinal
Prevention
Avoidance of above medications during pregnancy
Vitamin K prophylaxis at birth
Variable depending on age and conditions listed above Vitamin K Prothrombin complex concentrates for active bleeding, recombinant factor VIIa (for mild cases where only the prothrombin time is prolonged) Adequate vitamin K replacement (in many cases will need to be parenteral)
a Table adapted with permission from Jaffray J, Young G. Developmental hemostasis clinical implications from the fetus to the adolescent. Pediatr Clin N Am 2013; 60:1407e17.
almost universally in exclusively breastfed infants. Prior to the widespread use of vitamin K prophylaxis, the incidence of classical VKDB was reported to be as high as 1.5%; however, the condition is only rarely seen today, and is almost always associated with situations where vitamin K was not administered in the immediate newborn period. The clinical features of VKDB are similar to other bleeding diatheses and include bruising, mucus membrane bleeding, bleeding after trauma or invasive procedures, ICH, or signs of internal bleeding such as hematuria. The diagnostic evaluation for VKDB is straightforward as the PT is always prolonged and the aPTT is nearly always prolonged. In the typical scenario, the PT is prolonged out of proportion to the aPTT. In a newborn with the above clinical and laboratory findings, eliciting a history in which vitamin K was not administered is sufficient to make a presumptive diagnosis, and the administration of parenteral vitamin K should be undertaken immediately. Improvement, if not complete correction, of the PT and aPTT several hours after the administration of parenteral vitamin K serves as confirmation of the diagnosis. Whereas measuring factor levels (specifically FII, FVII, FIX, and FX) may assist in the diagnosis, they are not necessary and delays in instituting appropriate therapy could lead to severe, even catastrophic, bleeding complications. Without question, the most effective management for VKDB is prevention, and all newborns should receive vitamin K immediately after birth. Although the recommended route of administration varies between countries (intramuscular in the USA and oral in the UK, for example), both approaches are effective. Currently available treatment is generally in the form of vitamin K1 (also known as phytonadione), which can be administered parenterally via intravenous, intramuscular, and subcutaneous injection, and orally; however, intravenous administration is recommended in the acute setting. It is important to note that whereas the effect of parenteral vitamin K is rapid, it is not instantaneous and may take several hours. Thus, in a patient presenting with severe hemorrhage such as ICH, additional therapy with PCCs aimed at immediate correction of factor deficiencies is required. 3.3. Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a disorder characterized by consumption of procoagulant, anticoagulant, fibrinolytic proteins, and platelets [32]. Patients may develop
hemorrhagic and/or thrombotic complications. In some patients significant hemorrhage and thrombosis may occur simultaneously. DIC is always caused by an underlying medical disorder. In neonates, the most frequent etiology is sepsis. The pathophysiology of DIC is complex and not completely understood. Briefly, an inciting event triggers the release of proinflammatory cytokines, especially interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a). IL-6 leads to tissue factor-mediated activation of the coagulation system that in turn leads to enhanced fibrin formation, mostly in the microvasculature. TNF-a leads to inhibition of both the natural anticoagulants (antithrombin, proteins C and S) and fibrinolysis by increasing levels of plasminogen activator inhibitor-1. The sum of these effects is microvascular thrombosis, which often leads to organ dysfunction and consumption of procoagulant proteins and platelets, which may lead to hemorrhage. Bleeding may occur at any site but frequently involves the skin (at vascular access sites) and mucus membranes. Severe internal hemorrhage is less frequent, but ICH may occur and be catastrophic. When a patient at risk for DIC presents with hemorrhage, specific laboratory abnormalities can only provide supportive evidence, not confirm the diagnosis of DIC. Routine laboratory assays such as the CBC, PT, aPTT, and fibrinogen are often abnormal as a result of fibrin formation and degradation as well as consumption of coagulation proteins. Thrombocytopenia is often present, and e depending on the etiology e leukocytosis, leukopenia, and anemia. When DIC is suspected, measurement of fibrin degradation products (FDP) or D-dimers is helpful. The combination of thrombocytopenia, hypofibrinogenemia, prolonged PT and aPTT and elevated FDP or D-dimer is strongly suggestive for the presence of DIC. A scoring system has been developed by the ISTH which incorporates the results of the above assays [33]. The management of DIC most importantly requires treatment of the underlying condition causing the DIC. Correcting the coagulopathy will be impossible if the underlying disorder cannot be controlled. Since DIC is a derangement of all aspects of the coagulation system, both FFP (coagulant protein replacement) and cryoprecipitate (fibrinogen replacement) are usually first-line therapy. Importantly, FFP should be given to manage bleeding complications, not to improve laboratory values. In one study in neonates with DIC, FFP did not have an impact on survival or resolution of DIC [34]. For severe bleeding in patients with DIC, PCCs and rFVIIa can be used, but with caution due to the risk of thrombotic complications.
