Under normal homeostatic conditions, the human body is at a constant balance between clot formation and destruction. Physiologic hemostasis occurs as a result of a complex interaction among platelets, the vascular endothelium, the coagulation cascade, and the fibrinolytic system. Any disorder or xenobiotic that alters this equilibrium can produce either excessive thrombosis or hemorrhage. Numerous pharmacologic agents have been developed to prevent thrombus formation by interfering with platelet adhesion or aggregation, or by interfering with the clotting cascade. Numerous additional drugs, including those working by novel mechanisms, are in various stages of development.1
Thrombus formation involves an interaction between the coagulation cascade and platelets. The coagulation cascade (Figure 178-1) involves interplay between the contact activation pathway (formerly called the intrinsic system) and the tissue factor pathway (formerly referred to as the extrinsic system). This interaction ultimately produces thrombin, a critical enzyme in the coagulation system.2,3 The binding of tissue factor to factor VII activates the latter (factor VIIa), which subsequently catalyzes the conversion of factors IX and X to their active forms. The common pathway begins with the conversion of factor X to its active form (Xa), which in turn converts prothrombin to thrombin, which ultimately catalyzes the conversion of fibrinogen to fibrin.
Simultaneously, clot formation is also occurring at the local level, at the site of the damaged endothelium. The damaged endothelium releases endothelin, which results in vasoconstriction, one of the first steps in achieving hemostasis. The damaged endothelium also expresses tissue factor, ensuing platelet binding to the endothelium.4,5 Platelets are secured to the vascular injury via glycoprotein Ib/V/IX. Von Willebrand factor (VWF) is critical for the integrity of this glycoprotein complex.6 Platelet adhesion involves platelets binding to the damaged endothelium VWF.6,7 Platelet activation occurs in response to numerous mediators, including adenosine diphosphate (ADP), thromboxane A2, epinephrine, and thrombin.6 Ultimately, platelet aggregation occurs via the glycoprotein IIb/IIIa receptor.8 The absolute stability of the aggregated platelets requires fibrin connect the glycoprotein IIb/IIIa complexes between platelets.6
Because thrombus development is complex with numerous steps required for successful formation, multiple different classes of drugs, each with unique mechanisms of action have been developed to halt this process. This chapter focuses on different drugs the pediatric patient may be administered therapeutically or accidentally. The pathophysiology of each drug along with laboratory monitoring and treatment strategies are discussed. As specific recommendations for the management of pediatric patients are often lacking, recommendations are extrapolated from the adult literature, where applicable, and adjusted for pediatric patients when appropriate.
Vitamin K antagonists are used medically (e.g. warfarin) as well as industrially (e.g. long-acting anticoagulant rodenticides [LAAR], or “superwarfarins”) (Figure 178-2).
Vitamin K antagonists inhibit the vitamin K cycle, thereby resulting in accumulation of inactive vitamin K precursors. Specifically, warfarin inhibits vitamin K epoxide reductase, an enzyme encoded for by the VKORC1 gene.9,10 Normally, vitamin K quinol, a reduced form of vitamin K becomes oxidized to the inactive vitamin 2,3 epoxide via gamma glutamyl carboxylase. This leads to the conversion of the inactive vitamin K dependent clotting factors (II, VII, IX, X, protein C, and protein S) to their active forms.
Factor VII has the shortest half-life of all clotting factors, approximately 6 hours. Because factor VII concentration needs to be as low as approximately 30% of normal values before any increase in the prothrombin time (PT)/international normalized ratio (INR) occurs, there will be no symptoms, and no laboratory evidence of an ingestion for at least 2 to 3 half-lives, namely 12 to 18 hours postingestion. The peak INR may not increase for several days. Children 6 years and younger require increased dosing of warfarin per body weight and require a longer time before achieving a therapeutic INR.9
There should be no toxicity manifestations immediately following an ingestion, other than possibly mild gastrointestinal upset. Specifically, however, coagulation abnormalities should not manifest early in a vitamin K antagonist naive individual. The primary manifestation of toxicity is bleeding, which can be severe or life threatening.
The differential diagnosis of a coagulopathy in a pediatric patient includes various factor deficiencies, liver failure, rattlesnake envenomation, and vitamin K deficiency. Conditions such as disseminated intravascular coagulation (DIC) should be associated with concurrent thrombocytopenia, which is notably absent from vitamin K antagonist-induced bleeding. In addition, the fibrinogen should be normal with warfarin toxicity, which may differentiate this condition from other etiologies of coagulopathy.
Any patient with evidence of bleeding or intentional overdose of anticoagulants should be referred to an emergency department, and undergo a complete evaluation, including measurement of coagulation tests. Patients with unintentional ingestion of less than 1 mg LAAR can be observed at home without laboratory monitoring, including those ingestions by pediatric patients.11 Patients who are asymptomatic following an unintentional ingestion of more than 1 mg of LAAR, who are not normally on anticoagulant medications, should be evaluated for a coagulopathy 48 to 72 hours after exposure.11
The need for reversal of the elevated INR in a patient depends on the need for anticoagulation, the presence or absence of bleeding, and the degree of elevation. In a patient with life-threatening hemorrhage, immediate warfarin reversal is indicated with the combination of vitamin K as well as either fresh frozen plasma (FFP) or prothrombin complex concentrates (PCC).
