Developmental Hemostasis Research Articles

Hemostasis and Platelet Dysfunction in Asphyxiated Neonates

Hemostasis is the balance between bleeding and clotting and includes coagulation and fibrinolysis with platelet interactions. Despite developmental hemostasis that describes the major differences between neonates and older children and adults, neonates do not have increased bleeding or clotting unless clinical situations disturb the "balance." Perinatal asphyxia alters the balance of hemostasis, resulting in abnormalities that may result in bleeding and thrombosis. The following discussion will describe normal hemostasis, laboratory measures of hemostasis, developmental hemostasis, and the effects of asphyxia on hemostasis.

Thrombosis and thrombophilia: principles for pediatric patients

Thrombotic complications in pediatric patients are increasingly recognized due to increased use of invasive procedures, heightened awareness, improved imaging and prothrombotic lifestyle choices. Multiple risk factors are often present in pediatric patients with thrombosis. The most common risk factor is an indwelling catheter, followed by inflammatory conditions, malignancy, immobilization, thrombophilia and congenital heart disease. Rare severe thrombophilias, whether acquired or congenital, often present in children. Neonates have distinct patterns of thrombosis promoted by sepsis, inflammation, hypotension, hypoxia and the use of intravascular catheters in small caliber and umbilical vessels. Treatment of pediatric thromboembolic disease requires an understanding of developmental hemostasis, application of nonpediatric drug formulations and consolidation of expert guidelines and relevant adult literature. The acute and chronic consequences of thrombosis can be devastating in pediatrics and correlate with the length of time of vessel occlusion, underscoring the importance of rapid diagnosis and initiation of therapy. As trials begin to define recurrence risks, outcome predictors and optimal therapy for children with thrombosis and thrombophilia, consultation with an experienced pediatric hematologist provides the best available therapy today.

Hemostasis in neonates and children: Pitfalls and dilemmas

Developmental Hemostasis refers to the age-related changes in the coagulation system that are most marked during neonatal life and childhood. An understanding of these changes is crucial to the accurate diagnosis of hemostatic abnormalities in neonates and children. This paper explains the current understanding of developmental hemostasis and describes the common pitfalls observed in clinical practice through failure to implement the principles into routine diagnostic work. Finally, there is a brief discussion as to a potential physiological rationale for developmental hemostasis and the implications of this for hemostatic interventions in neonates and children. There remains a need for further study to improve our understanding of the implications of developmental hemostasis in normal growth and development.

Pediatric thrombosis

Thrombotic risk factors and thrombosis in children has been receiving increased attention. True idiopathic thrombosis is extremely rare in children. Most patients have a significant underlying medical condition and the presence of a central catheter is the most important risk factor. Children are more likely than adults to have one or more significant genetic abnormality or coagulation deficiency. This review discusses problems concerning the heterogeneity of thrombotic states in children and highlights the importance of understanding the concept of developmental hemostasis. Issues regarding step-wise test selection and the interpretation of results are addressed, as well as basic monitoring of anticoagulant drug effects.

Age-associated developmental changes in the activated partial thromboplastin time (APTT) and causes of prolonged APTT values in healthy Chinese children

The concept of developmental hemostasis has been universally accepted. Physiological reference ranges for coagulation tests are available for infants and children of different ages. However, on Oriental children they are rare. Results of preoperative activated partial thromboplastin time (APTT) in neonates, infants, children aged 1-18 years and adults with minor elective surgery in a university affiliated hospital were reviewed retrospectively. Plasma activity of factors VIII, IX, XI, XII (FVIII:C, FIX:C, FXI:C, FXII:C) and lupus anticoagulants (LAC) in 47 children with prolonged APTT and 34 adult controls were measured to investigate the causes of prolongation. Compared with adults, APTT values were prolonged significantly and were age-dependent in children, especially in neonates and infants aged 1-6 months. Mean values for FXII:C and FIX:C in children with prolonged APTT values were significantly lower than those in adults (p<0.001). Prolonged APTT values correlated negatively with FXII:C and FIX:C, and weakly with the LAC Screen ratio (LAC-SR) (r(0.01)=-0.808, -0.705 and 0.372, p=0.000, 0.000 and 0.001, respectively). There was weak negative correlation between FXII:C and LAC-SR (r(0.01)=-0.277, p=0.012). No significant correlation was seen between prolonged APTT values and FVIII:C or FXI:C. APTT values change dynamically with age during childhood and display a distinct pattern of evolution in children. Lower values of FXII:C and FIX:C, and presence of LAC contribute to the prolongation of APTT values in Chinese children.

The differences of platelet response to snake venoms: A comparative study of children and adults

Platelets play a vital role in the coagulation, yet the potential for differences in platelet function, between adults and children, remains underexplored. This is despite the age-related variation in haemostatic proteins, that is encompassed by the term Developmental Haemostasis. Hemotoxins found in the venoms of Australian snakes mimic human blood coagulation factors. The effects of Australian snake venoms on platelets, as well as the possible differential response in adults and children were subject of this study.

