Etiology

DIC is always a secondary phenomenon and not a disease entity in its own right. Thus its recognition should prompt the clinician to identify and treat the underlying cause rather than merely react to the bleeding manifestations. It most frequently occurs in the settings of sepsis, trauma, and systemic inflammatory syndrome, with an approximate frequency in hospitalized children of 0.4% to 1%, with sepsis accounting for approximately 95% of cases. It is primarily a clinical diagnosis based on the evaluation of laboratory results in patients with a clinical condition known to be associated with DIC ( Box 35-1 ).

Clinical Presentation

The clinical manifestations of DIC include bleeding, thrombosis, or both, however typically bleeding predominates. Early indicators are bleeding resulting from venipunctures, intravascular accesses, and surgical wounds. Mucocutaneous bleeding may manifest as bruising, petechiae, epistaxis, gum bleeding, blood from tracheal aspirates, gastrointestinal bleeding, and hematuria. In fulminant cases it may lead to bleeding into vital organs. However, with increasingly sensitive diagnostic tests that can detect endogenous activation of the hemostatic process, the clinical spectrum of DIC is broad. Nonovert DIC describes a stressed but compensated hemostatic system, in which the laboratory tests are abnormal but there are no clinical manifestations. Overt DIC is described as a stressed and decompensated hemostatic system, in which the laboratory tests are abnormal and clinical bleeding or microvascular thrombosis and organ dysfunction exists. Overt DIC may be controlled or uncontrolled depending on whether the process will resolve when the underlying stimulus is removed.

Diagnosis

The clinical presentation of a profoundly ill child with bleeding believed to be secondary to DIC can be supported by laboratory tests showing evidence of a consumptive coagulopathy with activation of the fibrinolytic cascade. Moderate to severe thrombocytopenia with or without anemia will be evident from the complete blood count. Thrombocytopenia is present in approximately 50% of patients and suggests consumption of platelets. Anemia could be caused by bleeding or, when accompanied by schistocytes on blood smear, evidence of microangiopathic hemolytic anemia. The PT and aPTT are prolonged in 50% to 60% of patients, reflecting consumption of many coagulation proteins, including prothrombin; factors V, VII, and VIII; and fibrinogen. Fibrinogen or fibrin degradation products (FDPs) and D-dimers are both increased in concentration in most patients with DIC, suggesting activation of the fibrinolytic process. Marked reductions in plasma anticoagulants including proteins C and S and antithrombin (AT) have also been described. The most sensitive tests for diagnosis of DIC are markers of endogenous thrombin generation: prothrombin fragment 1.2 and thrombin-AT (TAT) complexes. Prothrombin fragment 1.2 is released when thrombin is generated from prothrombin. TAT complexes are generated by binding of thrombin with its inhibitor AT. The standard assays (PT, aPTT, platelet count, and D-dimers) are relatively rapid and simple to perform. However, changes in these test results do not always occur at the same time, and laboratory values change rapidly depending on the patient’s clinical status. This may create confusion in patient management and make the diagnosis of DIC at an early stage particularly difficult. The International Society on Thrombosis and Haemostasis (ISTH) diagnostic scoring system for overt DIC has been widely used in intensive care units, and several publications have validated the score against morbidity scores. The five-step algorithm assigns a score based on the severity of abnormality for each of the following: platelet count (>100 × 109/L = 0; <100 × 109/L = 1; <50 × 109/L = 2), elevated fibrin-related markers (no increase = 0; moderate increase = 2; strong increase = 3), prolonged prothrombin time (<3 seconds = 0; <3 seconds but <6 seconds = 1; >6 seconds = 2), and fibrinogen level (>1 g/L =0; <1 g/L = 1). A total score of 5 or more is considered compatible with overt DIC. The sensitivity and specificity of this scoring system are greater than 90%. However, the algorithm should be applied only in the presence of an underlying disorder known to be associated with DIC. Despite its use in many pediatric intensive care units in the United States, there remains a paucity of clinical research studies examing the utility of the ISTH scoring system in children. Investigators at Texas Children’s Hospital have compared their institutional modified DIC criteria with the ISTH diagnostic score against a gold-standard diagnostic method of confirmation of DIC in a subset of children who died. Their modified criteria is not a scoring system but a sequential analysis of coagulation assays (PT, platelet count, fibrinogen, and D-dimer) as evaluated by transfusion medicine specialists along with the patient’s clinical condition. Such an approach yielded a higher sensitivity, owing to the inclusion of sequential testing, to recognize a trend in the evolution from an early-phase DIC to overt DIC.