Please cite this article in press as: Jaffray J, et al., The bleeding newborn: A review of presentation, diagnosis, and management, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.12.002
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No
Sick or acƟvely bleeding?
Isolated ated PT P prolongaƟon
Isolated ated aPTT a prolongaƟon
eck FV Check FVII acƟvity
Check ck FVIII, FVI FIX, FXI, FXII acƟvity
Normal ormal PT /aPTT
PT and aPTT aP prolonged
Yes Check fibrinogen, FII, FV, FX acƟvity
Check CBC, PT, aPTT, and fibrinogen.
MulƟpl MulƟple factor deficiencies
Consider nside rFVIIa
Give vitamin K
Treat the underlying disorder. FFP as needed.
No
Yes
Single ingle ffactor deficiency Vitamin tamin K given?
Is the paƟent in DIC?
FVIIII or FIX deficiency
Specific cific fa factor products
Liver failure
F FXI deficiency
Check Ch heck eck quanƟtaƟve FXIII level
Low ow FXI FXIII pdFXIII dFXIII o or rFXIII products
EvaluaƟo EvaluaƟon for VWD
VWD diagnosed
pdFVI pdFVIII
FFP orr cryoprecipitate
No May need platelets or further evaluaƟon.
Yes
Thrombocytopenic ombo
Fig. 2. Algorithm for the approach to a bleeding neonate. aPTT, activated partial thromboplastin time; CBC, complete blood count; DIC, disseminated intravascular coagulation; FFP, fresh frozen plasma; FII, factor II; FV, factor V; FVII, factor VII; FVIII, factor VIII; FIX, factor IX; FXI, factor XI; FXII, factor XII; FXIII, factor XIII; pdFVIII, plasma-derived factor VIII; pdFXIII, plasma-derived factor XIII; PT, prothrombin time; rVIIa, activated recombinant factor VII; rXIII, recombinant factor XIII; VWD, von Willebrand disease.
3.4. Therapeutic hypothermia Recently, therapeutic hypothermia has been used as a treatment for severe asphyxia to prevent the neurologic sequelae of hypoxiceischemic events (such as neonatal ICH) and to improve outcomes [35,36]. However, hypothermia may further increase the risk of ICH by causing changes in cerebral blood flow, increased fragility of injured tissues, hypotension, changes in the function of the coagulation system, thrombocytopenia, and metabolic derangements [37]. Current evidence suggests that coagulopathy, thrombocytopenia and bleeding may not be significantly increased with hypothermia [35,36,38]. Close attention should be paid to platelet count, coagulation measures (PT, aPTT, fibrinogen), and clinical signs of bleeding when neonates undergo hypothermic cooling protocols. If derangements in the coagulation measures are found and bleeding is present, they should be replaced with FFP or cryoprecipitate as indicated. 3.5. Extracorporeal life support Neonates requiring extracorporeal life support (including cardiopulmonary bypass surgery or extracorporeal membrane oxygenation) are at risk for significant bleeding. These patients often undergo large, complicated surgical procedures that stress the coagulation system. A discussion of all the issues related to bleeding related to extracorporeal life support is beyond the scope of this review, but in summary, treatment is based on supportive care with FFP, cryoprecipitate, platelet transfusions, and monitoring. 4. Conclusion Bleeding in the newborn period may result in catastrophic events and even death. Causes of neonatal bleeding range from congenital issues, such as factor deficiencies, to acquired problems, such as disseminated intravascular coagulation. Due to the developing hemostatic system, it may be difficult to make the proper
diagnosis and institute appropriate treatment. We have provided here a framework (see Fig. 2) to diagnose and treat neonates who are actively bleeding. Often initial care is supportive until confirmatory testing results return. A thorough history and physical can be key in making the proper diagnosis.
Practice points Neonates are in a continuous state of developmental hemostasis. Bleeding in neonates can be challenging to diagnose and treat. With systematic evaluation of various coagulation tests, the appropriate diagnosis can be made and treatment can be initiated. Initially, treatment is often supportive, but once a diagnosis is made, it can and should be tailored to specific etiologies.