The in vitro anticoagulant effects of Danaparoid, Fondaparinux, and Lepirudin in children compared to adults

Introduction Major physiological differences in the coagulation system of children compared to that of adults are well documented. We have previously investigated the age-related differences in response to Unfractionated Heparin (UFH). However, the impact of developmental haemostasis on more recent anticoagulant drugs is unknown. A number of these drugs are approved for use in specific indications in adults and none are approved for use in children. This study aimed to determine whether age-related differences in effect and impact on monitoring tests exist in vitro for danaparoid, fondaparinux and lepirudin. Materials and Methods Plasma samples were obtained from healthy children and pooled into age-specific pools, in order to obtain sufficient quantity of plasma required for the analysis of the three drugs. Each age-specific pool was spiked with different concentrations of danaparoid, fondaparinux and lepirudin and response was measured using standard techniques. All experiments were repeated using three separate plasma pools. The effect of each drug in children's plasma was compared to the effect in the respective adult plasma pool. Results Age-related differences in effect on thrombin potential and monitoring tests were observed only with the drug lepirudin. Specifically, APTT for children up to 5 years of age was increased compared to adults; all children had lower ECT results compared to adults; children up to 10 years of age had increased inhibition of ETP as compared to adults. Conclusions This study confirms age-related differences in response to anticoagulants with predominant anti-IIa effect and highlights the need for further research into this area.

Thrombin generation: the functional role of alpha‐2‐macroglobulin and influence of developmental haemostasis

Currently available chromogenic and fluorogenic substrates for endogenous thrombin potential (ETP) measurement are cleaved by both free (active) and alpha-2-macroglobulin-bound (inactive) thrombin, leading to an overestimation of ETP. Commercial methods for ETP measurement determine this using a mathematical algorithm, which assumes the contribution of alpha-2-macroglobulin to the ETP. This limits application of such methods to populations where variation in alpha-2-macroglobulin concentrations is observed, primarily children. This study examined the contribution of alpha-2-macroglobulin-bound thrombin to the ETP measurement in neonates, children and adults, to determine whether automated methods are appropriate for use in neonates and children.

Diagnostic et traitement de la maladie thromboembolique veineuse en pédiatrie

Thromboembolic events are an increasingly commonly recognized secondary complications in children treated for serious, life-threatening primary diseases. Nevertheless the incidence of venous thromboembolic disease remains 100 times less frequent in hospitalized children than hospitalized adults, as recent data suggest an incidence of 5,3/10.000 pediatric patients compared to an incidence of 2,5-5/100 in adult patients. Diseases usually associated with thromboembolic events in children are neoplasia, autoimmune or cardiac malformative disease. Contrarily to what is observed in the adult, the majority of deep vein thrombosis events occur at the upper limbs veins, usually at the place where devices for venous access like port-a-cath or central venous lines are inserted. Because of the relatively low incidence of venous thromboembolic events in children, the diagnostic approach used are largely extrapolated from guidelines obtained from adult studies. However, the diagnostic performances of some diagnostic tools like Doppler-Ultrasound are probably diminished in children. Moreover, the concept of developmental hemostasis, which stresses the point that the hemostatic system in children is quite different from the adult one, is widely accepted and clearly suggests that the diagnostic and therapeutic approach in pediatric patients may not be simply extrapolated from data obtained in adult studies. From a more practical point of view, the fact that the hemostatic system in children is a dynamic and evolving system, renders the therapeutic approach quite complex. In particular, doses of anticoagulants vary markedly across the pediatric age. The absence of adapted formulations of commonly used anticoagulants, for example the absence of liquid formulations of anti-vitamin K drugs, further complicates the administration and the correct monitoring of anticoagulation in children, and may diminish observance in adolescent patients. Even though the concept that “children are not little adults” is nowadays widely accepted, there is an urgent need for prospective studies to better assess the modalities of diagnosis and treatment of venous thromboembolic disease in this particular population. (J Mal Vasc 2006; 31: 135-142)

Developmental haemostasis

Developmental haemostasis is a concept, now universally accepted, introduced by Andrew et al. in the late 1980's. However, coagulation analysers and reagents have changed significantly over the past 15 years. Coagulation testing is known to be sensitive to changes in individual reagents and analysers. We hypothesised that the reference ranges developed by Andrew et al. may not be appropriate for use in a modern coagulation laboratory. Our study was designed to determine whether a current day coagulation testing system (STA Compact analyser and Diagnostica Stago reagent system) was sensitive to age-related changes in coagulation assays. This is the first large scale study since Andrew et al. to determine the age associated numerical changes in coagulation proteins. Our results confirm the concepts of developmental haemostasis elucidated by Andrew et al. However, our results clearly demonstrate that the absolute values of reference ranges for coagulation assays in neonates and children vary with analyser and reagent systems. The results confirm the need for coagulation laboratories to develop age-related reference ranges specific to their own testing systems. Without this, accurate diagnosis and management of neonates and children with suspected bleeding or clotting disorders is not possible. Finally we present age related reference ranges for D-dimers, TFPI, and endogenous thrombin potential, previously not described.