Treatment

The fundamental principal of DIC treatment is the specific and vigorous treatment of the underlying disorder. In some cases DIC will completely resolve within hours after resolution of the underlying condition (e.g., appropriate control of sepsis with antimicrobials). However, in other cases supportive measures are required to control the DIC until the underlying condition is resolved (e.g., the use of all- trans -retinoic acid and chemotherapy for the treatment of acute promyelocytic leukemia and DIC. ) Therapeutic interventions remain controversial and must be individualized according to the underlying basis for the DIC and severity of the clinical symptoms. For example, in nonovert DIC, children do not usually require therapy for the DIC itself. However, in the presence of uncontrolled overt DIC, therapeutic intervention including blood replacement products may be indicated to improve hemostasis while waiting for effective therapy for the underlying condition. Treatment modalities investigated include blood component therapy, anticoagulants, restoration of natural anticoagulant pathways, and other agents.

Pathophysiology

The liver is the main site of synthesis for most hemostatic components. However, the hemostatic impairment in liver disease involves a variety of mechanisms, including impaired hepatic synthesis, activation of the coagulation and fibrinolytic systems, poor clearance of activated hemostatic components, loss of hemostatic proteins into ascitic fluid, concurrent VK deficiency, thrombocytopenia, and impaired platelet function. When both procoagulants and anticoagulants are reduced, hemostatic dysregulation results in both a propensity to hemorrhage and a propensity to thrombose. Along with reduced synthesis there may be secretion of abnormal forms of the hemostatic proteins that may function as inhibitors to coagulation. For example, abnormal fibrinogens (dysfibrinogenemias) are very common in liver disease. Similarly, VK-dependent proteins (factors II, VII, IX, X, protein C, protein S, and protein Z) decrease in liver disease. However, they may also be secreted in forms with abnormal gamma-carboxylation reactions of the glutamic acid residues on the amino-terminal portion of the protein leading to reduced functional activity. Hypofibrinogenemia may be related to decreased synthesis, or increased consumption (e.g., DIC). However, in patients with acute liver failure, plasminogen activator inhibitor (PAI-1) is increased, shifting the balance toward hypofibrinolysis. This occurs despite elevated levels of tissue plasminogen activator (tPA) that may be secondary to increased release from the activated endothelium or reduced clearance by the diseased liver (or both). The other proteins involved in fibrinolysis (plasminogen, α2-antiplasmin, thrombin activatable fibrinolysis inhibitor, and factor XIII) are typically reduced because of decreased liver synthesis. In addition, several structural manifestations of liver disease can contribute to the bleeding in these patients, including portal hypertension, varices, gastritis, and hemorrhoids.

Clinical Presentation

Clinical symptoms are variable and dependent, to some extent, on the etiology of the liver failure and associated invasive procedures. Symptoms include ecchymosis and petechiae, mucous membrane bleeding, hemorrhage from gastrointestinal varices, and hemorrhage into the abdomen or central nervous system (CNS). However, clinically significant bleeding occurs rarely in acute liver failure (approximately 5% to 10% of cases). Coagulation screening tests (aPTT, PT, thrombin clotting time) are usually prolonged, platelet counts are reduced, and bleeding time is prolonged. Plasma concentrations of FVII; FV; and, less commonly, fibrinogen are decreased. Levels of FVIII may be normal or elevated, possibly reflecting reduced clearance via low-density-lipoprotein receptor-related protein, and can be helpful in distinguishing severe liver disease from DIC. However, both conditions may occur simultaneously. FDPs or D-dimer levels are often increased in hepatic failure and contribute to prolongation of the thrombin clotting time and impaired platelet function. Dysfibrinogenemia will contribute to prolongations of the PT and aPTT, but the thrombin time and reptilase assays are more sensitive. Dysfibrinogenemia may be confirmed by demonstrating an abnormal ratio of clottable fibrinogen (functional assay) to fibrinogen antigen (immunoassay).

Treatment

Treatment for the hemostatic manifestations of severe hepatic failure is difficult. Enhanced hemostasis after replacement therapy is usually transient because adequate volumes of FFP cannot be infused, owing to associated hypervolemia. In addition, many coagulation proteins are rapidly cleared, thereby limiting any beneficial effect. Usually, therapy specifically directed at the coagulopathy is reserved for active bleeding or to facilitate invasive procedures. A common indication for FFP is an international normalized ratio (INR) greater than 2 or a PT prolongation greater than 4 seconds. However, there are no firm guidelines, and some interventions may safely be performed with INR in the 2 to 2.5 range. Although desmopressin can induce the release of factor VIII and von Willebrand factor (VWF) with a shortening of the bleeding time, in randomized trials desmopressin failed to control bleeding from acute variceal hemorrhage or decrease blood loss with hepatectomy. Cryoprecipitate can be administered to increase plasma fibrinogen concentrations if necessary. Secondary VK deficiency owing to impaired VK utilization or impaired VK absorption owing to cholestasis from intrahepatic and extrahepatic biliary atresia requires treatment with VK. Isovolumetric plasmapheresis may aid in restoration of hemostasis by replacing coagulation factors while removing activated clotting factors, tPA, fibrin, and FDPs. Recombinant VIIa has been shown to correct the prolonged PT in nonbleeding cirrhotic patients and has been used to avoid volume overload before invasive procedures likely to cause bleeding. However, randomized trials in the setting of liver biopsy and variceal bleeding have shown either no difference in hemostasis or only early, modest reductions in rebleeding rate but no difference in overall bleeding or transfusion requirements. Larger studies are still required to evaluate the efficacy and safety of this agent in liver disease.