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[22] Acharya SS, Coughlin A, Dimichele DM, North American Rare Bleeding Disorder Study G. Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias. J Thromb Haemost 2004;2: 248e56. [23] Palla R, Peyvandi F, Shapiro AD. Rare bleeding disorders: diagnosis and treatment. Blood 2015;125:2052e61. [24] Acharya SS, Dimichele DM. Rare inherited disorders of fibrinogen. Haemophilia 2008;14:1151e8. [25] Seligsohn U. Factor XI deficiency in humans. J Thromb Haemost 2009;7(Suppl. 1):84e7. [26] Mariani G, Bernardi F. Factor VII deficiency. Semin Thromb Hemost 2009;35: 400e6. [27] Ivaskevicius V, Seitz R, Kohler HP, Schroeder V, Muszbek L, Ariens RA, et al. International registry on factor XIII deficiency: a basis formed mostly on European data. Thromb Haemost 2007;97:914e21. [28] Karimi M, Bereczky Z, Cohan N, Muszbek L. Factor XIII deficiency. Semin Thromb Hemost 2009;35:426e38. [29] Lak M, Peyvandi F, Ali Sharifian A, Karimi K, Mannucci PM. Pattern of symptoms in 93 Iranian patients with severe factor XIII deficiency. J Thromb Haemost 2003;1:1852e3. [30] Youssef WI, Salazar F, Dasarathy S, Beddow T, Mullen KD. Role of fresh frozen plasma infusion in correction of coagulopathy of chronic liver disease: a dual phase study. Am J Gastroenterol 2003;98:1391e4. [31] Young G, Wicklund B, Neff P, Johnson C, Nugent DJ. Off-label use of rFVIIa in children with excessive bleeding: a consecutive study of 153 off-label uses in 139 children. Pediatric Blood Cancer 2009;53:179e83. [32] Taylor Jr FB, Toh CH, Hoots WK, Wada H, Levi M, Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001;86:1327e30. [33] Gross SJ, Filston HC, Anderson JC. Controlled study of treatment for disseminated intravascular coagulation in the neonate. J Pediatr 1982;100: 445e8. [34] Mueller MM, Bomke B, Seifried E. Fresh frozen plasma in patients with disseminated intravascular coagulation or in patients with liver diseases. Thromb Res 2002;107(Suppl. 1):S9e17. [35] Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009;361:1349e58. [36] Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxiceischemic encephalopathy. N Engl J Med 2005;353:1574e84. [37] Rutherford MA, Azzopardi D, Whitelaw A, Cowan F, Renowden S, Edwards AD, et al. Mild hypothermia and the distribution of cerebral lesions in neonates with hypoxiceischemic encephalopathy. Pediatrics 2005;116:1001e6. [38] Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005;365(9460): 663e70.
Please cite this article in press as: Jaffray J, et al., The bleeding newborn: A review of presentation, diagnosis, and management, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.12.002
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Review
The bleeding newborn: A review of presentation, diagnosis, and management Julie Jaffray a, b, Guy Young a, b, Richard H. Ko a, b, * a b
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA, USA Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
s u m m a r y Keywords: Hemorrhage Hemostasis Infant Newborn
The neonatal hemostatic system is continuously developing with rapidly changing concentrations of many coagulation proteins. Thus, determining the etiology of bleeding in a newborn has additional challenges beyond those seen in older children or adults. Bleeding can be seen in both well and sick newborns due to congenital causes, such as hemophilia or von Willebrand disease, and acquired causes, such as liver failure or disseminated intravascular coagulation. Traditional coagulation testing should be interpreted with caution and with the help of a hematologist, if possible, due to the greatly different normal ranges between neonates as compared with older children and adults. However, despite these challenges, both clinical and laboratory clues can guide physicians appropriately to diagnose and treat the bleeding newborn. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction Bleeding in healthy neonates is rare, but in sick neonates, it is often serious and can be fatal. The clinical presentation of bleeding in neonates includes intracranial hemorrhage (ICH), cephalohematoma, bleeding after a procedure or venepuncture, or mucocutaneous bleeding such as bruising or gastrointestinal bleeding [1]. The etiology of such bleeding may arise from congenital issues, such as hemophilia, or from acquired issues including liver failure. Determining the cause of bleeding is a clinical challenge for both primary treating practitioners as well as hematology consultants due to the continuously evolving coagulation system in neonates. The coagulation system is comprised of cellular elements (platelets being the most important) and plasma proteins, all of which work in concert to protect from both hemorrhage and thrombosis. The concentrations of the plasma proteins are different in neonates when compared to older children and adults, and undergo rapid maturation over the first six months of life in a process
* Corresponding author. Address: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Mailstop #54, Los Angeles, CA 90027, USA. Tel.: þ1 (323) 361 5600; fax: þ1 (323) 361 7128. E-mail address: [email protected] (R.H. Ko).