In the case of a pediatric patient who ingests warfarin, prophylactic vitamin K should not be administered, but rather follow the INR and if it becomes supratherapeutic, vitamin K should be administered. Published guidelines exist for the management of patients with supratherapeutic INRs (Table 178-1).1,12 Though not explicitly stated, these guidelines were not designed for pediatric patients, those with intentional overdoses of warfarin, and those with superwarfarin ingestions. Rather, these guidelines are designed for the patient on therapeutic warfarin who develops a supratherapeutic INR as a result of excessive dosing or a drug-drug interaction. Unlike FFP or PCCs, reversal of an elevated supratherapeutic INR with vitamin K does not work immediately. With high-dose intravenous administration, vitamin K can begin reversal within 2 hours, but full reversal is not achieved until 24 hours.13 In contrast, the reversal provided by either FFP or PCCs begins rapidly, but provides only a temporary reversal. Thus, as a general rule, if FFP or PCCs are given, they should be given concurrently with vitamin K and not as a substitute for vitamin K. Vitamin K should be given orally or intravenously. Given intravenous vitamin K begins faster than oral vitamin K, the intravenous route is preferred for life-threatening hemorrhage.13 Intravenous vitamin K is potentially associated with anaphylactoid reactions. However, this reaction is relatively uncommon, occurring in approximately 3:100,000 doses. It appears to be more common with rapid administration or administration of formulations containing castor oil.14 The efficacy of subcutaneous vitamin K for warfarin reversal is equivalent to placebo.15
INR <4.5, no bleeding | Hold warfarin | INR 2-5, no bleeding | Lower or omit dose |
INR 4.5-10, no bleeding | Hold warfarin Vitamin K (1-2 mg PO or 0.5-1 mg IV) if bleeding risk high | INR 5-9, no bleeding | Hold 1-2 doses. OR Vitamin K (1-2.5 mg PO) |
INR >10, no bleeding | Hold warfarin Vitamin K (3-5 mg PO or IV) Consider 3 complex PCC | INR >9, no bleeding | Hold warfarin; Vitamin K (5 mg PO) |
| INR >1.5 with life-threatening bleeding | Vitamin K (5-10 mg IV AND 3-complex PCC and FFP) | Serious bleeding | Hold warfarin Vitamin K (10 mg IV, supplemented by FFP, PCC, or rVIIa) |
| INR >2 with clinically significant, but not life-threatening bleeding | Hold warfarin And vitamin K (5-10 mg IV) And 3 complex PCC | Life-threatening bleeding | Hold warfarin Give FFP, PCC, or rVIIa, supplemented by vitamin K (10 mg IV) |
| Any INR with minor bleeding | Hold warfarin If bleeding risk high or INR, 4.5, consider vitamin K (1-2 mg PO or 0.5-1 mg IV) |
Fresh frozen plasma is the most widely used factor replacement for urgent reversal of vitamin K anticoagulation. It contains all factors. Its use should be reserved for those patients with a supratherapeutic INR with life-threatening bleeding; the pediatric dosing is 10 mL/kg. Adverse effects with FFP include transmission of infectious diseases, volume overload, and transfusion-associated acute lung injury. More recently, PCCs have been recommended over FFP for reversal of warfarin-associated hemorrhage. However, it should be noted that the evidence for this recommendation is weak (level 2c). Prothrombin complex concentrates include three-factor (II, IX, and X) and four-factor concentrates (II, VII, IX, and X), and may be associated with higher rates of venous thromboembolism than FFP.12 Furthermore, because PCCs have a small amount of heparin, it should be administered cautiously, if at all, to patients with a history of heparin-induced thrombocytopenia.12 The PCCs do have several advantages over FFP, lack of a need to thaw the preparation and no need for ABO compatibility. The PCCs have less risk of viral transmission, although the risk is still not zero.16 In addition, because the concentration of the vitamin K dependent clotting factors is much greater with PCCs than with FFP, the required volume of administration is less with PCC than FFP.16
Patients with warfarin overdose often receive higher doses of vitamin K than would be expected strictly based on guidelines (unpublished data). Furthermore, patients with superwarfarin ingestions frequently require extremely large doses of vitamin K, often for prolonged periods of time.17-19 For pediatric patients who ingest warfarin who are not supposed to be on anticoagulation, a reasonable approach would be to administer vitamin K (0.5 to 2 mg PO or IV for infants or children with significant but non-life-threatening bleeding, and 5 mg IV for life-threatening bleeding). Adolescents and adults should receive 5 to 10 mg PO or IV for life-threatening bleeding with a supratherapeutic INR. For those patients whom anticoagulation is needed, lower, more frequent doses may be prudent to avoid over-reversal. Under no circumstances should intravenous vitamin K be administered as a bolus, but rather infused over 20 to 30 minutes to reduce the risk of an anaphylactoid reaction.