Patients requiring liver transplantation invariably have severe, end-stage hepatic failure with its associated hemorrhagic complications. Additional risk factors that contribute to bleeding in children during transplantation include extensive scar tissue from previous surgery, prolonged duration of the surgery, the need to reduce the size of the donor organ to fit the small patient, dilutional coagulopathy, and excessive activation of the fibrinolytic system during the anhepatic phase. Although treatment with antifibrinolytic agents is an attractive option, this approach should be used with caution because children who undergo liver transplant may later develop either hemorrhagic or thrombotic complications. The prophylactic use of recombinant VIIa to reduce blood loss and transfusion requirements in patients undergoing liver transplantation has been studied in two multicenter randomized controlled trials. These trials failed to demonstrate a benefit to support its use as a universal preemptive therapy for liver transplantation. Recombinant VIIa could be considered in individual cases as “rescue therapy” for patients with life-threatening coagulopathy and bleeding during transplantation or in situations where blood products are unavailable or unacceptable (e.g., the Jehovah witnesses).

Clinical Presentation

Clinical symptoms of VK deficiency include mild to moderate bleeding; ecchymoses; oozing from intravenous (IV) puncture sites; and, rarely, internal bleeding. The primary disorder is usually identified on the basis of the history and physical examination.

Primary VK deficiency in healthy children is uncommon because of a relatively low VK requirement and the widespread distribution of VK in plant and animal tissues. In plants the only important molecular form is phylloquinone (VK1). Bacteria synthesize a family of vitamin K compounds called menaquinones (VK2). The contribution of the microbiologic flora of the gut to VK dietary intake is unknown but may be as high as 50%. Although broad-spectrum antibiotics may reduce VK2 production by intestinal bacteria, VK deficiency is rare in the presence of a normal diet.

Groups of children at high risk for VK deficiency include breastfed newborns, chronically ill children with an inadequate dietary intake of VK, children with disorders that interfere with the absorption of VK (e.g., diarrhea, cystic fibrosis, cholestatic liver disease, celiac disease), and children with poor nutrition who are receiving broad-spectrum antibiotics. Cystic fibrosis, biliary atresia, and obstructive jaundice interfere with the absorption of fat-soluble vitamins and interfere with transport to the liver, with resultant VK deficiency. Therapeutic drugs can interfere with VK metabolism (e.g., phenytoin, warfarin). However, at least in the case of warfarin administration, this is an expected side effect. Accidental exposure to supratherapeutic doses may occur in small children with access to warfarin in the home. Anticoagulant rodenticides can be another source of accidental exposure. Owing to the emergence of warfarin-resistant strains of rats, newer “long-acting” second-generation compounds have been utilized. These so-called “superwarfarins” have higher affinity for vitamin K1-2,3 epoxide reductase, are able to disrupt the vitamin K1-epoxide cycle at more than one point, exhibit hepatic accumulation, and have unusually long biological half-lives as a result of their high lipid solubility and enterohepatic circulation. After accidental ingestion these compounds can cause anticoagulation for several days or even weeks. However, in most cases involving small children, the exposure is low and bleeding manifestations are rare. VK deficiency has been described in bone marrow transplant and oncology patients in whom the etiology is multifactorial as a result of drug antagonism, liver dysfunction, fat malabsorption, anorexia, or inadequate dietary intake. A study of children evaluated before undergoing bone marrow transplantation identified 31% (8 of 26) with evidence of VK deficiency (as evidenced by circulating PIVKA-II), although only one patient had a prolonged PT, highlighting that the PT alone is an insensitive marker of VK deficiency. Of the eight affected patients, six exhibited bleeding manifestations peri-transplant.

Laboratory Diagnosis

The PT and aPTT may both be abnormal in VK deficiency but should correct in a 1 : 1 mix with normal plasma. Other acquired or congenital coagulopathies can give similar screening test abnormalities. Therefore specific coagulation factor assays must be performed. The finding of more than one VK-dependent factor deficiency should increase the suspicion of an acquired deficiency. A normal factor V in addition to normal liver function studies would suggest that there is no significant liver disease underlying the presentation. A normal FVIII and fibrinogen level and absence of elevated D-dimers would make DIC unlikely. However, VK deficiency can complicate other coagulopathies, such as DIC or liver disease. If there is any doubt about the diagnosis, the patient should receive VK therapy in conjunction with other supportive care.