known as developmental hemostasis [2]. Figure 1 illustrates the fetal development of the pro- and anticoagulant proteins [3e5]. Procoagulants present at adult levels at birth include fibrinogen, factor V (FV), factor VIII (FVIII) and von Willebrand factor (VWF), whereas factors II (FII), VII (FVII), IX (FIX) and X (FX) (vitamin Kdependent factors), and factors XI (FXI), XII (FXII), prekallikrein and high-molecular-weight kininogen (contact factors) are present at about 50% of adult levels at birth [6,7]. To balance lower levels of procoagulants, most of the anticoagulants (antithrombin, heparin cofactor II, protein C and protein S) are also lower at birth, though as a compensatory mechanism, the anticoagulant a-2-macroglobulin is actually higher at birth than adult levels [6,7]. As a result of lower levels of the procoagulant proteins, the activated partial thromboplastin time (aPTT) and prothrombin time (PT) are prolonged in neonates when compared to the adult range. Previous studies reported reference ranges for the aPTT, PT and the pro- and anticoagulant protein levels, in term and premature neonates [6e8]. Unfortunately these reference ranges must be interpreted with caution due to the significant laboratory variability of reagents and instruments used. The Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (ISTH) recommends creating pediatric reference ranges in each hospital, although this is quite time-consuming and costly [9]. This review discusses the various causes of bleeding in neonates and provides guidance on how to arrive at the appropriate diagnosis and suggest different treatment options. Bleeding disorders
http://dx.doi.org/10.1016/j.siny.2015.12.002 1744-165X/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Jaffray J, et al., The bleeding newborn: A review of presentation, diagnosis, and management, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.12.002
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Fig. 1. Fetal development of the coagulation system. FV, factor V; FVII, factor VII; FVIII, factor VIII; FIX, factor X; AT, antithrombin; HCII, heparin cofactor II. Reproduced with permission from Jaffray J, Young G. Developmental hemostasis clinical implications from the fetus to the adolescent. Pediatr Clin N Am 2013; 60:1407e17.
caused by thrombocytopenia or platelet dysfunction will be addressed in another article.
2. Congenital causes of bleeding 2.1. Hemophilia Deficiencies of FVIII and FIX are known as hemophilia A and B, respectively, and are inherited in an X-linked recessive pattern. Female relatives are known as hemophilia carriers. The incidence of hemophilia is 1 per 5000 males (FVIII) and 1 in 20,000 males (FIX) [10]. Persons with hemophilia are classified based on their plasma factor activity [severe (<1%), moderate (1e5%) or mild (>5 to 40%)]. Bleeding in hemophilia (mostly the severe type) may present in neonates as either post-procedural bleeding (e.g. circumcision or heel sticks) or even as ICH. Newborns with hemophilia are 44 times more likely to have symptomatic ICH compared to normal newborns, and it is more likely to occur after an assisted vaginal delivery [11,12]. The mean age of patients with hemophilia having their first bleed is 28.5 days [13]. Although diagnosing hemophilia in neonates is usually straightforward, issues of developmental hemostasis can make it more challenging than in older children. Up to 70% of patients are diagnosed in the first month of life [14]. Any newborn with unexpected or excessive bleeding should have an aPTT, and, though many normal infants have a prolonged aPTT, this should not preclude an evaluation of factor levels in the above situation. As the FVIII activity in neonates approximates that of a normal adult, making the diagnosis of severe or moderate hemophilia A is straightforward. The diagnosis of mild hemophilia can be more difficult due to increased FVIII activity resulting from the stress of delivery, thus levels should be repeated at six to 12 months of age if mild FVIII deficiency is suspected [15]. When evaluating FIX levels, however, as stated previously, FIX activity is about 50% of adult levels at birth, which overlaps with the range of mild hemophilia, making the diagnosis of mild hemophilia B difficult, and, as above, testing should be repeated at six to 12 months. Treatment of hemophilia is based on replacing the missing protein with factor concentrates; if needed, consultation with a pediatric hematologist is suggested to assist in management.
