**2. Developmental hemostasis**

The hemostasis is a group of system which is responsible for the bleeding control after a vascular injury and also recanalization of that vessel when the bleeding is stopped. The balance between the bleeding control, which is the interaction between primary and secondary hemostatic systems, and the recanalization process, including anticoagulation and fibrinolytic systems, is crucial to maintain normal hemostasis in the body [2, 3]. The summary of normal hemostatic system is shown in **Figure 1**. The defects in the bleeding control cause bleeding disorders while the impairment of recanalization process lead to thrombotic disorders.

As same as other systems in the human body, the hemostatic system has been changed from the neonatal period to the adulthood in all parts of hemostatic system. The summary of developmental changes in hemostatic system in summarized in **Table 1**.

### **Figure 1.**

*The summary of normal hemostatic system. (a). Primary hemostasis. (b). Secondary hemostasis. (c). Anticoagulation system. (d). Fibrinolytic system.*


### **Table 1.**

*The summary of developmental changes of hemostasis [4, 5].*

## **2.1 Massive transfusion protocol in children**

In adult patients who undergo major surgeries or experience traumas, massive transfusion is defined by transfusion of blood components particularly red blood cell concentrate (RBC) equal or more than 10 units within 24 hours, receiving RBC more than 4 units in 1 hour or requirement of blood components more than 50% of total blood volume within 3 hours [6]. Although the definition of massive transfusion in children is unclear, some studies defined receiving transfusion volume of blood components more than 40 ml/kg within 24 hours as massive transfusion [7]. Moreover, adoption of adult's definitions of massive transfusion is not practical in pediatrics as some may not survive long enough to fit with those definitions. Moreover, Acker et al. showed that the adoption of assessment blood consumption (ABC) scale of adults in children had less sensitivity and specificity than those when it was studied in adult population [8]. Although the current proposed definition of pediatric massive transfusion is transfusion of blood components more than 37 ml/kg within 4 hours to make the diagnosis and initiate the intervention sooner [7], more studies are required to confirm the benefits of this definition.

The main mechanisms of massive transfusion consist of severe tissue injury from the surgery or trauma which releases abundant mount of tissue factor (TF) which

massively activated coagulation cascades and hemodilution of the inappropriate resuscitation with intravenous fluid and blood components. Those subsequently lead to a vicious cycle of progressive coagulopathy, acidosis and hypothermia which results in ongoing bleeding and multiorgan failure [6].

When the pediatric patients reach the definition of massive transfusion, the activation of the massive transfusion protocol (MTP) should be commenced. Currently, most MTPs are driven by blood components ratio protocol. The common MTPs suggest 1:1:1 ratio of fresh frozen plasma (FFP): RBC: platelet concentrate (PC) [10]. However, the most effective ratio between FFP and RBC is still controversy. Cunningham et al. reported that high (≥ 1: 1) FFP: RBC ratio, associated with better survival outcome at 4 and 24 hours than medium (≥ 1:2 to <1:1) and low (< 1:2) FFP: RBC ratios (P = 0.02). The survival outcome of medium PC: RBC ratio was higher than high and low ratios of PC:RBC without statistical significance [9]. In addition, Diab et al. recommended ratio of FFP:RBC:PC or cryoprecipitate (cryo) at 1:1:2 for massive transfusion in children [6]. However, the systematic review by Maw and Furyk showed minimal benefit of fixed ratio of FFP: RBC: PC at 1:1:1 in pediatric massive transfusion [10]. Though all blood components are derived from the whole blood (WB), hematocrit, platelet count and coagulation factors are higher in WB and lower volume than each separated blood component [7]. Furthermore, a few studies showed faster access with similar safety and clinical outcomes of using WB for resuscitation in children [11, 12].

Besides fixed ratio of blood components protocol for massive transfusion, thromboelastography (TEG) and rotational thromboelastometry (ROTEM), the viscoelastic test to measure global hemostasis and currently used as a point-of-care testing [POCT], have been used as a guided tool for management of massive transfusion [7, 10, 13]. The systematic review of using TEG or ROTEM to measure hemostasis in adults and children revealed lower dose of transfused blood components and decreased mortality than the fixed ratio for massive transfusion in patients with bleeding [13].

Other adjunctive treatments of massive transfusion include tranexamic acid (TXA) and recombinant activated factor VII (rFVIIa). Tranexamic acid, a lysine analogue, is an antifibrinolytic agent which inhibits plasminogen activation and prevent fibrinolytic process [7]. The pediatric trauma and tranexamic acid study (PED-TRAX) revealed TXA significantly decreased mortality rate (odds ratio 0.3) without increasing thromboembolic (TE) and cardiovascular events in pediatric population [14]. rFVIIa, a bypassing agent, which is used for bleeding control in both hemophiliac A and B patients who have inhibitor to factor VIII and IX, respectively [15]. The systematic review by McQuilten et al. showed no benefit of the decreased mortality for the off-label use of rFVIIa in massive transfusion and there was an increased risk of TE, particularly arterial TE, in patients using rFVIIa, therefore, routinely using rFVIIa as a part of MTP is not recommended [16].
