1066 SECTION IX Pediatric Critical Care Hematology and Oncology Warfarin Warfarin and vitamin K are structurally similar in their respective 4 hydroxycoumarin nucleus and naphthoquinone ring The mecha[.]
1066 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology Warfarin Warfarin and vitamin K are structurally similar in their respective 4-hydroxycoumarin nucleus and naphthoquinone ring The mechanism of action of warfarin is through competitive inhibition of vitamin K epoxide reductase required to regenerate the reduced form of vitamin K, which is a necessary cofactor in the postribosomal modification of the vitamin K–dependent coagulation proteins (FII, FVII, FIX, and FX) g-carboxylation This post-synthetic modification produces a calcium-binding site on the molecule that, when occupied, allows for the efficient activation of the zymogen clotting factor to its enzymatically active form When warfarin is present in sufficient plasma concentrations, the active (g-carboxylated) forms of vitamin K–dependent factors are depleted, thereby limiting the reaction Decay of anticoagulant activity following cessation of vitamin K antagonist therapy with warfarin is dependent on several genomic factors and varies among racial/ethnic groups.75 The PT/INR is an accurate indicator of the effects of warfarin when its use has continued beyond or days FVIIa (the active form) has a half-life of only to hours and is rapidly depleted after one or two doses of warfarin The remainder of the vitamin K–dependent factors take longer to deplete owing to their longer half-lives: FII, approximately 72 to 96 hours, FIX, approximately 24 hours, and FX, approximately 48 hours While the PT becomes prolonged upon FVII depletion, this does not reflect an overall state of anticoagulation until an equilibrium period of several days has passed, generally once the INR is at or near target value for to days Over this interval, the other vitamin K– dependent factors become depleted and PT prolongation, as measured by the INR, can then be used to assess the anticoagulant effects of warfarin In severe cases of warfarin overdose, the aPTT also becomes prolonged as a result of a marked reduction of the active forms of FII, FIX, and FX Several drugs and pathophysiologic conditions are associated with potentiation of warfarin’s effects on coagulation Many of the drugs known to prolong the effects of warfarin are listed in eBox 89.5 These drugs have a variety of mechanisms that generally include either inhibition of function or competitive binding of the enzymes that are responsible for active warfarin metabolism Aspirin does not seem to have any direct influence on warfarin metabolism but so profoundly influences qualitative platelet function that it increases the bleeding risk of warfarin therapy The same is true for clofibrate Ingestion of large doses of aspirin may also impair prothrombin (FII) synthesis, further increasing the effects of warfarin administration As warfarin is metabolized by the liver, conditions of acute and chronic hepatic dysfunction may alter (decrease) warfarin metabolism and vitamin K–mediated g-carboxylation of the vitamin K–dependent coagulation proteins, increasing the anticoagulant effect of warfarin Broad-spectrum antibiotics also may limit vitamin K availability through suppression of the gut flora (in addition to any direct effect on vitamin K metabolism) All these factors may ultimately influence a patient’s response to warfarin A clinical syndrome referred to as warfarin necrosis has been noted during the initial stages of anticoagulation with a vitamin–K antagonist It is characterized clinically by the development of skin and subcutaneous necrosis, particularly in areas of subcutaneous fat, and pathologically by the thrombosis of small blood vessels in the fat and subcutaneous tissues This syndrome occurs predominantly, though not exclusively, in individuals who are heterozygous for PC deficiency and is caused by the rapid depletion of the vitamin K–dependent anticoagulant PC prior to achieving depletion of procoagulant proteins.76 Although anticoagulation generally requires a decrease in procoagulant protein levels to approximately 20% to 25%, a prothrombotic milieu is created with PC levels of 40% or less Consequently, individuals who are heterozygous for PC deficiency and have baseline PC levels of 50% to 60% may develop a prothrombotic environment during the first few days of warfarin therapy This syndrome has also been noted in individuals who are heterozygous for PS or ATIII or who are positive for procoagulant antiphospholipid antibodies The risk of developing warfarin necrosis appears to be greater when an initial dose of warfarin greater than 10 to 15 mg is administered The development of this syndrome generally can be avoided if heparin and warfarin therapy are overlapped until “coumadinization” is complete and if