2.2. von Willebrand disease von Willebrand Disease (VWD) is the most frequently inherited bleeding disorder, affecting ~1% of the population, and is transmitted in autosomal dominant or recessive patterns [16,17]. There are three main categories of VWD based on the quantitative level or function of von Willebrand factor (VWF): type 1, 2, or 3. Most patients with VWD have type I, which is due to a partial quantitative deficiency of VWF and is usually associated with a mild phenotypic bleeding presentation [18]. Type 2 VWD is a qualitative dysfunction of VWF and is typically associated with a more severe bleeding phenotype. Type 2 is further divided into four separate subtypes, 2A, 2B, 2M, and 2N, which are based on the functional and structural interactions between VWF and platelets or FVIII. Type 3 is the rarest form of VWD in which patients have complete or almost complete deficiency of VWF and have the most severe bleeding phenotype [18,19]. Typically only patients with type 3 or some type 2 VWD present with bleeding as neonates [20]. Mucocutaneous bleeding is the hallmark of VWD; patients can have epistaxis, bruising, gum bleeding, and gastrointestinal bleeding, but also bleeding after trauma or surgery. The diagnosis of VWD is based on three main laboratory assays: (i) a quantitative measure of VWF in the plasma, (ii) the activity of VWF and its ability to bind platelets (iii) and FVIII activity [21]. High molecular weight multimer analysis can also be performed to help differentiate type 2 varieties. Table 1 shows the laboratory values that are consistent with each type of VWD. At birth, neonates have normal to increased levels of VWF activity and high-molecular weight VWF multimers compared to adult levels, which is why most patients with type 1 and 2 VWD do not present with bleeding until later in life [7,8]. The management of bleeding in a neonate with VWD is typically with plasma-derived FVIII (pdFVIII) products that contain VWF, and consultation with a pediatric hematologist is suggested to assist in management.
2.3. Rare inherited bleeding disorders Patients with rare factor deficiencies represent 3e5% of all coagulation disorders, with an incidence of 1:500,000 to
Please cite this article in press as: Jaffray J, et al., The bleeding newborn: A review of presentation, diagnosis, and management, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.12.002
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Table 1 Typical laboratory values for the main types of von Willebrand disease.
VWF antigen VWF activity FVIII activity Platelet count VWF multimers
Type 1
Type 2A
Type 2B
Type 2M
Type 2N
Type3
Low Low Low Normal Normal or mildly decreased expression in all sizes
Low Very low Normal or low Normal Loss of high and intermediate weight multimers
Low Very low Normal or low Low Decreased high molecular weight multimers
Low Very low Normal or low Normal Normal
Low Normal or low Very low Normal Normal
Absent Absent Extremely low Normal Absent
VWF, von Willebrand factor; FVIII, factor VIII.
1:2,000,000 [22,23]. Deficiencies in fibrinogen, FII, FV, FVII, FX, FXI, or FXIII may present in neonates, and each will be discussed briefly below. 2.3.1. Disorders of fibrinogen Fibrinogen is converted to fibrin and, along with platelets, forms the structure of blood clots. Patients with disorders of fibrinogen may have either decreased or complete absence of fibrinogen levels (hypofibrinogenemia, afibrinogenemia), or dysfunctional fibrinogen (dysfibrinogenemia). Afibrinogenemia is inherited in an autosomal recessive pattern, whereas the heterozygous form is hypofibrinogenemia. Neonates may present with prolonged bleeding from the umbilical cord stump, post circumcision, ICH, or mucocutaneous bleeding [24]. Patients with disorders of fibrinogen will have a prolonged PT and aPTT. Decreased functional or antigenic fibrinogen assays are the confirmatory tests. Normal term neonates have fibrinogen levels equal to adult normal values at birth [7,8]. Fibrinogen concentrates are the ideal treatment for bleeding episodes. Fresh frozen plasma (FFP) or cryoprecipitate may also be used for bleeding when fibrinogen concentrates are unavailable. 2.3.2. Prothrombin (FII), FV, FVII, FX, and FXI deficiency Patients with FII, FV, FVII, FX, and FXI deficiency are inherited in an autosomal recessive pattern, and there is a higher incidence of FXI deficiency in those of Ashkenazi Jewish descent [25]. Most factor deficiencies in neonates can lead to mucocutaneous bleeding, ICH, prolonged umbilical stump bleeding, or bleeding after procedures or trauma. FVII and FXI levels do not correlate well with bleeding phenotype; some patients with very low factor levels do not have any bleeding, and those with higher factor levels may have profuse bleeding [25,26]. Diagnosing rare factor deficiencies should begin with a PT and aPTT. Isolated prolongation of the PT is seen with FVII deficiency, and isolated prolongation of the aPTT is seen with FXI deficiency. Patients with FII, FV and FX deficiency will result in a prolongation of both the PT and aPTT. When a specific factor deficiency is suspected, confirmatory factor-specific assays should be performed. As above, diagnosing these factor deficiencies in a newborn is challenging due to the issues of developmental hemostasis [7,8]. Factor concentrates are available for the replacement of FVII (rFVIIa) and FII, FVII, FIX, and FX (prothrombin complex concentrates). FXI concentrate is available in some countries but not in the USA currently. FFP is the only treatment for patients with deficiencies of FV and FXI. 2.3.3. FXIII deficiency FXIII, composed of two A and two B subunits, cross-links fibrin and stabilizes clots. FXIII deficiency is inherited in an autosomal recessive pattern and clinical manifestations may occur in neonates, most commonly with umbilical cord stump bleeding