Treatment

The route and specific type of therapy are dictated by the urgency of the clinical situation and potential side effects of therapy. For example, severe anaphylactoid reactions, although rare, have complicated IV VK administration, even when the solution is diluted and infused slowly. Therefore IV administration of VK, at a rate no faster than 1 mg per minute, should be restricted to those situations in which other routes are not feasible and the risk is justified. Intramuscular VK is not recommended because it can result in pain, swelling, and hematoma formation. The preferred systemic route is subcutaneous because it is safe and effective. Oral VK is effective if absorption is unimpaired. Although oral administration is generally thought to produce a slower correction of the PT (6 to 8 hours) compared with parenteral VK (2 to 6 hours), a study in adults suggested that the oral route may actually be faster, at least in reversing the effect of warfarin.

Asymptomatic patients with mildly abnormal coagulation results that are presumed secondary to VK deficiency should be given VK subcutaneously (1 to 5 mg depending on size). This approach is both therapeutic and diagnostic, with coagulation abnormality correction within 2 to 6 hours. A patient bleeding because of VK deficiency should receive 2 to 10 mg of VK subcutaneously. FFP (10 to 20 mL/kg) is particularly useful when the precise nature of the coagulopathy is unknown and bleeding is severe. However, the amount of plasma needed for total correction of a severe VK deficiency is so great that it may result in volume overload. A patient with a life-threatening hemorrhage or an intracranial hemorrhage (ICH) would likely benefit from prothrombin complex concentrates at a minimum dose of 50 units/kg, in addition to systemic VK (5 to 20 mg). Prothrombin complex concentrates contain relatively uniform amounts of factors II, IX, and X, with amounts of factor VII/VIIa varying. Recombinant VIIa has been used anecdotally.

Prevention

Prophylactic VK should be given to patients at risk, such as patients with inadequate nutrition and those who are receiving broad-spectrum antibiotics. Most patients requiring total parenteral nutrition (TPN) are supplemented with VK. There has been concern in the past that maternal anticonvulsant therapy may be associated with increased risk of neonatal bleeding linked to enzymatic degradation of VK. This has prompted recommendations for VK prophylaxis to pregnant mothers on anticonvulsants. However, recent studies have demonstrated that the incidence of bleeding in infants exposed to these drugs antenatally is not higher than controls and have shown no benefit to routine VK prophylaxis.

Acquired Inhibitors to Factor VIII

Anti–factor VIII autoantibodies are rare in children but can result in severe bleeding and significant morbidity. They are associated with underlying medical conditions in half of those affected, including malignancy, autoimmune disease, lymphoproliferative disorders, and drugs (e.g., penicillin). Patients can present with bleeding symptoms ranging from easy bruising to intracranial hemorrhage. In one patient the clinical course was also complicated by nephrotic syndrome. Laboratory screening studies will show a prolonged aPTT that does not fully correct on mixing with normal plasma in a 1 : 1 mix (“Inhibitor Screen”). In addition, this can be distinguished from an LA by performing the aPTT 1 : 1 mix again with an incubation phase (typically at least 30 minutes at 37° C) in which the aPTT will show further prolongation indicating progressive neutralization of factor VIII provided by the normal plasma mixing. There will be no significant additional prolongation seen on incubation in the presence of an LA. In contrast to congenital hemophilia with inhibitors, these antibodies typically demonstrate type II (nonlinear) inactivation kinetics. Thus the baseline factor VIII levels may be higher than 1% despite high titer inhibitory antibodies.

Treatment is two-pronged, directed at stopping the bleeding and eradicating the inhibitor. Hemostasis can be achieved with high doses of factor VIII concentrates, activated prothrombin complex concentrates (APCC), and recombinant VIIa. Immunosuppression may be accomplished with steroids alone or in combination with mycophenolate-mofetil, rituximab, γ-globulin, or cytotoxic agents such as cyclophosphamide. Inhibitors have also been eradicated through extracorporeal immunoadsorption and immune tolerance with regular exposure to high-dose factor VIII infusions. Review of the available literature suggests that, in contrast to adults, anti–factor VIII autoantibodies in children may resolve more quickly and easily and do not necessarily require steroids and cytotoxic agents. Recombinant factor VIII should be considered in the initial treatment with additional hemostatic support from APCCs and recombinant VIIa as needed. Withdrawal of instigating drugs such as penicillin may also facilitate resolution.