Maturation of the coagulation system during childhood

Recent advances in tertiary care pediatrics have significantly increased the survival of children with complex pathologic disorders which were previously frequently fatal. Paradoxically, these advances in treatment have led to an increased frequency of acquired haemorrhagic and thrombotic disorder in these children. As the hemostatic system in children is profoundly different from that in adults, knowledge about developmental hemostasis is essential for optimal prevention and treatment of hemostatic disorders in children. The current paper reviews the development of pro- and anticoagulant systems throughout childhood.

Developmental hemostasis: pro- and anticoagulant systems during childhood.

An understanding of developmental hemostasis is pivotal for optimal prevention, diagnosis, and treatment of hemostatic problems during childhood. The development of microassays in the early 1980s enabled researchers to delineate age-dependent features of the coagulation system and to establish reference ranges for healthy children of all age groups, from premature infants to adolescents. Based on the results from these studies, the hemostatic system in the young can be described as evolving, and yet functional, since healthy fetuses, infants, and children do not suffer hemorrhagic nor thromboembolic complications spontaneously or in the presence of minor challenges. Plasma concentrations of most pro- and anticoagulant proteins are decreased throughout childhood but provide an effective hemostatic balance on a lower level compared with adults. The current article describes the development of pro- and anticoagulant systems throughout childhood.

The Influence of Developmental Haemostasis on the Laboratory Diagnosis and Management of Haemostatic Disorders During Infancy and Childhood

The physiology of the hemostatic system in children is different from that in adults. Reference ranges for components of the hemostatic system are age dependent. During early childhood, physiologic values may overlap with values observed in congenital deficiencies of acquired pathological conditions. Physiologically decreased plasma concentrations of hemostatic components also influence the response to antithrombotic therapy. The relevance of developmental hemostasis for the laboratory diagnosis and management of hemorrhagic and thrombotic disorders during childhood is discussed.

The relevance of developmental hemostasis to hemorrhagic disorders of newborns

The hemostatic system is a dynamic evolving process that is age-dependent. Components of the hemostatic system are synthesized in early fetal life and do not cross the placenta from mother to fetus. However, plasma concentrations of proteins involved in hemostasis significantly differ from adults. Physiological reference ranges are available for premature infants, full-term infants and children from ages 1 to 16 years. In the coagulation system, plasma concentrations of the vitamin K-dependent and contact factors are decreased at birth, whereas other factors such as fibrinogen, FV, FVIII, and FXIII are similar or increased compared with adults at birth. In the fibrinolytic system, plasma concentrations of plasminogen are decreased at birth, whereas tissue plasminogen activator and plasminogen activator inhibitor are increased. Clinically, the hemostatic system of the young is effective and healthy infants do not suffer from spontaneous hemorrhagic complications. However, infants are more vulnerable, compared with older patients, for bleeding in the presence of either congenital or acquired haemostatic defects. Severe congenital bleeding disorders, although rare, frequently present in the newborn period. The most common acquired causes of bleeding newborns include disseminated intravascular coagulation, vitamin K deficiency, and liver disease. A description of these disorders and treatment guidelines are provided.

Developmental hemostasis: relevance to hemostatic problems during childhood.

Congenital and acquired hemostatic disorders present during childhood. An accurate diagnosis is critically important in order to implement optimal therapy. Over the last century, several investigators have measured plasma concentrations of hemostatic components in newborns and compared the results to adult values. Clinically significant differences exist for many hemostatic components. Recently, three large studies in more than 400 healthy children have provided reference ranges for hemostatic components throughout childhood. Together, these studies provide insight into the regulation of coagulation and fibrinolysis in children in physiologic and pathologic states. Some examples of the influence of age on hemostasis are: (1) the diagnosis of some congenital factor deficiencies, based on plasma levels, can be difficult due to physiologically low values; (2) despite very low levels of many inhibitors of hemostasis, thrombotic complications are rare; (3) the interaction of anti-coagulants and thrombolytic agents is profoundly influenced by the relative immaturity of hemostasis at birth; and (4) in contrast to the risk of thrombosis, healthy infants are at risk for vitamin K deficiency bleeding due to poor transport of vitamin K across the placenta and plasma concentrations of the vitamin K dependent proteins of less than 50% of adults values. The following review discusses the age dependency of hemostasis during childhood and the effect of the physiologically immature system on the diagnosis and treatment of hemostatic disorders.

Developmental Hemostasis: Relevance to Thromboembolic Complications in Pediatric Patients

Developmental Hemostasis: Relevance to Thromboembolic Complications in Pediatric Patients