Endothelial cells maintain the integrity of the blood vessel and prevent the extravasation of blood into the surrounding tissue. Endothelium has a significant impact on hemostasis by the pro- and anticoagulation properties of endothelial cells and the extracellular matrix. Passive thromboresistance is provided by endothelial proteoglycans, primarily endogenous heparan sulfate. Active thromboresistance is achieved through several mechanisms, including the synthesis and release of prostacyclin, a potent vasodilator and an inhibitor of platelet adhesion and aggregation. ^,

When the endothelium is injured, tissue factor (thromboplastin) is produced and rapidly promotes local thrombin formation. Tissue factor binds factor VII and converts it to factor VIIa ( Fig. 4.1 ), which is the first step in activation of the extrinsic coagulation pathway. It also activates factor IX, which activates the common pathway, resulting in fibrin formation. Capillaries seal with little dependence on the hemostatic system, but arterioles and venules require the presence of platelets to form an occluding plug. In arteries and veins, hemostasis depends on both vascular contraction and clot formation around an occluding primary hemostatic plug.

The coagulation cascade.

In the resting state, platelets circulate as disk-shaped, anuclear cells that have been released from megakaryocytes in the bone marrow. They are 2–3 μm in size and circulate for approximately 5–9 days unless they participate in coagulation reactions or are removed by the spleen. Normal blood contains 150,000–400,000 platelets/μL. In the resting state platelets do not bind to intact endothelium. Once platelets bind to injured tissue and are activated, their discoid shape changes. They spread on the subendothelial connective tissue and degranulate, releasing serotonin, adenosine diphosphate, adenosine triphosphate, and calcium. Alpha granules release factor V, fibrinogen, VWF, fibronectin, platelet factor 4, β-thromboglobulin, and platelet-derived growth factor. ^, This activity recruits and aggregates more platelets from the circulation onto the already adherent platelets.

When a vessel is disrupted, platelet adhesion occurs through the binding of collagen and VWF (found in the subendothelium) to the platelet membrane ( Fig. 4.2 ). For platelet adhesion to occur, platelets must express specific glycoprotein Ib receptors on their surface to bind the VWF complex. If this specific glycoprotein is missing, platelets are unable to adhere to areas of injury. Platelets in Bernard-Soulier syndrome lack glycoprotein Ib and are unable to adhere and form the initial hemostatic plug. If the VWF is defective or deficient, platelets do not adhere to vascular injury sites. The result is von Willebrand disease (VWD), of which several specific types and subtypes have been defined. Very high concentrations of prostacyclin can also inhibit platelet adhesion to exposed subendothelium.

Schematic representation of platelet adhesion and aggregation under flow conditions. (A) Rolling of platelets over collagen-bound von Willebrand factor (vWF) mediated by glycoprotein (GP)Ib. (B) Firm attachment mediated by α2β1 and GP VI binding to collagen and by αIIbβ3 binding to collagen-bound vWF. (C) Platelet activation, secretion, and spreading. (D) Aggregate formation.

Routine preoperative hemostatic testing is not indicated for pediatric patients without bleeding risk factors such as personal or family history of bleeding. In pediatric patients with concerns for a bleeding disorder, the next step is laboratory screening. Basic coagulation screening consists of a complete blood count (CBC), prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen. Additional tests should be ordered in conjunction with a pediatric hematologist and can measure specific factor levels, perform inhibitor screening tests, test for platelet function disorders, and identify VWD. Because no method can reliably predict all bleeding complications, postoperative hematologic monitoring remains important for all patients.