For the asymptomatic patient without bleeding with an elevated INR, there is no data that admission is mandatory.20 However, it may be indicated on a case-by-case basis (see Special Considerations below).
Consultation with the regional poison control center (800-222-1222) or a medical toxicologist is recommended for optimal management of individual patients.
There is no data suggesting that inpatient admission is mandated for a patient with an elevated INR.20 However, each case should be evaluated with discretion, and in a toddler who is learning to walk, admission may be indicated if there is significant concern regarding potential falls and head trauma at home.
In recent years, numerous agents have been developed as a potential alternative to vitamin K antagonists. The direct thrombin inhibitors (DTIs) are one of these new drug classes. Unlike the heparins, which inhibit thrombin indirectly via their action on antithrombin, DTIs inhibit thrombin directly, thus producing more predictable pharmacokinetics and pharmacodynamics.9 Parenterally administered DTIs include lepirudin, desirudin, bivalirudin, and argatroban, while dabigatran is an orally administered DTI. Dabigatran is administered as dabigatran etexilate, an inactive prodrug, which is rapidly absorbed in the acidic gastrointestinal tract, and converted to dabigatran by hepatic and plasma esterases.21 Lepirudin, and another DTI, ximelagatran, have been withdrawn from the market.
The direct thrombin inhibitors have been used for prophylaxis and treatment of venous thromboembolism, heparin-induced thrombocytopenia, acute coronary syndromes, and prophylaxis of thrombus formation in non-valvular atrial fibrilation.22
Thrombin can be inhibited by binding to a drug at one of three sites: the active site, exosite 1, and exosite 2. Unlike the heparins, which inhibit thrombin indirectly and require a cofactor for their inhibition, the direct thrombin inhibitors are able to independently inhibit thrombin.22,23 Heparin products inhibit free thrombin indirectly by binding simultaneously to antithrombin and exosite 2. Argatroban and dabigatran interact with the active site of thrombin alone, while lepirudin and desirudin bind to exosite 1.
The primary expected toxicity would be hemorrhage, including gastrointestinal hemorrhage and intracranial hemorrhage. Despite early concerns of excessive hemorrhage with dabigatran, the risk of hemorrhage with therapeutic dosing appears to be equal if not greater with warfarin than with dabigatran.24-26 In one of the largest studies examining therapeutic usage of dabigatran, the risk of bleeding appears to be dose dependent.27
The differential diagnosis of anticoagulation from a direct thrombin inhibitor would be the same as for heparin, namely hereditary or acquired factor deficiencies resulting in a prolongation of the activated thromboplastin time (aPTT).
The preferred laboratory test for monitoring anticoagulation with direct thrombin inhibitors is the thrombin time (TT) or the ecarin clotting time (ECT).28 However, neither the TT nor the ECT are readily available. The aPTT can be used to screen for the presence of direct thrombin inhibitor-induced anticoagulation; a normal aPTT excludes significant anticoagulation.28 However, the aPTT reaches a plateau with direct thrombin inhibitors. Thus, the degree of elevation in the aPTT does not correlate well with the degree of anticoagulation.29 While the PT does have a linear response, the response curve is relatively flat, thus, precluding accurate measurement of the degree of anticoagulation.28 Furthermore, the aPTT response to dabigatran, and likely all direct thrombin inhibitors, is reagent dependent.29
The primary management is supportive. No single reversal agent has clearly been identified as beneficial. There are no evidence-based recommendations for reversal of any of the direct thrombin inhibitors.28,30 The 2011 ACCF/AHA guidelines recommend patients with life-threatening dabigatran-associated hemorrhage receive packed red blood cells and fresh frozen plasma, or surgical interventions to control bleeding.31 While the recommendation for Packed Red Blood Cells (PRBCs) to support the patient may have some benefit, FFP is unlikely to be beneficial.28 There is limited data to suggest that recombinant factor VIIa (rFVIIa) may be beneficial. For those agents (e.g. dabigatran) that are amenable to hemodialysis, this therapy has been successfully utilized to reverse anticoagulation28,32 Activated prothrombin complex concentrates may be useful.33
There are no established guidelines for discharge from the emergency department. Certainly, any patient with clinical evidence of bleeding should be admitted. It seems prudent to observe patients in the hospital for 24 hours following a large ingestion and those with renal failure, as the risk of bleeding is dose dependent, and increased in patients with renal failure. For patients with minor supratherapeutic ingestions, it seems prudent to observe the patient in the emergency department for 6 hours, and discharge the patient if there is no clinical or laboratory evidence of bleeding.
Consultation with the regional poison control center (800-222-1222) or a medical toxicologist is recommended for optimal management of each patient.
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