large loading doses of warfarin (.15 mg) are avoided Management atients who exhibit a higher INR than desired but not exhibit P bleeding may be observed while the dose of warfarin is decreased and not necessarily require treatment to actively decrease the INR (i.e., FFP, PCC, or vitamin K) However, when overanticoagulation with warfarin presents with bleeding, immediate reversal is usually mandated The treatments of choice are products that provide prompt restoration of the deficient vitamin K–dependent coagulation proteins to restore hemostatic function While FFP was previously preferred (10–15 mL/kg of FFP is usually sufficient to produce significant correction of the PT), repeat infusions of FFP are necessary for continued correction of the PT due to the short half-life of FVII Currently, PCCs are the preferred blood products to correct a prolonged INR resulting from warfarin therapy, with 4PCCs being preferred due to the inclusion of FVII in these products However, studies comparing FFP, 3PCC, and 4PCC in the correction of warfarin-induced prolonged INR have reached variable conclusions Vitamin K also may be administered, particularly in situations that are less acute, although this will make it more difficult to “recoumadinize” the patient afterward There does not appear to be any advantage to the routine use of rF VIIa to treat patients with warfarin-induced bleeding Use of this agent should be reserved for patients with life-threatening bleeding unresponsive to standard treatment (i.e., 4PCC).77 Heparin Heparin is a repeating polymer of two disaccharide glycosaminoglycans commercially prepared from either porcine intestinal mucosa or bovine lung Heparin is currently available in two types of preparations: unfractionated heparin (UH) and low-molecularweight heparin (LMWH) It is important to understand the differences between these two forms of the drug, as they have different mechanisms of action and associated precautions UH has an immediate effect on coagulation that is mediated primarily through its association with ATIII; the resulting heparin-ATIII complex possesses a much greater affinity for thrombin than ATIII alone It inactivates thrombin, thereby dampening clot formation In addition, heparin has an anti-FXa effect that is also dependent on an association with ATIII, although this represents a smaller component of the anticoagulant action of UH.78 Achieving a therapeutic anticoagulation with UH is very difficult in the face of low levels of ATIII The degree of anticoagulation produced by heparin is monitored by the prolongation of the aPTT, which is variably sensitive to this effect Consequently, UH infusion doses frequently need to be adjusted to maintain aPTT within a desired therapeutic range In contrast, LMWH, produced by controlled enzymatic cleavage of heparin polymers, 1066.e1 • eBox 89.5 Drugs That Potentiate Anticoagulant Effects of Warfarin Antibiotics Broad-spectrum antibiotics (especially cephalosporins) Griseofulvin (oral) Metronidazole Sulfonamides Trimethoprim-sulfamethoxazole Antiinflammatory Drugs Steroids (anabolic in particular) Acetylated salicylates Phenylbutazone (oxyphenbutazone) Sulfinpyrazone Other Drugs Clofibrate Disulfiram Phenytoin Thyroxine (both D- and L-isomers) Tolbutamide CHAPTER 89 Coagulation and Coagulopathy affects anticoagulation almost exclusively through inhibition of FXa This also requires association with ATIII, but the anticoagulant effect is less dependent on variation in ATIII plasma levels, resulting in a more stable degree of anticoagulation being produced Due to its longer half-life (,3–5 hours) and biological activity (,24 hours), LMWH allows for intermittent bolus therapy (i.e., every 12 or 24 hours) while maintaining a steadystate effect However, LMWH does not produce consistent prolongation of the aPTT and requires assay of anti-Xa activity for monitoring.78,79 Heparin is metabolized in the liver by the heparinase enzyme in a dose-dependent fashion, with excess heparin then being excreted through the kidneys As the rate of heparin administration is increased, the half-life of the drug is prolonged due to the increase in the percentage of the drug being excreted by the kidney For example, when a 100 U/kg bolus of heparin is infused IV, the average half-life of the drug is hour If the bolus is increased to 400 or 800 U/kg, the half-life is prolonged to 2.5 and hours, respectively The nonlinear response results in greater drug effects on coagulation with smaller dosage increments When one “reboluses” or increases a heparin infusion rate in response to insufficient anticoagulation (i.e., inadequate prolongation of the aPTT), a point will be reached when further small increments in the heparin infusion rate may result in a substantially greater prolongation of the aPTT The risk of pathologic bleeding associated with heparin increases when the prolongation of