The platelet count measures the adequacy of platelet numbers to provide initial hemostasis. Thrombocytopenia (a platelet count of <150,000/μL) is one of the most common problems that occur in hospitalized patients. The risk of bleeding is inversely proportional to the platelet count. When the platelet count is <50,000/μL, minor bleeding occurs easily and the risk of major bleeding increases. Counts between 20,000 and 50,000/μL predispose to bleeding with even minor trauma; with counts <20,000/μL, spontaneous bleeding may occur; with counts <10,000/μL, severe spontaneous bleeding is more likely. Surgical bleeding does not usually occur until the platelet count is <50,000 platelets/μL. A platelet count of <50,000/μL is considered a cut-off criterion for transfusions preoperatively. Patients with significant clinical bleeding and an abnormal platelet count should also be transfused with platelets.

The PT is a measure of the function of the extrinsic and common coagulation pathways. It represents the time (in seconds) for the patient’s plasma to clot after the addition of calcium and thromboplastin (an activator of the extrinsic pathway). ^, Isolated prolongation of the PT is seen in patients who are deficient in vitamin K leading to factor VII deficiency due to previous antibiotic treatment. It also occurs with factor VII deficiency and warfarin therapy. The aPTT may also be prolonged with significant liver dysfunction or severe vitamin K deficiency, due to lack of other vitamin K dependent factors II, IX and X. ^,

The aPTT measures the function of the intrinsic and common coagulation pathways. The aPTT represents the time (in seconds) for the patient’s plasma to clot after the addition of phospholipid, calcium, and an intrinsic pathway activator. The aPTT detects deficiencies in factors XII, XI, IX, and VIII, and in the common pathway, but mild factor deficiencies may be missed. The aPTT also is used to monitor anticoagulation with heparin and the heparin-neutralized aPTT is used to monitor anticoagulation with direct thrombin inhibitors. ^,

Several inherited disorders of coagulation are not detected by the preceding tests. Results from standard hemostatic screening tests, such as the PT and aPTT, are normal in factor XIII deficiency. Therefore, assessment of clot stability is the most common screening test used for factor XIII deficiency with a quantitative assay required to confirm the diagnosis of factor XIII deficiency. Most patients with VWD will have normal aPTTs unless factor VIII, which acts as a cofactor for VWF, is also decreased. PT and aPTT are both prolonged in patients with deficiencies of factors X and V, prothrombin, and fibrinogen, and in patients with DIC or severe liver disease. ^,

The standard method for fibrinogen determination measures clottable fibrinogen by using a kinetic assay. Normal levels of fibrinogen are 150–350 mg/dL. As fibrinogen is the substrate for the final reaction in the formation of a clot and all plasma-based screening tests depend on the formation of a clot as the end point of the reaction, fibrinogen levels below 80 mg/dL prolong the PT, aPTT, and thrombin time, and therefore make the results uninterpretable. Large amounts of fibrin degradation products interfere with the formation of fibrin and cause an artificially low level of measured fibrinogen. An immunologic-based assay for fibrinogen is used to measure both clottable and nonclottable fibrinogen. This test is most often used in identifying patients with a dysfibrinogenemia in whom the functional level of fibrinogen is low, and the immunologic level is normal. ^,

Repeating the PT or aPTT by using a 1:1 mix of patient plasma with normal plasma (mixing test) is a useful procedure for investigating a prolonged PT or aPTT. Normal plasma has, by definition, 100% levels of all factors. When mixed with an equal volume of patient plasma, if there is a minimum of 50% of any given factor present, the PT or aPTT should normalize ( Fig. 4.3 ). Correction of the clotting time suggests the presence of a factor deficiency and further testing for specific factor deficiencies which prolong the aPTT should follow. Lack of normalization suggests the presence of an inhibitor that interferes with either thrombin or fibrin formation. ^,

Abnormal coagulation screening that corrects with mixing studies.

Two types of acquired inhibitors prolong the aPTT. One blocks or inactivates one of the intrinsic factors, whereas the other is a lupus-like inhibitor that interferes with phospholipid-based clotting reactions. The first type of inhibitor occurs in 10%–15% of hemophilia A patients and can occur spontaneously, but it is extremely rare in children who do not have hemophilia. The lupus-like inhibitor is associated not with bleeding problems but rather with an increased risk of thrombotic problems in adults. Lupus-like inhibitors are mentioned because they commonly cause prolongations of the aPTT after viral infections in children. A child with a prolonged aPTT that does not correct with mixing study can be presumed to have a transient inhibitor and is not at increased bleeding risk.