Acquired Inhibitors to Factor IX

Few cases of spontaneous factor IX inhibitors have been described in nonhemophiliac patients, and most adult cases have been related to underlying systemic disorders such as systemic lupus erythematosus, hepatitis, multiple sclerosis, rheumatic fever, collagen vascular disease, postpartum status, and postprostatectomy status. Reports in children are limited to a few case reports. Bleeding manifestations included cutaneous ecchymoses and soft tissue hematomas. Diagnostic studies are similar to those with anti–factor VIII inhibitors. Treatments have included corticosteroids, γ-globulin, and cyclophosphamide, with rapid resolution of the inhibitor. One child had a spontaneous resolution. Recombinant factor IX and recombinant VIIa can be considered for acute management of bleeding.

Acquired Inhibitors to Factor V

Most cases of inhibitors directed against factor V develop as a result of risk factors such as surgical procedures, antibiotic administration (typically the β-lactam group), blood transfusions, cancers, and autoimmune disorders. However, the majority of cases arise after exposure to bovine thrombin. Topical preparations of bovine thrombin are widely used for surgical hemostasis and contain fibrinogen as well as small amounts of factor V and other proteins. Acquired inhibitors to coagulation factors, as a consequence of exposure to this highly immunogenic agent, is a frequent occurrence, albeit often unrecognized. In this context antibodies directed against factor V are most frequent, although anti-prothrombin and anti–factor X antibodies have also been described. The incidence of symptomatic inhibitors is not known. In a study of 151 adult patients exposed to bovine thrombin during cardiac surgery, 56% of the patients developed antibodies directed against human coagulation proteins. However, adverse clinical outcomes did not correlate with antibody formation. A literature review identified 12 cases of inhibitors in pediatric patients after thrombin exposure. In eight cases the antibodies were directed against human coagulation proteins; five of these patients had hemorrhagic complications. Bleeding manifestations included cutaneous, gastrointestinal, pulmonary, and cerebral hemorrhages. Patients exhibited both PT and aPTT prolongations and mixing studies consistent with an inhibitor. Specific factor activity assays revealed the target for the inhibitor. However, there was no correlation between laboratory studies and clinical bleeding. Corticosteroids and γ-globulin have been used with resolution of the inhibitor over days to weeks. Platelet transfusions are another option, insofar as approximately 20% of factor V activity is present in platelet granules that are shielded from circulating antibodies. Coagulation factor inhibitors should be suspected in any postoperative patient exposed to topical bovine thrombin presenting with a prolonged PT and aPTT.

Acquired Inhibitors to Other Coagulation Factors

Antifibrinogen antibodies are extremely rare and may or may not be associated with clinical bleeding. An increased rate of fibrinogen antibodies has been described in pregnant and peripartum women. Acquired inhibitors directed against coagulation factors VII and X have been observed with malignancies, autoimmune disorders, and drug exposure. In addition, acquired inhibitors against factor XI have been rarely reported, including in patients with underlying SLE.

Acquired von Willebrand Syndrome

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder with clinical and laboratory findings similar to those in inheritedVWD. Since its original description in 1968 in a patient with systemic lupus erythematosus, fewer than 700 cases have been reported. AVWS usually occurs in individuals with no personal or family history of VWD and is accompanied by bleeding symptoms in about three quarters of patients, whereas others are diagnosed on the basis of abnormalities found during routine hemostasis screening tests. As would be expected, mucocutaneous bleeding symptoms predominate. Underlying disorders are identified frequently and fall into the following main categories: lymphoproliferative and myeloproliferative disorders; solid tumors; immunologic and cardiovascular disorders; and other miscellaneous conditions, including drug associations. It is typically a syndrome of advanced age, although it has also been reported in children, and is primarily associated with congenital heart disease, collagen vascular diseases, Wilms tumor, hypothyroidism, and use of certain drugs. Drug-associated AVWS has been described in up to 20% of pediatric patients who received valproic acid, although bleeding manifestations were mild and did not require discontinuation of the anticonvulsant.

Four main pathogenic mechanisms can lead to AVWS: (1) reduced VWF synthesis (as seen in severe hypothyroidism or certain drugs (e.g., valproic acid); (2) inhibition or clearance by paraproteins or autoimmune inhibitors (this has been observed in association with B-cell lymphomas, monoclonal gammopathies, multiple myeloma, and autoimmune disorders); (3) absorption of VWF high-molecular-weight multimers onto malignant cell clones or platelets; (4) increased shear stress and proteolysis, as may occur with aortic stenosis, artificial heart valves, left ventricular assist devices, or other cardiac defects with disturbed flow. Laboratory studies rely on detecting abnormally reduced functional VWF studies (ristocetin cofactor activity, collagen-binding assay) in comparison to VWF antigen and a selective deficiency of the high-molecular-weight multimers. A search for evidence of an inhibitor should be performed by measuring VWF activity after mixing experiments involving patient plasma and normal plasma incubated at 37° C.