the aPTT is beyond the therapeutic window (generally considered to be 1.5– 2.5 times the patient’s baseline aPTT, corresponding to a plasma heparin concentration of 0.2–0.4 U/mL or an anti-Xa level of 0.3–0.7 U/mL) As a corollary, administration of heparin as a continuous infusion rather than in an intermittent bolus dose regimen is less likely to be associated with pathologic bleeding Management S erious bleeding associated with heparin overdose can be rapidly reversed by protamine sulfate Protamine binds ionically with heparin to form a complex that lacks any anticoagulant activity As a general rule, mg of protamine neutralizes ,100 U of heparin (specifically, 90 US Pharmacopeia [USP] U of bovine heparin or 115 USP U of porcine heparin).80 The dose of protamine required is calculated from the number of units of active heparin remaining in the patient’s system This, in turn, is estimated from the original heparin dose and the typical half-life for that infusion rate (generally ,1 hour in usual clinical settings, longer immediately post-bypass surgery dosing) The aPTT is used to gauge the residual effects of heparin During and after cardiopulmonary bypass surgery, the activated clotting time (ACT) is frequently used to measure the heparin effect and to judge the effectiveness of and need for protamine neutralization This methodology is sometimes employed in the ICU However, the equipment used for this measurement is poorly standardized and different systems give different results Consequently, care must be taken when using one of these methods in the ICU Protamine itself potentially has anticoagulant effects; thus, precautions are necessary during its administration The drug should be given by slow IV push over to 10 minutes A single dose should not exceed mg/kg (50 mg maximum dose) This dose may be repeated, but no more than mg/kg (100 mg maximum dose) should be given as a cumulative dose without rechecking coagulation parameters The dose of protamine should always be monitored by coagulation studies Significant side effects are most commonly seen in situations of overly rapid drug administration 1067 and include hypotension and anaphylactoid-like reactions.81 The allergic reactions to protamine represent type I anaphylactic reactions between an antigen (protamine) and antibody (IgE or IgG) and result in histamine release Consequently, H2 blockers have been shown to be effective in treating and minimizing these reactions In addition, complement activation, thromboxane, and nitric oxide production have all been shown to play some role in the pathogenesis of these reactions Risk factors for protamine hypersensitivity reactions include prior exposure to protamine, insulin-dependent diabetes (with NPH exposure), fish allergy, and vasectomy In that LMWH is not predictably neutralized by protamine, invasive procedures should not be performed within 24 hours of administration Bleeding following LMWH therapy has been treated effectively with rF VIIa New Oral Anticoagulants Several new direct-acting oral anticoagulants (DOACs) that can be administered have become available for clinical use The mechanism of anticoagulant effect is either through direct inhibition of thrombin or through inhibition of FXa (eTable 89.5) While none has approval for use in children, use in this age group is increasing.82 As dosing recommendations for adults is largely based on schedule and not weight, pediatric use has been limited to larger/older children, with doses extrapolated from adult doses Consequently, there is a potential for unanticipated overdose in the pediatric population The current tests available to monitor anticoagulant effects of warfarin, UH, or LMWH are not sensitive enough to monitor the effect of these agents in vivo Due to this lack of widely available commercial tests to measure drug level or intensity of anticoagulation for any of these drugs, the therapeutic dose to prevent thrombotic events was determined by direct comparison to standard therapy (warfarin with transition to LMWH) in adults Consequently, extrapolation of adult dosing to the pediatric population is imprecise.83 While there are fewer identified drug interactions for DOACs than for warfarin, clinical data suggest moderate to severe drugdrug interactions when dabigatran is used in combination with verapamil, amiodarone, and dronedarone.84 Similarly, some other drugs commonly known as CYP inhibitors—including ketoconazole, itraconazole, macrolides, and human immunodeficiency virus protease inhibitors—have been shown to increase the serum DOACs concentration However, other CYP inductors—such as phenytoin, phenobarbital, rifampicin, and carbamazepine—may decrease the anticoagulant effect of DOACs Consequently, drugs in both categories are not recommended to be used in conjunction with these anticoagulants Management Bleeding associated with the DOACs can be managed