(50e70% of cases), ICH, and prolonged bleeding after procedures or trauma [27e29]. Low levels of FXIII do not prolong the PT or aPTT. Thus if both the PT and aPTT are within the normal range for age, and a bleeding disorder is suspected, then a quantitative FXIII assay should be performed. The clot solubility assay previously used to diagnose FXIII deficiency lacks sensitivity for very low levels of FXIII. Plasmaderived and recombinant FXIII products are available, although the recombinant form can only be used for A-subunit deletions. Cryoprecipitate should be used if FXIII concentrate is unavailable. 3. Acquired causes of bleeding 3.1. Liver failure The liver is responsible for the synthesis of most pro- and anticoagulant proteins (except FVIII and VWF) and thrombopoetin, which stimulates platelet production. A disruption in liver function may have a significant impact on the coagulation system, exacerbating the effects in neonates whose systems are already delicately balanced. Patients with liver failure may present with both bleeding and thrombosis, and the etiology, diagnosis, and treatment are all challenging. Neonates with liver disease may present with any manner of bleeding. Coagulation laboratory abnormalities seen in liver failure are elevated PT, aPTT and D-dimer, decreased fibrinogen activity, and decreased platelet count. The treatment for bleeding in liver failure is difficult due to the risks of fluid overload and thrombosis. FFP has historically been the first line of treatment for bleeding due to liver failure in neonates since it replaces all coagulation proteins. Studies have shown that large volumes of FFP are required to correct the coagulation abnormalities [30]. Off-label use of rFVIIa has been used and resulted in excellent control of bleeding due to liver disease in neonates; however, this medication carries with it a risk for thrombosis [31]. Cryoprecipitate to correct low fibrinogen, and prothrombin complex concentrates (PCCs) to correct deficiencies of factors II, VII, IX, and X can be used for bleeding due to liver disease. 3.2. Vitamin K deficiency bleeding Vitamin K is a crucial cofactor in the production of procoagulant proteins factors II, VII, IX and X, and of natural coagulation inhibitors, proteins C and S. Vitamin K is essential for the gcarboxylation of these clotting factors which is required for their functionality. Vitamin K deficiency bleeding (VKDB) is classified as early, classical, or late (see Table 2). Early onset VKDB is due to cross-placental transfer of compounds that interfere with vitamin K metabolism. Classical VKDB is due to a physiologic deficiency in vitamin K at birth combined with either a lack of vitamin K in breast milk or inadequate feeding. Late onset VKDB is again due to inadequate vitamin K content in breast milk and is thus found
Please cite this article in press as: Jaffray J, et al., The bleeding newborn: A review of presentation, diagnosis, and management, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.12.002
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Table 2 Vitamin K deficiency classification.a Early
Classical
Late
Age Risk factors
<24 h Maternal medications (vitamin K antagonists, anticonvulsants, antituberculin drugs)
1e7 days Lack of prophylactic vitamin K treatment, poor feeding (particularly if breastfed)
Sites of bleeding
Cephalohematoma, umbilical stump, intracranial
Frequency
Less than 5% in at-risk population
Treatment
Prothrombin complex concentrates, vitamin K (may not be effective)
Gastrointestinal, umbilicus, mucocutaneous, circumcision, intracranial With prophylactic vitamin K: extremely rare, Without prophylactic vitamin K (0.01e1%) Parenteral vitamin K (intravenous preferred) Prothrombin complex concentrates for active bleeding
2 weeks Exclusive breastfeeding, poor feeding, gastrointestinal disorders, liver disease, pancreatic disease, antibiotic therapy Intracranial, mucocutaneous, gastrointestinal
Prevention
Avoidance of above medications during pregnancy
Vitamin K prophylaxis at birth
Variable depending on age and conditions listed above Vitamin K Prothrombin complex concentrates for active bleeding, recombinant factor VIIa (for mild cases where only the prothrombin time is prolonged) Adequate vitamin K replacement (in many cases will need to be parenteral)
a Table adapted with permission from Jaffray J, Young G. Developmental hemostasis clinical implications from the fetus to the adolescent. Pediatr Clin N Am 2013; 60:1407e17.