The three goals of treatment should be control of active bleeding, prevention of bleeding with necessary invasive procedures, and treatment of the underlying disease. Desmopressin and factor VIII/VWF concentrates have provided only short-term control of bleeding in the presence of autoantibodies. In those cases γ-globulin, corticosteroids, or other immunosuppressive agents have been administered. Recombinant VIIa may also be effective with this presentation. In noninhibitor-associated AVWS, factor VIII/VWF concentrates are effective in most patients, although the half-life may be shorter. Desmopressin may be used to control bleeding, although there is a relatively lower rate of success among patients with cardiovascular or myeloproliferative disorders. Ultimately, normalization of hemostasis may not be seen until the underlying precipitating condition is treated effectively (e.g., with surgery or chemotherapy for Wilms tumor).

Epidemiology

Several national or international registries in the past two decades have evaluated the occurrence of venous thromboembolism (VTE) in children. From these data a cumulative incidence of 0.07 per 10,000 (5.3 per 10,000 hospitalizations) was estimated for extremity deep venous thrombosis (DVT) and PE among non-neonatal Canadian children, and an incidence rate of 0.14 per 10,000 children per year was reported for all VTE in the Netherlands. In 2004 evaluation of the National Hospital Discharge Survey and census data for all VTE in the United States disclosed an overall incidence rate of 0.49 per 10,000 per year. More recently, an analysis of the Pediatric Health Information System database revealed a nearly 70% increase in the diagnosis of VTE among hospitalized children, as defined by International Classification of Disease-9 diagnostic codes, over a 7-year period from 2001 to 2007.

Closer examination of epidemiologic data reveals that the age distribution of the incidence rate for VTE in children is bimodal, with peak rates in the neonatal period and adolescence. With regard to the newborn period, the cumulative incidence of venous or arterial TE was reported to be 0.51 per 10,000 births in Germany and 24 per 10,000 admissions to neonatal intensive care units in Southern Ontario. The Dutch registry indicated a VTE-specific incidence rate of 14.5 per 10,000 per year in the neonatal period, approximately 100 times greater than the overall rate in childhood. Among adolescents 15 to 17 years of age, the VTE-specific incidence rate in the United States was determined to be 1.1 per 10,000 per year, a rate nearly threefold that observed overall in childhood.

Although differing selection criteria have contributed to the considerable variability in occurrence estimates in the preceding example, it is clear that the incidence of VTE in children is lower than that among middle-aged and elderly adults. Nevertheless, as discussed later in this chapter, the sequelae of VTE in children, particularly with regard to the post-thrombotic syndrome (PTS), appear to be at least as frequent and severe as those among adults.

Etiology

The pathogenesis of VTE can be readily appreciated by considering Virchow’s triad, consisting of venous stasis, endothelial damage, and the hypercoagulable state. In children, greater than 90% of VTE are risk-associated (compared with approximately 60% in adults), with risk factors often disclosed from more than one component of this triad. Specific examples of VTE risk factors in children are shown in Figure 35-1 . Among the most common of clinical prothrombotic risk factors in childhood is an indwelling central venous catheter. Over 50% of cases of DVT in children and over 80% of cases in newborns occur in association with central venous catheters. The reported cumulative incidence or prevalence of catheter-related thrombosis (CRT) in children receiving home TPN ranges widely, from 1% to 80% ; this broad variation is largely influenced by differing study designs, selection criteria, and diagnostic imaging modalities. The presence of an indwelling central venous catheter, the underlying malignancy or disorder for which bone marrow transplantation was undertaken, and congenital cardiac disease and its corrective surgery were all highly prevalent in the Canadian pediatric thrombosis registry, whereas underlying infectious illness and the presence of an indwelling central venous catheter were identified as pervasive clinical risk factors in a recent cohort study analysis from the United States. It is likely that differences in the composition of referral populations strongly contribute to differences in the composition of VTE etiologies across major pediatric thrombosis centers.

Clinical prothrombotic risk factors: Virchow’s triad applied to venous thromboembolism in children.

With regard to blood-based risk factors for VTE, thrombophilic conditions (e.g., severe anticoagulant deficiencies , antiphospholipid antibodies [APAs]) in children are frequently acquired, and severe inherited thrombophilias are rare. By contrast, mild congenital thrombophilic traits (e.g., the factor V Leiden and prothrombin 20210 mutations) are common in Caucasian children, as in adults (see Chapter 33 ). Thrombophilia is potentially caused by any alteration in hemostatic balance that increases thrombin production, enhances platelet activation or aggregation, mediates endothelial activation or damage, or inhibits fibrinolysis. Common examples of acquired thrombophilia in children include increased factor VIII activity with significant infection and inflammatory states, anticoagulant deficiencies resulting from consumption in bacterial sepsis and DIC, the production of inhibitory antibodies in acute viral infection, and parainfectious development of APA. To provide an appreciation of the magnitude of VTE risk increase associated with several congenital or genetically influenced thrombophilia traits, population-based VTE risk estimates derived from the adult literature are shown in Table 35-1 . For example, the addition of standard-dose estrogen oral contraceptive pill to underlying heterozygous factor V Leiden substantially increases the risk for VTE from a baseline risk of 15 per 10,000 U.S. females aged 15 to 17 years per year to a risk of more than 500 per 10,000 (or 5%) per year.