with plasma products or, when available, with specific reversal agents.77,85 Bleeding in the presence of the direct thrombin inhibitor dabigatran therapy has been effectively controlled by idarucizumab, a humanized monoclonal antibody fragment directed against dabigatran and its major biologically active metabolites Binding of idarucizumab neutralizes dabigatran and reversal of anticoagulant effect Near normalization of thrombin effect has been reported after or doses Reversal of the anti-Xa effect of rivaroxaban and apixaban has been produced with the recently approved smallmolecule drug andexanet alfa A drug bolus followed by a 3-hour infusion resulted in marked reduction in plasma levels of drug (,80), with return to normal in vitro thrombin generation and 1067.e1 eTABLE New Oral Anticoagulant Drugs 89.5 Drug Class t½ (h) Reversal Agent Monitoring Rivaroxaban (Xarelto) Anti-Xa 7–11 Andexanet alfa Chromogenic anti-Xa: Accurate and precise; requires special calibration PT: Low specificity; identifies presence of drug but not intensity of anticoagulation dRVVT: Low specificity; requires special calibration, etc Apixaban (Eliquis) Anti-Xa 12 Andexanet alfa Chromogenic anti-Xa: Accurate and precise; requires special calibration Edoxaban (Savaysa) Anti-Xa Dabigatran (Pradaxa) DTI Anti-IIa 12–17 Idarucizumab dTT: Accurate and precise measurement of plasma concentration; requires special calibration ECA: Accurate and precise; requires specific calibration ECT: Requires special calibration aPTT: Low specificity; identifies presence of drug but not intensity of anticoagulation TT: Low specificity dRVVT: Low specificity aPTT, Activated partial thromboplastin time; dRVVT, dilute Russell viper venom time; ECA, ecarin chromogenic assay; ECT, ecarin clotting time; PT, prothrombin time; TT, thrombin time 1068 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology control of bleeding The level of free drug continued to decline over the ensuing 24 hours Data on its ability to reverse other oral anti-Xa agents or LMWH are not available Platelet Disorders Platelets are necessary for efficient clot formation They not only produce a physical barrier at the site of vascular injury (the socalled platelet plug), they also serve to focus the clotting process at the point of bleeding by delivering vasoconstrictors and clotting factors to the bleeding site and by providing a surface on which clot development occurs (see Fig 89.6) Quantitative and qualitative platelet disorders are a common cause of clinical bleeding in the PICU; of these, thrombocytopenia is the most common An overview of platelet disorders based on this classification scheme is presented in eTable 89.6 Thrombocytopenia on admission to or developing during an ICU admission has been shown to correlate with worse outcome We now know that platelets, through linkage with the immune response, play an important role in host response to pathogens and clearance of bloodstream pathogens Furthermore, thrombocytopenia has been shown to alter this important host response.86,87 Quantitative Platelet Disorders A decrease in the number of circulating platelets indicates increased peripheral destruction, sequestration, decreased marrow production, or a combination of these factors Examples of increased peripheral destruction include immune-mediated processes (both autoimmune and drug induced), abnormal consumption (as in DIC), and mechanical destruction (e.g., cardiopulmonary bypass, hyperthermia) Autoimmune processes—such as idiopathic thrombocytopenic purpura (ITP; now referred to as immune thrombocytopenia), SLE, or acquired human immunodeficiency syndrome can result in increased peripheral destruction and increased splenic sequestration of platelets Autoimmune destruction also may occur in conjunction with lymphocytic leukemia or lymphoma The prototypic example of immune thrombocytopenia is ITP, in which immunoglobin (generally IgG) directed against specific platelet antigens results in platelet destruction by a cell-mediated mechanism Acute ITP is usually self-limited while chronic ITP generally requires immunosuppressive therapy to maintain an acceptable platelet count Although life-threatening bleeding may occur in either acute or chronic ITP, it is a rarity The incidence of intracranial hemorrhage in ITP (acute or subacute) is estimated to be less than 1%; in most series, it is between 0.1% and 0.2% Severe bleeding is more likely to occur in chronic ITP dependent on the severity and duration of the thrombocytopenia Most episodes of severe bleeding occur when the platelet count is less than 10,000 to 20,000/mL, but a decision to institute therapy should be based on the overall clinical setting and not just the platelet count Steroids given orally (2–4 mg/kg per day of prednisone or its equivalent) represents a standard therapy for acute ITP However, high-dose methylprednisolone (50 mg/kg IV daily 3 days; maximum daily dose 1500 mg) or high-dose dexamethasone (20 mg/m2 per day days either PO or IV; maximum dose 40 mg/d) have been shown to frequently result in a more rapid increase in platelet count High doses of IV g-globulin (IVIG; 1–2 g/kg given over 2–5 days) and infusions of anti-RhD antigen antibody (WinRho; 25–60 mg/kg) are equally efficacious in producing at least transient elevations in platelet counts Note, however, that WinRho should only be used in patients who are Rh (1) and have a functioning spleen Agents such as vincristine/ vinblastine, cyclophosphamide, and, with increasing frequency, rituximab (anti-CD20 monoclonal antibody) also have been used as immunosuppressants with variable success, although responses are generally not immediate Splenectomy may be required to avert serious bleeding complications in patients who not respond to medical management, although this approach is chosen much less often in children than in adults In ITP, the degree of bleeding attributed to thrombocytopenia is generally less than that noted when thrombocytopenia results from decreased platelet production due to a rebalancing of hemostasis, as documented by an increase in vWF and by normal thromboelastometry parameters.88 In general, severe bleeding is not noted until the platelet count is less than 10,000/µL, although levels below 40,000 to 50,000/mL may increase the risk of bleeding associated with invasive procedures The use of firstgeneration thrombopoietin-like drugs to stimulate platelet production (romiplostim, eltrombopag) or investigational secondgeneration Syk-pathway inhibitor (fostamatinib) developed to treat chronic ITP does not appear to play a role in the management of immune thrombocytopenia in the ICU, as platelet counts only demonstrate a significant increase after several weeks of therapy.89 Platelet transfusions are not indicated in ITP (and other immune-mediated thrombocytopenia) except as a component of therapy for life-threatening bleeding The development of drug-induced, immune-mediated platelet destruction should always be considered in the thrombocytopenic PICU patient.90 When present, it is usually reversible; withdrawal of the offending drug prevents further immune-mediated platelet destruction The exact mechanism of platelet destruction may be related to the binding of drug to the platelet membrane, with subsequent binding to the platelet, platelet-drug complex, or both, of a specific antibody The resulting platelet-drug-antibody complexes are then cleared by the reticuloendothelial system (e.g., the spleen), and thrombocytopenia develops Drugs used in the ICU that are most commonly associated with this clinical picture include quinidine, quinine, heparin, gold salts, various penicillin and cephalosporin antibiotics, and the sulfonamides The anticonvulsant valproic acid frequently produces a dose-dependent thrombocytopenia that is, at least in part, immunologic in nature A variety of drugs are associated with the nonimmune development of thrombocytopenia by bone marrow suppression Most cancer chemotherapeutic agents produce thrombocytopenia as a consequence of marrow suppression The thiazide diuretics, cimetidine, ethanol, and several of the cephalosporin and penicillin antibiotics may also suppress platelet production Generalized infection (such as bacterial sepsis) and many viral illnesses are also associated with bone marrow suppression and thrombocytopenia, even if an element of immune platelet destruction is present Disorders such as Gaucher disease may produce a mild-to-moderate thrombocytopenia as a result of marrow replacement by nonhematopoietic cells Platelet transfusions may be useful in the management of patients with thrombocytopenia secondary to decreased production In the setting of cancer therapy, prophylactic platelet transfusions are generally considered in nonbleeding patients when platelet count is less than 10,000 mL A recent survey of platelet transfusion practices in PICU and neonatal ICU patients indicates that most transfusions were prophylactic and administered with patient platelet counts greater than established guidelines.91 Additionally, these studies demonstrated a higher mortality in those patients who received more platelet transfusions ... effectiveness of and need for protamine neutralization This methodology is sometimes employed in the ICU However, the equipment used for this measurement is poorly standardized and different systems... required is calculated from the number of units of active heparin remaining in the patient’s system This, in turn, is estimated from the original heparin dose and the typical half-life for that infusion... Coagulation and Coagulopathy affects anticoagulation almost exclusively through inhibition of FXa This also requires association with ATIII, but the anticoagulant effect is less dependent on variation