almost universally in exclusively breastfed infants. Prior to the widespread use of vitamin K prophylaxis, the incidence of classical VKDB was reported to be as high as 1.5%; however, the condition is only rarely seen today, and is almost always associated with situations where vitamin K was not administered in the immediate newborn period. The clinical features of VKDB are similar to other bleeding diatheses and include bruising, mucus membrane bleeding, bleeding after trauma or invasive procedures, ICH, or signs of internal bleeding such as hematuria. The diagnostic evaluation for VKDB is straightforward as the PT is always prolonged and the aPTT is nearly always prolonged. In the typical scenario, the PT is prolonged out of proportion to the aPTT. In a newborn with the above clinical and laboratory findings, eliciting a history in which vitamin K was not administered is sufficient to make a presumptive diagnosis, and the administration of parenteral vitamin K should be undertaken immediately. Improvement, if not complete correction, of the PT and aPTT several hours after the administration of parenteral vitamin K serves as confirmation of the diagnosis. Whereas measuring factor levels (specifically FII, FVII, FIX, and FX) may assist in the diagnosis, they are not necessary and delays in instituting appropriate therapy could lead to severe, even catastrophic, bleeding complications. Without question, the most effective management for VKDB is prevention, and all newborns should receive vitamin K immediately after birth. Although the recommended route of administration varies between countries (intramuscular in the USA and oral in the UK, for example), both approaches are effective. Currently available treatment is generally in the form of vitamin K1 (also known as phytonadione), which can be administered parenterally via intravenous, intramuscular, and subcutaneous injection, and orally; however, intravenous administration is recommended in the acute setting. It is important to note that whereas the effect of parenteral vitamin K is rapid, it is not instantaneous and may take several hours. Thus, in a patient presenting with severe hemorrhage such as ICH, additional therapy with PCCs aimed at immediate correction of factor deficiencies is required. 3.3. Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a disorder characterized by consumption of procoagulant, anticoagulant, fibrinolytic proteins, and platelets [32]. Patients may develop
hemorrhagic and/or thrombotic complications. In some patients significant hemorrhage and thrombosis may occur simultaneously. DIC is always caused by an underlying medical disorder. In neonates, the most frequent etiology is sepsis. The pathophysiology of DIC is complex and not completely understood. Briefly, an inciting event triggers the release of proinflammatory cytokines, especially interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a). IL-6 leads to tissue factor-mediated activation of the coagulation system that in turn leads to enhanced fibrin formation, mostly in the microvasculature. TNF-a leads to inhibition of both the natural anticoagulants (antithrombin, proteins C and S) and fibrinolysis by increasing levels of plasminogen activator inhibitor-1. The sum of these effects is microvascular thrombosis, which often leads to organ dysfunction and consumption of procoagulant proteins and platelets, which may lead to hemorrhage. Bleeding may occur at any site but frequently involves the skin (at vascular access sites) and mucus membranes. Severe internal hemorrhage is less frequent, but ICH may occur and be catastrophic. When a patient at risk for DIC presents with hemorrhage, specific laboratory abnormalities can only provide supportive evidence, not confirm the diagnosis of DIC. Routine laboratory assays such as the CBC, PT, aPTT, and fibrinogen are often abnormal as a result of fibrin formation and degradation as well as consumption of coagulation proteins. Thrombocytopenia is often present, and e depending on the etiology e leukocytosis, leukopenia, and anemia. When DIC is suspected, measurement of fibrin degradation products (FDP) or D-dimers is helpful. The combination of thrombocytopenia, hypofibrinogenemia, prolonged PT and aPTT and elevated FDP or D-dimer is strongly suggestive for the presence of DIC. A scoring system has been developed by the ISTH which incorporates the results of the above assays [33]. The management of DIC most importantly requires treatment of the underlying condition causing the DIC. Correcting the coagulopathy will be impossible if the underlying disorder cannot be controlled. Since DIC is a derangement of all aspects of the coagulation system, both FFP (coagulant protein replacement) and cryoprecipitate (fibrinogen replacement) are usually first-line therapy. Importantly, FFP should be given to manage bleeding complications, not to improve laboratory values. In one study in neonates with DIC, FFP did not have an impact on survival or resolution of DIC [34]. For severe bleeding in patients with DIC, PCCs and rFVIIa can be used, but with caution due to the risk of thrombotic complications.
