icente Rey y Formoso · RiVcardo Barreto Mota · Henrique Soares ,

Abstract

Keywords Coagulation factors · Developmental hemostasis · Hemostasis · Newborn · Platelets

Introduction

The hemostatic system undergoes a process of evolution and maturation [ 1- 3], beginning in utero [ 1, 4- 10] (fetal clotting and fibrinolytic activity are present as early as 10 weeks gestation [ 2, 8, 10- 13]) and progressing through the neonatal period and beyond in a physiologic process known as “developmental hemostasis” [ 4, 9, 14- 17]. This leads to innumerous differences between newborns’ and other age groups’ hemostatic systems. Knowledge of these differences is essential for any professional caring for newborn patients and in this review, we describe the maturation process of the neonatal hemostatic system, focusing on the reported differences between newborns and other age groups.

Developmental hemostasis--the neonatal period

The physiologic and dynamic [ 2- 5, 9, 10, 18, 19] process of developmental hemostasis leads to considerable differences between adults and even pediatric patients,and neonates [ 1, 5, 6, 8- 10, 15, 18- 25], especially given that coagulation proteins do not cross the placenta [ 6- 8,10]. Even among neonates, several disparities are found,not only between different chronological ages (CA) [ 1- 4,9, 10, 15, 18, 19, 26] but also distinct gestational ages(GA) [ 2, 3, 19] and birth weights [ 27, 28]. There is even considerable variability within apparently similar groups[ 19], possibly due to differences in liver maturity [ 28,29], maternal vitamin K (VK) reservoirs [ 29], and VK administration [ 29].

In general, all elements of the hemostatic process are present at birth [ 5, 6, 28, 30] but when compared to adults,most components’ neonatal concentrations are lower [ 1, 2,6, 9, 22, 31]. However, each element’s maturation pattern is different, and some are even increased in this period [ 1, 19].Both the physiologic rationale and the regulatory mechanisms responsible for this process remain to be elucidated[ 2, 4, 9] and, as later described, they may be, at least in part,unrelated to hemostasis per se [ 1, 2, 4, 6, 20, 32, 33].

These patterns have been studied and are now, at least partially, known and predictable [ 4, 10, 23, 34, 35]. As described below, the changes are not only quantitative [ 5,6, 10, 18- 20, 23, 26] but may also be qualitative, as even some components’ structure may vary with age [ 1, 5, 20,23, 26]. Most components undergo rapid maturation over the first 6 months of life [ 3, 18] with most achieving nearadult values in that time [ 6, 7, 19], while others only reach maturity in adolescence [ 1].

Importantly, in neonates, these physiological differences(with values, many of which would be considered pathological in adults [ 2, 4, 8, 22]) do not encompass a tendency towards bleeding or thrombosis but really confer a very balanced hemostatic system [ 4- 10, 20, 22- 25, 36, 37],illustrated by the fact that most neonates do not suffer from hemorrhagic complications after the trauma of birth [ 38]and that healthy newborns do not generally manifest easy bruising [ 6, 22- 24, 36]. However, there are conflicting data when comparing neonatal and adult bleeding and thrombotic tendencies. Some authors argue that neonates may even have a slight coagulation advantage [ 4, 20, 39] and that this age group’s differences may be protective against both thrombosis and bleeding [ 1, 2, 4, 8]. Others disagree, stating that the immature neonatal coagulation system has a low functional reserve capacity [ 31, 34], and is, as such, relatively fragile,describing that, sometimes, stimuli that would be harmless to adults, in neonates, may tilt the scale towards an unbalanced state, leading to symptomatic hemostatic conditions[ 4, 30, 35, 36].

Due to the differences mentioned below, neonates are usually less capable of generating thrombin [ 3, 9, 14, 17,40], even though its generation may be faster [ 6], but this is relatively counterbalanced by physiologic coagulation inhibitor deficits [ 3, 6, 9, 22, 41].