The PFA-100 Analyzer (Siemens Healthcare Diagnostics, Deerfield, IL) is a screening test for some types of VWD and platelet function disorders. It creates an in vitro high shear stress condition that results in the activation of platelet-dependent and VWF-dependent attachment, and aggregation of platelets to a collagen-ADP or collagen-epinephrine surface. However, test results can be influenced by the sample’s hematocrit and exposure to drugs such as NSAIDs and aspirin. Although the PFA-100 does not detect all platelet dysfunctions or cases of VWD, when used in conjunction with a standardized questionnaire, it can be useful for detecting impaired hemostasis in most cases. It can also produce false-positive test results. ^, An abnormal PFA-100 needs to be followed with confirmatory testing for VWD and platelet function disorders by using platelet aggregation and secretion testing under guidance of a hematologist.

The tests available in most hospital laboratories for the identification of disseminated intravascular coagulation (DIC) are semiquantitative fibrin or fibrinogen degradation product assays, which involve a slide agglutination procedure or a d -dimer assay. An increased amount of these degradation products suggests that either plasmin has circulated to lyse fibrin, or the patient’s hepatic function is insufficient to clear the small amounts of regularly produced degradation products. The d -dimer test is a slide agglutination procedure that tests for two d subunits of fibrin that are cross-linked by factor XIII. This test provides specific evidence that plasmin has digested the fibrin clot and not fibrinogen. It is positive in patients with DIC, resolving large intravascular clots and gastrointestinal bleeding, following major surgery, and in patients with hepatic insufficiency. Specific assays to demonstrate the presence of soluble fibrin monomer complexes or fibrinopeptides produced by the conversion of prothrombin to thrombin are also useful in some situations and available in specialized laboratories. ^,

The thromboelastograph (TEG) and rotational thromboelastometry (ROTEM) are viscoelastic assays that measure coagulation in whole blood during each phase of clot formation. This allows for the assessment of global clot formation and dissolution in real time. Advantages of ROTEM include the ability to analyze four samples simultaneously, less sensitivity to mechanical shear forces, and automatic pipetting. Both tests quantify the contribution of coagulation factors, platelets, and fibrinogen to clot formation. Fibrinolysis is also assessed, and hyperfibrinolysis can be targeted with antifibrinolytic agents. TEG and ROTEM are used in pediatric trauma, cardiac surgery, liver failure, and liver transplant to guide blood product and hemostatic replacement for these pediatric patients.

Hemophilia A and B are X-linked recessive bleeding disorders caused by decreased levels of factor VIII and factor IX, respectively. Approximately 80% of hemophilia patients have factor VIII deficiency, and 20% have factor IX deficiency. These are rare disorders, with a prevalence of only 13.4/100,000 males. In laboratory screening, these patients will have a prolonged aPTT.

Children with hemophilia A and B can be classified into three categories based on their level of circulating factor. Severe hemophilia is defined as a factor level less than 1%. These children are typically diagnosed before 1 year of age and present with neonatal bleeding such as intracranial hemorrhage or bleeding with circumcision or joint bleeding and hematomas once they become mobile. Bleeding can be spontaneous or occur in areas subjected to minor trauma. Recurrent hemarthroses can cause pseudotumors of the bone, whereas hematomas can cause ischemic compartment syndromes. Retroperitoneal hemorrhage can happen in the absence of injury and is life-threatening. Commonly presenting symptoms include vague groin pain, numbness in the femoral nerve distribution, holding the hip flexed and inwardly rotated with the inability to extend the hip. Moderate hemophilia is classified by factor levels between 1% and 5%. In these individuals, spontaneous hemorrhage occurs infrequently, but relatively minor trauma can cause bleeding into joints or soft tissues. Some children with moderate hemophilia will have more of a severe phenotype, including spontaneous hemarthroses. Mild hemophilia is factor levels between 5% and 40%. These children rarely have clinical bleeding problems with routine activities and typically have problems only with major trauma and surgical or dental procedures. Individuals with mild hemophilia may not be diagnosed until late childhood or adulthood. Therefore, the history may not be helpful in alerting the pediatric surgeon about the risk of bleeding. Moreover, because one-third of all cases of hemophilia are caused by new mutations, there may not be a family history to arouse suspicion of a bleeding problem.