Please cite this article in press as: Jaffray J, et al., The bleeding newborn: A review of presentation, diagnosis, and management, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.12.002
J. Jaffray et al. / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e6
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No
Sick or acƟvely bleeding?
Isolated ated PT P prolongaƟon
Isolated ated aPTT a prolongaƟon
eck FV Check FVII acƟvity
Check ck FVIII, FVI FIX, FXI, FXII acƟvity
Normal ormal PT /aPTT
PT and aPTT aP prolonged
Yes Check fibrinogen, FII, FV, FX acƟvity
Check CBC, PT, aPTT, and fibrinogen.
MulƟpl MulƟple factor deficiencies
Consider nside rFVIIa
Give vitamin K
Treat the underlying disorder. FFP as needed.
No
Yes
Single ingle ffactor deficiency Vitamin tamin K given?
Is the paƟent in DIC?
FVIIII or FIX deficiency
Specific cific fa factor products
Liver failure
F FXI deficiency
Check Ch heck eck quanƟtaƟve FXIII level
Low ow FXI FXIII pdFXIII dFXIII o or rFXIII products
EvaluaƟo EvaluaƟon for VWD
VWD diagnosed
pdFVI pdFVIII
FFP orr cryoprecipitate
No May need platelets or further evaluaƟon.
Yes
Thrombocytopenic ombo
Fig. 2. Algorithm for the approach to a bleeding neonate. aPTT, activated partial thromboplastin time; CBC, complete blood count; DIC, disseminated intravascular coagulation; FFP, fresh frozen plasma; FII, factor II; FV, factor V; FVII, factor VII; FVIII, factor VIII; FIX, factor IX; FXI, factor XI; FXII, factor XII; FXIII, factor XIII; pdFVIII, plasma-derived factor VIII; pdFXIII, plasma-derived factor XIII; PT, prothrombin time; rVIIa, activated recombinant factor VII; rXIII, recombinant factor XIII; VWD, von Willebrand disease.
3.4. Therapeutic hypothermia Recently, therapeutic hypothermia has been used as a treatment for severe asphyxia to prevent the neurologic sequelae of hypoxiceischemic events (such as neonatal ICH) and to improve outcomes [35,36]. However, hypothermia may further increase the risk of ICH by causing changes in cerebral blood flow, increased fragility of injured tissues, hypotension, changes in the function of the coagulation system, thrombocytopenia, and metabolic derangements [37]. Current evidence suggests that coagulopathy, thrombocytopenia and bleeding may not be significantly increased with hypothermia [35,36,38]. Close attention should be paid to platelet count, coagulation measures (PT, aPTT, fibrinogen), and clinical signs of bleeding when neonates undergo hypothermic cooling protocols. If derangements in the coagulation measures are found and bleeding is present, they should be replaced with FFP or cryoprecipitate as indicated. 3.5. Extracorporeal life support Neonates requiring extracorporeal life support (including cardiopulmonary bypass surgery or extracorporeal membrane oxygenation) are at risk for significant bleeding. These patients often undergo large, complicated surgical procedures that stress the coagulation system. A discussion of all the issues related to bleeding related to extracorporeal life support is beyond the scope of this review, but in summary, treatment is based on supportive care with FFP, cryoprecipitate, platelet transfusions, and monitoring. 4. Conclusion Bleeding in the newborn period may result in catastrophic events and even death. Causes of neonatal bleeding range from congenital issues, such as factor deficiencies, to acquired problems, such as disseminated intravascular coagulation. Due to the developing hemostatic system, it may be difficult to make the proper
diagnosis and institute appropriate treatment. We have provided here a framework (see Fig. 2) to diagnose and treat neonates who are actively bleeding. Often initial care is supportive until confirmatory testing results return. A thorough history and physical can be key in making the proper diagnosis.
Practice points Neonates are in a continuous state of developmental hemostasis. Bleeding in neonates can be challenging to diagnose and treat. With systematic evaluation of various coagulation tests, the appropriate diagnosis can be made and treatment can be initiated. Initially, treatment is often supportive, but once a diagnosis is made, it can and should be tailored to specific etiologies.
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Please cite this article in press as: Jaffray J, et al., The bleeding newborn: A review of presentation, diagnosis, and management, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.12.002