In utero, the hemostatic system matures with GA [ 11] and concentrations of coagulation proteins, in general, increase during fetal maturation [ 8, 9]; thus, generally, preterm newborns have lower concentrations of these elements [ 2, 6, 9,13, 24, 42] and, in the neonatal period, extreme preterms have lower concentrations of hemostatic elements than those born at 34/36 weeks GA [ 24]. Despite the differences at birth[ 2, 6, 13, 43], and during the first months of life, hemostasis is also balanced in preterms [ 25, 27, 43] and thrombin generation is similar in very preterm and term infants [ 11].Also, developmental hemostasis occurs faster in preterms[ 6, 13, 33] and, at the CA of 6 months, the preterm infant’s hemostatic system is generally equivalent to its term counterparts [ 13, 33].

Small for gestational age (SGA) term neonates have significantly lower concentrations of several coagulation factors, even though most values are still within full-term, reference range values [ 44]. SGA preterms, generally, also have several differences in the activity of the different coagulation proteins [ 24, 45 ], but their hemostatic system is, typically,also balanced [ 27, 28, 45]. Despite this generally present balance, both very low birthweight (VLBW) and preterm neonates are at a higher risk of hemostatic complications than appropriate for gestational age (AGA) term newborns[ 39, 46- 48]. Concerning twins, twin B has been described to have lower coagulation factor activities than twin A [ 24].

Nowadays, it is widely accepted that in vivo hemostasis is not, as previously thought, a simple “cascade” but instead results of complex interactions between blood vessel walls, coagulation proteins, and cellular components, such as endothelial cells and platelets as well as leucocytes and erythrocytes (cell based model of hemostasis) [ 35, 49, 50].Understanding the importance of cellular components on hemostasis is essential to fully comprehend some of the differences between neonatal and other age groups’ hemostasis[ 33, 35].

Coagulation factors

In general, neonatal levels of most coagulation factors are about 50% of adult values with most reaching adult levels by 6 months [ 3, 38, 43], while others do not reach those until adolescence [ 6].

Fibrinogen

There is an overlap between neonatal and adult levels[ 5- 7, 10, 18, 19, 51 ]. Fibrinogen concentrations continue to increase after birth and posteriorly reduce towards adult levels [ 3, 8, 15, 43].

Studies have shown that neonates have a“fetal”/“neonatal” form of fibrinogen [ 1, 4, 6, 8], which has functional and structural differences [ 1, 5, 8, 20, 26, 38].These differences, according to some authors, may lead to a certain “dysfunction” [ 1, 4, 6, 8] that persists during the first year of life [ 5, 30, 35]. Data on the difference between term and preterm neonates’ fibrinogen concentration are conflicting [ 11, 52], but its clearance is reportedly accelerated in the latter [ 8, 10].

There are, reportedly, no differences between the fibrinogen levels of SGA and AGA full-term healthy newborns[ 44]. However, lower levels of fibrinogen have been reported in preterm SGA, in comparison with premature AGA neonates [ 28, 45].

Vitamin K-dependent factors (VKDF)

Factors II, VII, IX, and X are reduced at birth [ 2, 3, 5- 10,18, 20, 24, 29, 35, 53], at about 50% of normal adult values[ 3, 6, 7, 9, 18], even after VK prophylaxis [ 2, 53], but gradually increase, approaching adult levels by 6 months of life[ 2, 6, 8, 20].

VKDF evolve independently in different ways, postnatally: FVII rises to near-adult levels at day 5, probably contributing to the short prothrombin time (PT) found in this period while FII, IX, and X rise relatively later [ 15, 19]. All four factors are, reportedly, within adult ranges by 6 months of life [ 19].

The reduced levels of FIX, in contrast to the relatively higher levels of FVll and FX in this age group, hint that early activation of FX may be mediated directly through the FVlla/tissue factor mechanism and not the FlXa and FVllla pathways [ 54], indicating an important role of the FVlla/tissue factor pathway during the intrauterine period and in developmental hemostasis until birth [ 55].

In preterm infants, mean values for VK-dependent factors are even more reduced [ 3, 7, 24, 43] but, as is the case with term infants, all VKDF usually reach adult levels by 6 months [ 15].