For children with either severe hemophilia or moderate hemophilia with frequent bleeding, prophylaxis is the standard of care. For those with hemophilia A, this consists of administration 2–3 times per week of plasma-derived or recombinant factor VIII standard, or extended half-life infusions, or emicizumab-kxwh. Emicizumab is a humanized bispecific monoclonal antibody that acts in the place of factor VIII to allow activated factor IX to activate factor X. It is a subcutaneous injection that can be given weekly, every 2 weeks, or monthly. It is important to note that when patients have bleeding while taking emicizumab, they still need to be treated with a factor VIII infusion or bypassing agent if they have an inhibitor. It also affects certain coagulation laboratory tests, including clotting-based aPTT, one-stage aPTT-based single-factor assays, Bethesda assays for factor VIII inhibitors, aPTT-based activated protein C resistance, and the activated clotting time—so these labs should not be obtained while on this medication. Chromogenic factor VIII and Bethesda inhibitor assays are valid and should be used instead. For children with severe hemophilia B or moderate bleeding, factor infusions remain the standard option for prophylaxis.

The most common surgical procedures in children with hemophilia are circumcision, dental procedures, central venous access device insertion, and tonsillectomy. Preoperative management of children with hemophilia requires close cooperation among surgeons, hematologists, and personnel in the hemophilia center, the coagulation laboratory, and the pharmacy or blood bank. Careful preoperative planning is essential to the success of the intervention, and an adequate supply of clotting factor concentrate must be available before admission to cover the child’s needs. The patient also must be screened for the presence of an inhibitor to either factor VIII or factor IX during the 1–2 months before the operation. A low-titer inhibitor may be overcome with increased doses of factor, but high-titer inhibitors may require the use of activated prothrombin complex concentrate (factor eight inhibitor bypassing activity [FEIBA]) or recombinant activated factor VII (rFVIIa) to bypass the effect of the antibody against either factor VIII or factor IX. FEIBA should not be used in patients on emicizumab. These patients may be desensitized through daily doses of human factor concentrate for months to years, restoring their response to regular infusions of factor VIII or factor IX. ^,

Preoperative planning should be tailored to the type of surgery and bleeding risk and the patient’s disease severity, bleeding history, and current prophylaxis regimen. All patients with hemophilia who need to undergo a surgical procedure should have a hemostatic plan in place from a hematologist prior to the procedure. For minor procedures or surgeries, patients on emicizumab prophylaxis may not need additional factors preoperatively, but this should be decided in conjunction with a hematologist. For most surgical procedures, a bolus dose of factor is given prior to surgery, and factor VIII or IX is checked after the infusion to ensure it is above 80%. Antifibrinolytics such as aminocaproic acid or tranexamic acid are also started preprocedure to supplement hemostasis. Postoperatively, factor dosing may be repeated depending on the bleeding risk of the procedure, and antifibrinolytics are also continued for a duration based on the specific procedure. For neurosurgical or orthopedic procedures, much longer periods of factor coverage are utilized, especially if significant physical therapy is planned.