Clinical Presentation

The degree of clinical suspicion for acute VTE in children should be principally influenced by clinical prothrombotic risk factors and family history of early VTE or other vascular disease elicited on thorough interview, known thrombophilia traits and risk factors, and clinical signs and symptoms. The signs and symptoms of VTE depend on anatomic location and organ systems affected and are influenced by characteristics of veno-occlusiveness and chronicity. The classic manifestation of acute extremity DVT is painful unilateral limb swelling. The lack of other physical examination findings (e.g., Homans sign, the presence of a palpable cord in the popliteal fossa in the clinical evaluation for lower extremity DVT) should not reduce the clinical index of suspicion of DVT. In upper extremity DVT with extension into, and occlusion of, the superior vena cava (SVC), signs and symptoms may include swelling of the neck and face, bilateral periorbital edema, and headache. PE is classically manifested by sudden-onset, unexplained shortness of breath with pleuritic chest pain. When PE is proximal or extensive bilaterally in the distal pulmonary arterial tree, hypoxemia is often demonstrated. Associated right-sided heart failure may manifest with hepatomegaly and peripheral edema. Proximal PE and especially saddle embolus can present with cyanosis or sudden collapse. However, in many cases PE may be asymptomatic or produce only subtle symptoms in children, especially when involving limited segmental branches of the pulmonary arteries and not eliciting a significant pleural reaction. In one retrospective series 14% of affected children had no clinical symptoms attributable to PE. Acute cerebral sinovenous thrombosis (CSVT) may present with unusually severe and persistent headache, blurred vision, neurologic signs (e.g., cranial nerve palsy, papilledema), or seizures. The classic findings in renal vein thrombosis (RVT) are hematuria and thrombocytopenia, sometimes associated with uremia (especially when bilateral). Presenting signs include oliguria (especially when bilateral), and in the neonatal period (the time at which RVT is most common during childhood) a flank mass is often palpable on examination. RVT in older children is often associated with nephrotic syndrome (a risk factor for VTE in general owing to the loss of anticoagulant proteins) and hence may present with associated stigmata of peripheral and periorbital edema when diagnosed at presentation of nephrosis. Thrombocytopenia may be a presenting manifestation not only of RVT but also of intracardiac (e.g., right atrial) thrombosis, especially as a CRT associated with sepsis. Isolated intracardiac thrombosis in association with cardiac surgery or central venous catheter placement is most often asymptomatic. Portal vein thrombosis is one of the most common causes of portal hypertension in children, characteristically presenting with splenomegaly, and is associated with findings of hypersplenism (anemia, neutropenia, and thrombocytopenia); gastrointestinal bleeding at presentation typically signals the presence of gastroesophageal varices. Internal jugular vein thrombosis may manifest with neck pain or swelling, and when part of Lemierre syndrome is classically also associated with fever, trismus, pain on lateral neck rotation, and a palpable mass in the lateral triangle of the neck.

Chronic VTE may be diagnosed incidentally without signs or symptoms (as sometimes occurs for CSVT during unrelated brain imaging), or it may present with signs and symptoms of chronic venous obstruction or PTS, including pain and edema of dependent extremities, dilated superficial collateral veins, venous stasis dermatitis, and frank ulceration of the skin.

Diagnosis

Whereas venography has historically been the gold standard for diagnosis of venous thrombosis, this modality is invasive and has become less prevalent in recent years with the development of effective noninvasive or minimally invasive radiologic imaging technologies. Radiologic imaging is used not only to confirm the clinical diagnosis of VTE but also to define both the extent and occlusiveness of thrombosis. For suspected DVT of the distal or proximal lower extremity, compression ultrasound with Doppler is typically employed for objective confirmation. When the thrombus may affect or extend into deep pelvic or abdominal veins, computed tomography (CT) is often necessary. For circumstances in which radiation exposure is a significant concern or alternative diagnoses (e.g., myositis) are being evaluated, magnetic resonance imaging (MRI) may alternatively be employed. Magnetic resonance venography may be useful in documenting May-Thurner syndrome, an uncommon cause of all lower extremity DVT (but seemingly a common cause of spontaneous or minimally provoked left-sided iliofemoral DVT) in which the iliac vein is compressed by an overriding right common iliac artery. In suspected DVT of the upper extremity, compression ultrasound with Doppler effectively evaluates the limb, but echocardiography or CT is required to disclose involvement of more central vasculature (e.g., right atrial thrombosis). In the case of asymptomatic nonocclusive extremity DVT, venography may be used as an alternative to CT. It is important to recognize that venography (in which radiographic contrast is administered into a vein in the limb) should not be confused with “line-o-grams” (in which radiographic contrast is instilled into a central venous catheter). The latter studies are useful for delineating catheter tip thrombi but cannot reliably detect DVT along the intravascular length of a central venous catheter. Magnetic resonance venography has replaced conventional venography in most centers. However, dynamic conventional venography may be required to evaluate for thoracic outlet syndrome (mechanical compression and entrapment of the subclavian vessels in the region of the thoracic outlet, whether owing to a congenitally narrow subclavian passage between the clavicle, first rib, and a hypertrophied subclavius muscle in athletes [Paget-Schroetter syndrome] or to an accessory rib). To establish a diagnosis of DVT of the jugular venous system, compression ultrasound with Doppler is typically sufficient.