Data are conflicting regarding mean concentrations/activities of FVII in SGA neonates. While lower values in these newborns have been reported [ 24], other studies found no differences in these values between SGA and AGA fullterm newborns [ 44]. Concerning twins, median activities of FII, VII, and X are reportedly lower in twin B [ 24].

Contact factors

Levels of these factors--XI, XII, prekallikrein, and highmolecular-weight kninogen--are low at birth [ 2, 3, 5, 6, 9,10, 18- 20, 22, 24], decreased to about 50% of adult normal values [ 3, 6, 9, 18], progressively approaching these during the first 6 months of life [ 2, 6, 8, 10, 19, 20]. These low levels are possible contributors to the prolonged activated partial thromboplastin time usually found in neonates [ 19].In preterm infants, mean values are even more reduced [ 3,11, 13] and reportedly, SGA full-term newborns have lower levels of FXII than AGA neonates [ 28, 44].

FV

While, in term newborns, values are within adult range at birth [ 2, 6- 8, 10, 19], levels may be decreased in preterms [ 15], with lower values described in extreme preterms [ 13, 24]. Data regarding SGA newborns are conflicting, as lower concentrations, when compared to AGA neonates, have been described [ 24] but a more recent study found no difference between both groups[ 44]. In twins, the median activity of FV is reportedly lower in twin B [ 24].

FVIII

Concentrations are normal to high at birth [ 2, 3, 6- 8, 10,18- 20, 42, 56], reaching adult levels by 6 months [ 28]. Data are contradictory regarding SGA neonates’ FVIII levels,given that some studies reported no difference in concentrations between these and AGA newborns [ 44], while others describe higher levels in the former [ 47].

FXIII

Levels are, usually, within adult ranges at birth [ 6- 8, 10].

von Willebrand factor (vWF)

Levels are elevated at birth [ 5, 37] and decrease towards adult values by 3 to 12 months of age [ 6, 8, 10, 19, 38]. In newborns, besides generally increased concentrations, relatively higher levels oflarge vWF multimers [ 5, 8, 10, 18, 20,37, 38, 40] are present and these characteristics encompass a higher efficiency [ 5, 31, 33] in promoting platelet aggregation and vessel wall adhesion [ 5, 31, 35, 38]. Higher vWF activity levels [ 57] and its larger dimensions [ 38] may play a part in compensating for a relative neonatal platelet hypofunction [ 57] (vide infra).

Inhibitor system

With the exception of α2-macroglobulin (α2-MG), generally, all other natural inhibitor levels are fairly reduced in the neonatal period [ 5, 42, 58], many of which to values that would be considered pathological in adults [ 4, 10, 19].This is thought to compensate for the lower levels of procoagulant elements in this period [ 1, 18, 22, 38]. In preterms,generally, levels are even lower [ 42].

Antithrombin (AT)

Levels are relatively low at birth and in the first weeks of life, but gradually increase, approaching adult levels by 3-6 months of life [ 1- 4, 6- 8, 10, 18- 20, 22, 38]. Preterms,at birth, have even lower concentrations [ 20, 33]. While some authors describe lower levels in SGA newborns [ 28],others found no difference in its levels between these and AGA neonates [ 44]. AT occurs in two different isoforms,native AT and latent AT-the latter, present in much lower concentrations in newborns (30% of adult values) [ 1, 8],is known to be associated with severe and sudden onset of thrombosis [ 1].

Heparin cofactor II (HCII)

Levels are low at birth [ 6, 10, 18- 20] (about 50% of adult values [ 6, 59]) and in the first weeks of life, but gradually increase, approaching adult levels by 3-6 months of life [ 6,35].

Tissue factor pathway inhibitor (TFPI)

Concentrations are low in term [ 20, 22, 33, 35, 38] and preterm [ 20] neonates, but gradually increase, approaching adult levels by 6 months of life [ 35].

α1-antitrypsin

Levels are at a minimum at the time of birth, but they gradually increase, approaching adult levels by 6 months of life[ 35].