Many hemophilia patients perform their own factor infusions at home supported by home care pharmacies. With the advent of home nursing services, patients are being discharged home with prolonged periods of factor coverage. Hemophilia center personnel must be closely involved in planning these discharges to ensure that sufficient clotting factor is available at home and that close follow-up is maintained during periods of scheduled home therapy. Hemophilia patients should not receive any compounds that contain aspirin or ibuprofen. Any minor procedures that require factor correction should be combined with the major procedure, if possible, to save on the use of factor concentrate.

VWD is the most common inherited bleeding disorder, with a prevalence estimated at 1% of the population. Not all individuals with low VWF levels will have clinically significant bleeding. Type 1 VWD is due to a mild to moderate decrease in VWF. Type 2 has various subtypes that are defined by the abnormal function of VWF. Type 3 occurs due to extremely low levels of VWF. VWF is bound to circulating factor VIII in plasma and extends the half-life of factor VIII, so decreased factor VIII levels may be seen in certain types of VWD. People with VWD typically present with mucocutaneous bleeding such as epistaxis, easy bruising, oral bleeding, and heavy menstrual bleeding. Postoperative bleeding is also common. Evaluation for VWD includes measuring circulating plasma VWF antigen and qualitatively assessing VWF function. VWF function can be assessed using the VWF ristocetin cofactor assay, VWF collagen binding assay, or the GP1bM binding assay. A factor VIII assay should also be obtained. As VWF is an acute phase reactant, diagnosis is made based on two sets of labs at least 4–6 weeks apart. In individuals with personal bleeding symptoms or a family history of VWD, diagnostic criteria are met with VW testing <50% on two occasions. If a family history of VWD is absent and no personal bleeding is evident, levels must be <30% on two occasions. Inheritance is mostly autosomal dominant, but some types have autosomal recessive inheritance.

Perioperative management of children with VWD is similar to those with hemophilia. Characterizing bleeding phenotype and baseline VWF levels is important in determining bleeding risk. The type of procedure (minor vs. major) is also important. Minor surgeries include dental extractions, endoscopy with biopsy, and gingival surgeries. Major procedures in children include tonsillectomy, spinal or neurosurgical procedures, and cardiac surgeries. DDAVP causes a release of VWF from endothelial cells. Children with VWD can undergo a DDAVP challenge to determine their plasma VWF response to DDAVP, and if adequate (often defined as >80%), this can be used preoperatively before minor surgeries. DDAVP can cause fluid retention with hyponatremia and seizure risk, so fluid status must be watched closely. Tachyphylaxis can occur, so DDAVP should not be used for more than 3 days consecutively. DDAVP can be given subcutaneously or intravenously, as a nasal formulation is not available at the time of this publication. For major surgeries, recombinant or plasma-derived VWF factor, with or without factor VIII, is used preoperatively. If a patient has known decreased factor VIII levels, a factor product with VWF and factor VIII must be used. After the preoperative infusion, VWF Ag should be obtained to ensure it is appropriate for the procedure (typically >80%). Factor can be repeated postoperatively based on the bleeding risk of the procedure. As mentioned above, some neurosurgical and orthopedic procedures will need hemostatic coverage for longer periods, such as 7–14 days in VWD patients. Antifibrinolytics are also used frequently.

The newborn’s coagulation system is not fully mature until 6 months after birth. The lower levels of procoagulant, fibrinolytic, and anticoagulant proteins in neonatal patients complicate both operations and the care of sick and preterm infants. Platelet counts are within the usual adult normal range. These platelets have a lower function than those of adults but enough to produce a normal bleeding time. Because circulating coagulation factors do not cross the placenta, infants with inherited deficiencies of clotting factors, fibrinolytic proteins, or natural anticoagulants can initially be seen in the neonatal period. The levels of fibrinogen and factors V and VIII are within the adult normal range at birth. VWF may be elevated due to physiologic stress at birth and fall to baseline levels by 6 months of age. All other procoagulants are normally at reduced levels, depending on gestational age. Vitamin K–dependent factors may become further depressed in infants who are breastfed and not given vitamin K at birth.