PE in children is commonly diagnosed by spiral CT or, alternatively, by ventilation-perfusion scan, the latter generally being suboptimal in cases wherein other lung pathology exists and at centers wherein availability of, and expertise with, this modality are limited. CSVT is typically diagnosed by standard CT or CT venography, and alternatively by MRI or magnetic resonance venography. The diagnosis of RVT is most often made clinically in neonates and is supported by Doppler ultrasound findings of intrarenal vascular resistive indices; however, in some cases a discrete thrombus may be suggested by Doppler ultrasound, especially when extending into the inferior vena cava. When RVT occurs in older children, Doppler ultrasound or CT is often diagnostic. Similarly, portal vein thrombosis is typically visualized by Doppler ultrasound or CT.

When new-onset venous thrombosis is being evaluated in patients in areas of anatomic abnormality of the venous system (e.g., extensive collateral venous circulation caused by a prior VTE episode, May-Thurner anomaly, atretic inferior vena cava with azygous continuation), more sensitive methods such as CT or magnetic resonance venography are often required to adequately delineate the vascular anatomy as well as the presence, extent, and occlusiveness of thrombosis.

Diagnostic laboratory evaluation for pediatric acute VTE includes a complete blood count, evaluation for thrombophilia (see “ Etiology ”), and beta-human chorionic gonadotropin in postmenarchal women. Additional laboratory studies may be warranted depending on associated medical conditions and VTE involvement of specific organ systems.

Treatment

A summary of conventional antithrombotic agents and corresponding target anticoagulant levels, based on recent pediatric recommendations, is provided in Table 35-2 for both initial (i.e., acute phase) and “extended” (i.e., subacute phase) treatment. Conventional anticoagulants attenuate hypercoagulability, decreasing the risk of thrombus progression and embolism, and rely on intrinsic fibrinolytic mechanisms to break up the thrombus over time. The most commonly employed conventional anticoagulants in children include heparins and warfarin. Heparins, including unfractionated heparin and low-molecular-weight heparin (LMWH), enhance the activity of AT, an intrinsic anticoagulant that serves as a key inhibitor of thrombin. Warfarin acts through antagonism of VK, thereby interfering with γ-carboxylation of the VK-dependent procoagulant factors II, VII, IX, and X.

Outcomes

Complications of VTEs can occur both acutely and over the long term and are germane to both CRT and non-CRT. Short-term adverse outcomes include major hemorrhagic complications of antithrombotic interventions, as well as of the thrombotic event itself (e.g., post-thrombotic hemorrhage in the brain or adrenal gland); thrombus progression (involvement of previously unaffected contiguous venous segments, or change from nonocclusive to occlusive); early recurrent VTE (including DVT and PE ); SVC syndrome in DVT of the upper venous system ; acute renal insufficiency in RVT ; catheter-related sepsis, PE, and catheter malfunction (sometimes necessitating surgical replacement) in CRT; severe acute venous insufficiency leading to venous infarction with limb gangrene in rare cases of occlusive DVT involving the extremities; and death from hemodynamic instability in extensive intracardiac thrombosis or proximal PE. Long-term adverse outcomes in pediatric VTE have been previously reviewed and include recurrent VTE; chronic hypertension and renal insufficiency in RVT; variceal hemorrhage in portal vein thrombosis ; chronic SVC syndrome in CRT involving SVC occlusion; loss of availability for venous access in recurrent or extensive CRT of the upper venous system; and development of PTS, a condition of chronic venous insufficiency following DVT. The manifestations of PTS include (in order of increasing severity) edema, visibly dilated superficial collateral veins, venous stasis dermatitis, and venous stasis ulcers ( Fig. 35-2 ). Given the long-term and sometimes lifelong risks of disease sequelae as in RVT and functional impairment as in PTS, venous thrombosis is best considered a chronic disorder in children.

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