C1-inhibitor

Levels are low at birth [ 19, 35, 60], but, reportedly, rise above adult values during the first 6 months of life [ 19, 35].

Protein C (PC)

Levels are low at birth [ 2, 3, 6- 8, 10, 18- 20, 29, 38] (usually ＜ 50% of adult values [ 33, 43, 59]) and in the first weeks of life, approaching adult levels by 6-12 months of life [ 2, 6,8, 20, 28]. Also, PC exists in a “fetal” form at birth [ 6, 10],although its physiologic differences remain unclear [ 10].Preterms have even lower values at birth [ 20, 33], while SGA neonates reportedly have a certain degree of resistance to activated PC [ 47].

Protein S (PS)

Levels are low at birth [ 2, 3, 6- 8, 10, 18- 20, 29, 38] (usually ＜ 50% of adult values [ 33, 43, 59, 61]) and in the first weeks of life, approaching adult levels by 6-12 months of life [ 28, 30, 35, 38, 62]. Low levels of PS may be partially counterweighed by a higher proportion of free PS [ 10, 38],since its carrier protein, C4b-binding protein, is also reduced[ 38, 43, 59, 61] (or may even be undetectable [ 2, 8, 10, 38])in newborns. In preterm infants, values are even lower at birth [ 33]. Lower levels of free PS have also been described in SGA neonates, when compared to AGA term newborns[ 28, 44].

Placental-derived proteoglycan dermatan sulfate

There are also unique neonatal forms of proteins, such as the placental-derived proteoglycan dermatan sulfate [ 8, 34].Produced by the placenta and also present in the plasma of pregnant women, this circulating physiological anticoagulant has properties similar to those of dermatan sulfate and catalyzes thrombin inhibition by means of HCII [ 8]. The length of time this component remains in neonatal plasma is unknown [ 8].

α2-macroglobulin

α2-MG, usually of limited importance in adults [ 8, 19, 20],is present in a much higher concentration in neonates [ 6,10, 18- 20, 32, 38] (including 30-36 weeks GA preterms[ 33]), playing a very important part in thrombin inhibition[ 1, 8, 20], possibly compensating for the low levels of other inhibitors [ 6, 8, 10, 18- 20].

Thrombomodulin

Plasma concentration is increased at birth [ 10, 20] and remains high during early childhood [ 10, 38] possibly due to increased endothelial expression [ 38].

Fibrinolytic system

Although the differences are not fully known yet [ 32], the fibrinolytic system, as is the case with coagulation, is age dependent [ 10, 16, 32] and, as such, is extremely different in neonates and adults [ 32]. Although all fibrinolytic components are present at birth, their concentrations are dependent on both gestational and postnatal age [ 32] as fibrinolytic proteins are decreased in neonates, with even lower levels found in preterms [ 42].

Neonatal fibrinolytic function remains controversial[ 41]. While some authors classify it as immature [ 32, 41] or impaired [ 41], describing a relatively decreased fibrinolytic capacity [ 5, 9, 32, 41] (especially in PT [ 41]), others consider it physiologic [ 32 ], with some even arguing fibrinolysis may be augmented when compared to adult values [ 41].Further studies are required on this subject.

The normal range for D-dimers (indicators of the extent of active fibrinolysis) in newborns is unknown [ 2] but these are, generally, increased in newborns [ 17, 33] (in the first 3 days, up to 8 times normal adult values [ 33]), hinting possible coagulation system activation during childbirth [ 33].

Plasminogen

Plasminogen exhibits both quantitative and qualitative differences in neonates [ 5]. At birth, plasminogen values are usually low [ 2, 3, 7, 10, 19, 20, 32, 33], about 50-66% of adult values[ 5, 10, 19, 32], remaining so during the neonatal period [ 33] and rising to adult values by 6-12 months [ 5, 19, 32]. The relative decrease in plasmin/plasminogen activity [ 10, 33, 38] results in a relatively hypofibrinolytic state [ 3, 59].

In newborns, plasminogen is present in a fetal form [ 10, 32],whose structural differences may be responsible for its diminished activation rate [ 32]-possibly in relation with slower activation by tissue plasminogen activator (tPA), its main activator[ 5 ]-decreased binding to cellular receptors [ 38], and decreased functional activity [ 38].