Of more concern are the low levels of anticoagulant and fibrinolytic proteins. Very low levels of protein C have been associated with purpura fulminans in newborns. In sick infants, levels of antithrombin III and plasminogen may be inadequate to deal with increased levels of clot-promoting activity in the blood. Sick infants with indwelling catheters are at significant risk of thrombotic complications.

The pathogenesis of DIC involves excessive thrombin generation with loss of localization, the degradation and dysfunction of the anticoagulation pathway, impaired fibrinolysis, and derangement of microvascular endothelium—all resulting in intravascular fibrin deposition. DIC can manifest as hemorrhage due to depletion of clotting factors and/or massive thromboembolic disease and contribute to multiple organ dysfunction and death. It may follow sepsis, hypotension, hypoxemia, trauma, malignancy, burns, and extracorporeal circulation.

Acute DIC is associated with the consumption of factors II, V, VIII, X, and XIII, as well as fibrinogen, antithrombin III, plasminogen, and platelets. A review of the peripheral smear usually shows microangiopathic hemolytic anemia. The PT and aPTT may both be prolonged, and the fibrinogen level decreases as the DIC worsens. The presence of d -dimers may indicate the presence of DIC, but they may also be elevated due to thrombus or hepatic dysfunction. Antithrombin III levels may be low, and antithrombin III concentrates have been used as part of the treatment of DIC due to septic shock. However, adult studies have not shown any improvement in mortality for patients with sepsis treated with antithrombin III. At present, the major therapy for DIC is correction of the underlying disorder and replacement with fresh frozen plasma (FFP) and platelet transfusions as needed to support hemostasis. Low-dose heparin infusions have also not been shown to appreciably improve the outcome.

Thrombocytopenia is caused by either inadequate production of platelets by the bone marrow, or by increased destruction or sequestration of the platelets in the circulation. The history and physical examination may be suggestive of a diagnosis that can be confirmed by laboratory testing. Medication use, a family history of blood disorders, a history of recent viral infection, short stature, absent thumbs or radii, or other congenital malformation may indicate a defect in platelet production. The destruction may be immunologic, as in immune thrombocytopenic purpura (ITP); mechanical, as in septicemia; or drug induced, as in patients with sensitivity to heparin or cimetidine. Establishing the cause of the thrombocytopenia determines the therapy needed to restore the platelet count in preparing the patient for operation. The clinical response to therapeutic modalities, such as a platelet transfusion, can be an important test and can help direct further investigations. In patients with immune-based platelet consumptions, such as ITP, usually no response is found to platelet transfusion. Moreover, only a very short response may be seen in patients with other causes of increased consumption. In patients with ITP, adjuvant medications such as steroids, IVIG (intravenous immune globulin), in addition to platelet transfusion, may be needed for surgical procedures. Management of the child with platelet consumption not due to ITP is then aimed at reducing the consumption and should involve consultation with a hematologist about the use of FFP, clotting factor or platelet transfusions, the discontinuation of medications, and other treatment modalities.

If the thrombocytopenia is caused by a lack of production of platelets, due to disease processes such as aplastic anemia, malignancy, or inherited thrombocytopenia; or the result of chemotherapy, transfusion with platelet concentrates to increase the platelet count above a minimum of 50,000/μL will allow minor procedures to be performed safely. Most surgeons and anesthesiologists prefer the platelet count to be greater than 100,000/μL before major surgery. Continued monitoring of the platelet count is vital because further transfusions may be needed to keep the platelet count above 50,000/μL for 3–5 days after operation.