The reportedly decreased [ 32 ] and slower [ 33] plasmin generation coupled with the decreased inactivation of plasmin by α2-antiplasmin [ 32] may justify the generally adequate fibrinolytic activity present at birth, without consumption oflarge amounts of plasminogen or α2-antiplasmin [ 32]. GA reportedly influences the plasminogen/plasmin system [ 16], but its effect is still not fully known [ 33] (in preterms, levels of plasminogen are reduced to about 25% of adult values [ 32]).

Tissue plasminogen activator

Concentrations are reportedly increased [ 10, 20, 59], generally over double those of adults[ 33]. Higher levels have been described in SGA (when compared to AGA) full-term newborns [ 28, 44, 47] and preterms [ 28, 45].

Urokinase-type plasminogen activator (uPA)

Studies have found contradicting evidence regarding this component’s relative values in newborns [ 32]. While some found reduced levels in comparison with adults [ 63], later research described no significant differences [ 64]. Pediatric reference values are still not available [ 32].

Plasminogen activator inhibitor-1

At birth, levels are increased [ 10, 20, 32, 38, 41] (almost twofold[ 33]) when compared to adult values, with both term and preterm neonates reaching adult concentrations by day 5 of life [ 33].No differences in values have been reported between preterm and term AGA neonates [ 33]. However, higher levels in preterm SGA, when compared to AGA neonates, have been described[ 45], while the same was not found in term newborns [ 44].

Plasminogen activator inhibitor-2

Levels are reportedly increased in newborns [ 32].

Lipoproteins

Their antifibrinolytic effect appears to be less pronounced in neonates, possibly in relation with lower plasminogen levels[ 15].

α2-antiplasmin

Reduced at birth [ 10, 32], levels reach adult ranges in the first 5-7 days of life in term neonates [ 32, 33]. Concentrations are generally lower in preterms with a 30-36 weeks GA, with values remaining low for a longer period [ 33].Levels are also lower in term SGA newborns when compared to term AGA neonates [ 28]. There seems to be a slight structural difference in newborns’ α2-antiplasmin that seems to lead to a lower plasmin-inhibiting power [ 32].

Ptlaelets

Platelets appear in the fetus in the 5th-6th weeks of gestation [ 2, 37], increasing during fetal life [ 2, 51] until about 22 weeks of GA, when platelet counts reach adult ranges [ 33,37, 51], remaining, afterward, stable until term [ 33]. Platelet counts increase immediately after birth and later decrease to adult ranges [ 25]--term neonates’ platelet counts [ 3, 5, 7, 9,14, 23, 37] are similar to adults and older children [ 65] and thrombopoietin levels, in non-thrombocytopenic newborns,do not differ from adults’ [ 14].

Differences in neonatal platelet ultrastructure [ 9, 37] and volume [ 9, 46] when compared to the adult’s platelets have been described, but the general presence of these disparities is controversial [ 5, 9, 14, 23, 37, 46]. Despite reportedly similar platelet counts, several other differences are present [ 3,46] since, as with other elements of the hemostatic systems,platelets also undergo a process of age-dependent maturation[ 3, 46, 51], mainly at the functional level [ 9].

Assessment of platelet function (PF) is challenging in any age group since its study often requires large blood samples and specialized laboratories, and often poorly replicates in vivo conditions, hindering clinical and investigative efforts [ 23, 37]. Functional differences have been consistently reported [ 5, 7, 9, 26, 46, 51]: neonatal platelets are hyporeactive [ 3, 7, 9, 14, 22, 25, 37, 46, 65] and hypofunctional [ 5, 14, 23, 24, 37, 51] and seem to have limited functional reserve capacity [ 37]. They reportedly have decreased numbers of certain receptors [ 9, 24, 37, 40, 46](and decreased agonist-stimulated expression of receptors[ 37]), fibrinogen binding [ 26], granule content [ 37]/secretion [ 5, 14, 23, 25, 26, 37, 46], aggregation [ 5, 14, 24- 26,40, 65], spreading [ 46], calcium flux [ 14, 22, 23, 25, 46],expression of activation markers [ 37], thromboxane synthesis [ 23, 25, 37, 59], signal transduction [ 9, 14, 22, 23, 37,46, 59], and responsiveness to certain agonists [ 9, 22- 24, 26,40, 46] as well as a deficient phospholipid metabolism [ 14,37]--mechanisms that probably play a part in the aforementioned hyporeactivity [ 37].

These disparities lead to an in vitro dysfunction of neonatal platelets [ 40, 51], clearly at odds with in vivo studies [ 35,51] which describe primary hemostasis as more effective in newborns than other age groups [ 23, 39]. This is probably due, not only to the aforementioned differences in vWF concentrations and its characteristics [ 2, 3, 14, 23, 33- 35,37- 40, 51, 59, 66], the differences in hematocrit [ 3, 23, 31,34, 37- 39, 57, 66], an increased red blood cell size [ 2, 23,31, 33, 34, 38, 39, 57, 66], and higher levels of FVIII [ 33](vide supra), but also to higher levels of platelet glycoprotein Ib (vWF receptor) [ 24, 40, 51].

This only reiterates the concept that although neonatal hemostasis may be different and apparently deficient when each element is studied separately, in vivo, all differences are physiologically balanced towards a stable hemostasis. This is apparent in most in vivo studies of neonatal PF [ 5] (e.g.,bleeding time which is shorter in neonates than in adults[ 40]) or whole blood (WB) studies that show normal or even enhanced platelet aggregation in healthy neonates [ 46].

When adult platelets are experimentally placed in neonatal blood, they become hyperreactive, while, physiologically, in that same medium, neonatal platelets are functionally sufficient--the procoagulant activity of newborn WB is likely sufficient to compensate for the aforementioned platelet functional insufficiencies[ 46]. The clinical impact [ 9, 23, 51] and duration [ 9, 14, 22, 23,37] of this relative platelet hypofunction is still unclear. The differences may reflect the disparities in hemostatic (and general)homeostasis and probably play a part in protecting neonates from the harmful effects of birth stresses on the coagulation system [ 51] and preventing unwanted clot formation, while still maintaining appropriate hemostasis [ 46].

In preterms, platelet counts are, generally, lower [ 3, 14, 25],but still within the normal adult ranges [ 3, 14]. At birth, platelet hyporeactivity [ 9, 14, 25, 46, 51] seems to be more pronounced in preterms, more evidently in those with a GA under 30 weeks[ 39, 66], hinting at a correlation between GA and platelet hyporeactivity [ 39]. The fact that platelet hyporeactivity is more prominent in preterms, particularly during the first 10 days of life, led to the hypothesis that this fact may contribute to the higher bleeding risk observed during this period [ 39], but this enhanced hyporeactivity’s relation with the rates of preterm bleeding remains to be elucidated[ 23].

Platelet adhesion capacity also seems to correlate with GA--although still better than adults’, it is apparently decreased in preterms when compared to term infants [ 39]. Reportedly, at birth, both SGA [ 24, 28] and VLBW [ 47] newborns have lower platelet counts. Median platelet counts do not seem to differ between twins [ 24].

Megakaryopoiesis

Although platelet counts are similar to adults’, newborns have higher numbers of circulating progenitor and mature megakaryocytes [ 14, 37]. Megakaryocytes are developmentally regulated and, in neonates, they seem to have a higher proliferative potential [ 37, 51] and a higher sensitivity to thrombopoietin although they are generally considered immature and produce fewer platelets than adults’ [ 14, 37,51]. There are also disparities in size, ploidy, cytoplasmic maturation, polyploidization, and signaling pathways [ 14,37, 51].