Qualitative platelet defects can be caused by rare congenital defects such as Bernard–Soulier syndrome, Glanzmann thrombasthenia, or platelet storage pool disease. Alternatively, they can be caused by drug ingestions such as an aspirin-induced cyclooxygenase deficiency. In these situations, transfusion of normal donor platelets provides adequate hemostasis for the operation. Discontinuation of all aspirin-containing products 1 week before operation permits correction of the cyclooxygenase deficiency as new platelets are produced. ^,

Patients with rare deficiencies of other clotting factors, such as factors XI, X, VII, V, prothrombin, and fibrinogen, can have clinical bleeding depending on the level of deficiency. Most of these disorders are inherited in an autosomal recessive manner. Replacement therapy with specific recombinant factor products, FFP or, in certain situations, with prothrombin complex concentrates corrects the deficiency, and should be conducted under the direction of a hematologist.

Vitamin K deficiency, both in the neonatal period and from malabsorption, can cause deficiencies of factors II, VII, IX, and X. Treatment with 1–2 mg of intravenous vitamin K may begin to correct the deficiencies within 4–6 hours. However, if a procedure is contemplated, FFP (15 mL/kg) should be given with the vitamin K. Also, the PT should be monitored for correction of the coagulopathy before the operation and repeat FFP dosing given if the PT does not fully correct. Prothrombin complex concentrates are also used in the rapid reversal of warfarin therapy. Laboratory monitoring should be maintained during the postoperative period to ensure continuation of the appropriate factor levels.

Patients with factor XIII deficiency often present with delayed bleeding from the umbilical cord, rebleeding from wounds, intracranial hemorrhage, poor wound healing, and pregnancy complications that include miscarriage, antepartum hemorrhage, and postpartum hemorrhage. These problems may be treated with relatively small amounts of FFP (5–10 mL/kg) or factor XIII concentrate, which is available in both plasma-derived and recombinant formulations. Because factor XIII has a half-life of 6 days, this treatment is usually needed only once to stop bleeding or at the time of operation. ^, Patients with dysfibrinogenemia or afibrinogenemia may be given FFP or cryoprecipitate. There are also fibrinogen concentrates now available for these conditions as well.

Failure to control excess fibrinolysis can result in a bleeding problem, and deficiencies of the naturally occurring anticoagulants may result in excess clot formation. A severe hemorrhagic disorder due to a deficiency of α-2-antiplasmin has responded to treatment with aminocaproic acid or tranexamic acid, both antifibrinolytic agents. Tranexamic acid (TXA) has proven to be successful in reducing mortality in adult bleeding trauma patients. The Hospital for Sick Children has developed a massive transfusion protocol for the indication and dosing of TXA in pediatric trauma. The protocol recommends an immediate need for transfusion with signs of shock such as low systolic blood pressure poor blood pressure response to crystalloid 20–40 mL/kg, or obvious significant bleeding. The recommended dosing of TXA for pediatric trauma is as follows:

• 1.

  For age >12 years: 1 g IV over 10 minutes within the first 3 hours followed by a subsequent dose of 1 g IV over 8 hours.

• 2.

  For age <12 years: 15 mg/kg IV over 10 minutes with a maximum dose of 1 g within 3 hours followed by a subsequent dose of 2 mg/kg/h IV over 8 hours or until bleeding stops.

Recombinant activated factor VII (rFVIIa) was developed for the treatment of bleeding in patients with hemophilia A or B who had inhibitors, and was approved by the US Food and Drug Administration (FDA) for this indication in 1999. Good hemostasis with few side effects has been found in patients with intracranial hemorrhage, post laparotomy and postpartum hemorrhage, and for surgical prophylaxis for major and minor procedures. Home treatment programs for those hemophilia patients with inhibitors now use rFVIIa as front-line therapy for bleeding. Recombinant factor VIIa was approved by the FDA in 2006 for its use in acquired hemophilia with inhibitors to factor VIII or factor IX, and in 2014 for Glanzmann thrombasthenia patients with platelet refractoriness. Children have a more rapid rate of clearance of rFVIIa (elimination mean half-life, 1.3 hours in children vs. 2.7 hours in adults). They also seem to have fewer side effects with this treatment. Although various dosages and schedules have been studied, initial recommended therapy in hemophilia A or B with inhibitors is 90 μg/kg intravenously every 2 hours until the bleeding is controlled.