Neonates may have an impaired ability to respond to platelet stress because, even though, in cases of, e.g.,enhanced consumption, they can increase the number of megakaryocytes, they do not enhance their volume[ 37] or ploidy [ 33] (mechanisms which are all present in adults [ 33]). Differences in neonatal megakaryocytes may be responsible for this age group’s characteristic responses and increased susceptibility to thrombocytopenia [ 51]. Even though some studies have found higher mean thrombopoietin levels in preterms than term newborns [ 14], the former seem to have an impaired ability to increase the hormone’s concentrations in response to thrombocytopenia [ 24].

Tissue factor (TF)

TF levels in newborns are higher [ 33], possibly aiding in compensating for relatively lower levels of procoagulants[ 33] and relative platelet hypofunction [ 38]. Preterms,reportedly, have lower TF activity levels, when compared to term newborns, possibly due to differences in TFPI concentrations or function [ 11].

Non-hemosttaic influences on/of developmental hemostasis

The hemostatic system is not completely independent as it coexists, and often interacts, with multiple other physiological systems [ 1, 2, 6, 8, 20] and there is evidence that hemostasis-related components may influence several other physiologic processes [ 1, 2, 4, 6, 8]. Thus, there may be non-hemostasis-related physiologic motives for the existence/importance of developmental hemostasis [ 1, 2, 4, 6, 17,20, 33, 35]. Some hemostatic system changes may be justified by these processes, while other disparities may actually constitute compensatory mechanisms, aiming to preserve hemostatic balance [ 4].

Angiogenesis

AT has strong anti-angiogenic properties, and the neonatal period is one of very active angiogenesis and therefore, this may be one of the motives for its low levels in neonates [ 1, 8, 20],while other protein levels may be altered to maintain a healthy hemostatic profile [ 20]. The low levels of AT may allow for the necessary angiogenesis while elevated a2-MG levels maintain hemostatic balance [ 8, 10]. This justifies why AT substitution therapy in this age group, as was already suggested in a randomized controlled trial [ 67], may be deleterious [ 1, 8], as may be the case with platelets, fresh frozen plasma, or cryoprecipitate[ 20].

tPA also has also been suggested to influence vascular development: its expression is dynamic during this process,varying widely throughout the progress of vessel maturation[ 68]. TF [ 6], thrombomodulin [ 6], and platelets [ 46] also influence angiogenesis [ 39]. These elements’ developmental differences may also be, at least partially, motivated by nonhemostasis-related factors.

Inflammation

The hemostatic and inflammatory cascades are deeply correlated, and many hemostasis-related elements, such as thrombin, factors Xa and VIIa and TF as well as vascular epithelial cells, also play a role as inflammatory mediators [ 60].α2-MG, thrombomodulin, and platelets are also involved in inflammation [ 6, 46] and AT has been shown to possess anti-inflammatory properties [ 17].

Immunity

Platelets play a part in immune defenses [ 3, 46] and have antimicrobial properties [ 39, 46]. They are known to guide leucocytes to extravasation sites and differences in platelet-leucocyte interactions between neonatal and adult platelets have been shown in animal models [ 46]. Platelets also play a part in lymphatic vessel growth and lymph node integrity [ 46]. AT may also have antimicrobial properties [ 17]and α2-MG also has innate immunity-related functions [ 1].

Role of vitamin K in fetal development

Intrauterine levels of VK may indirectly influence fetal development processes, and it has been proposed that intrauterine low VK levels may play a role in preventing premature cartilage maturation, as well as other cellular-level processes. This may be an explanation for the near-universal low VK levels found in neonates [ 33].

Brain development

Both tPA and uPA have been reported to contribute in brain development [ 69].

Conclusions

The neonatal hemostatic system is profoundly different from the one present in other age groups-even though its components are the same, there are several quantitative and even qualitative differences. All of these differences should be taken into account in both clinical practice and research as well as when designing newborn focused hemostasis-related policies.

Author contributions

RYFV and SH conceived the general idea behind the project. All the authors participated in the gathering of data and in writing the manuscript. All the authors reviewed the final manuscript and accepted the version that was submitted.

Funding

No funding to declare.

Data availability Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Ethical approval

Consisting of a review of previously published material, the present study did not require ethics committee approval.

Conflict of interest

No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. The authors have no conflict of interest to declare.