The FDA has also approved the use of rFVIIa in congenital FVII deficiency. The recommended dose is 15–30 μg/kg every 4–6 hours until bleeding is controlled. The off-label use of rFVIIa has been reported in therapy-resistant severe bleeding from other conditions such as active bleeding in trauma, spontaneous intracranial hemorrhage (ICH), chronic liver disease, and inherited platelet disorders. ^, The reported dosages have ranged from 5 to 300 μg/kg/dose. Successes in patients without a known bleeding disorder who have trauma or postoperative hemorrhage have also been described. ^, These reports should be interpreted with caution because rFVIIa is currently not the standard of care in any of these off-label uses and exceptional circumstances impelled its use.

A physician experienced in using rFVIIa should oversee its administration due to potential risks, especially thrombosis, which occurs in 1%–3% of patients. ^,

Treatment of VTE in children requires anticoagulation. Heparin, which potentiates the action of antithrombin, is an intravenous (IV) anticoagulant historically used for critically ill children or in scenarios where anticoagulation is required, but rapid reversal might be needed. Heparin is monitored using the aPTT (goal 60–90 seconds) and/or standard heparin level (goal 0.3–0.7 IU/mL). Advantages of heparin are that it can be used in patients with renal failure and is fully reversible with protamine sulfate. Disadvantages include variable bioavailability in children, protein binding, antithrombin dependence, risk of heparin-induced thrombocytopenia (although extremely rare in children), and discordances of aPTT and standard heparin levels. Due to these reasons, IV direct thrombin inhibitors such as bivalirudin and argatroban have grown in use in children who require IV anticoagulation. Both have extremely short half-lives and act on thrombin directly, negating the need for antithrombin as a substrate. Bivalirudin is mostly metabolized via proteolysis with a small amount of renal metabolism, and argatroban is predominantly hepatically metabolized. Both are monitored using heparin-neutralized aPTT with a goal of 60–90 seconds. No current reversal agent exists for these medications.

For patients who do not require IV anticoagulation and are more clinically stable, low-molecular-weight heparin (LMWH) has been the mainstay of treatment with enoxaparin being the type most frequently used. LMWH also acts via antithrombin but also inhibits factor Xa. LMWH is given twice daily subcutaneously and monitored with an anti–factor Xa assay, with a goal level of 0.5–1. LMWH cannot be used in patients with renal failure.

For patients with renal failure, mechanical valves, or antiphospholipid antibody syndrome, warfarin remains the drug of choice. Warfarin is a vitamin K antagonist and works by blocking the gamma carboxylation of the vitamin K–dependent factors (II, VII, IX, X). It is monitored using the INR with a typical goal range of 2–3 except for patients with mechanical valves. It is an oral medication but is fraught with challenges in children, including food and drug interactions, therapeutic monitoring with INR, genetic variants that affect metabolism, and a long half-life. It is important to bridge with another anticoagulant when starting warfarin due to the risk of warfarin-induced skin necrosis from the drug’s inhibition of proteins C and S.

Recently, two oral anticoagulants received FDA approval for use in children. The first is rivaroxaban, which is an anti-Xa inhibitor. Rivaroxaban is available in liquid or a tablet form that can be crushed. It does not require drug monitoring but cannot be used with liver or renal failure. It must be taken with food or enteral nutrition being given via the stomach to be absorbed. Andexanet alfa is a recombinant modified factor Xa protein that is approved to reverse rivaroxaban. Prothrombin complex concentrates have also been used for reversal. The other drug is dabigatran, which is an oral direct thrombin inhibitor. It is available as pellets or capsules. Dabigatran is mainly renally excreted and thus cannot be used in renal failure. It also does not require drug monitoring and can be reversed with idarucziumab. Dabigatran should be started after 5 days of treatment with a parenteral anticoagulant like LMWH.