1061CHAPTER 89 Coagulation and Coagulopathy To confirm a diagnosis of suspected DIC, tests that indicate increased fibrinogen turnover (i e , elevated FDPs or D dimer as say) may be necessary The D di[.]
CHAPTER 89 Coagulation and Coagulopathy To confirm a diagnosis of suspected DIC, tests that indicate increased fibrinogen turnover (i.e., elevated FDPs or D-dimer assay) may be necessary The D-dimer assay, which measures the D-D fragment of polymerized fibrin, has been shown to be both highly sensitive and specific for proteolytic degradation of polymerized fibrin (fibrin clot that has been produced in the presence of thrombin) Consequently, this test is employed with increasing frequency in patients with suspected DIC and is often stated to be the preferred test of fibrin/fibrinogen consumption However, remembering that thrombin is produced whenever coagulation is activated in the presence of bleeding, the clinician must interpret a modest elevation of D-dimer in a postoperative or trauma patient with some degree of caution, as D-dimer may be elevated in several other conditions The presence of a marked elevation of D-dimer in a nonbleeding patient essentially excludes primary fibrinogenolysis as the sole cause of measurable FDPs in the serum The TT is a less sensitive test for DIC, but it may be useful in cases of suspected heparin overdose, as addition of protamine sulfate or toluidine blue to the specimen will result in correction of the prolonged TT Similarly, the euglobulin clot lysis time may not be sensitive to fibrinolysis associated with DIC but is significantly shortened in most cases of primary fibrino(geno)lysis While other tests reflective of ongoing fibrinolysis—including plasmin-antiplasmin complex, PAI-1 level, soluble fibrin monomer or thrombin-antithrombin complex formation—have been shown to help predict the presence of DIC, they either have problems with sensitivity or are impractical for widespread clinical use outside of a research setting.45,52 Meningococcal Purpura Fulminans Purpura fulminans is a systemic coagulopathy similar, if not identical, to DIC that classically accompanies meningococcal sepsis and is sporadically noted with other similarly severe infections The hallmark of this syndrome is tissue ischemia and necrosis due to marked microvascular thrombosis similar to that often present in congenital PC deficiency Patients with meningococcal sepsis and purpura fulminans are generally noted to have severely depressed levels of PC, with the degree of suppression being shown to correlate with mortality Patients with meningococcal sepsis who express the PAI-1 4G/4G genotype associated with the highest plasma levels of PAI-1 have been found to have increased rates of sepsis and higher mortality but not an increased incidence of meningococcal meningitis.46 While meningococcal sepsis has been considered as a model for sepsis-associated PC deficiency, open-label studies of PC replacement therapy in this patient population have demonstrated variable benefits Management The primary treatment for DIC is correction of the underlying problem that led to its development While there are no general guidelines, there is general consensus that specific therapy for DIC should not be undertaken unless the patient has significant bleeding or organ dysfunction secondary to DIC, significant thrombosis has occurred, or treatment of the underlying disorder (e.g., acute promyelocytic leukemia) is likely to increase the severity of DIC.47 Supportive therapy for DIC includes the use of several component blood products.35 Packed RBCs are given according to accepted guidelines in the face of active bleeding Fresh whole blood (i.e., to ,24 hours old) may be given to replete both volume and oxygen-carrying capacity, with the potential additional benefit of providing coagulation proteins, including fibrinogen and platelets Fresh frozen plasma (FFP) is of limited value for the 1061 treatment of significant hypofibrinogenemia because of the inordinate volumes required to make any meaningful contribution to plasma fibrinogen concentration Cryoprecipitate contains a much higher concentration of fibrinogen than does whole blood or FFP and therefore is more likely to provide the quantity of fibrinogen necessary to replenish fibrinogen that is consumed by DIC Commercial fibrinogen concentrate contains even greater amounts of fibrinogen (by volume) than does cryoprecipitate and has the advantage of being processed to reduce the risk of viral transmission and enables the clinician to infuse a known amount of fibrinogen FFP infusions may effectively replete other coagulation factors consumed with DIC, such as PC, although the increase in these proteins may be quite small unless large volumes of FFP are infused The use of cryoprecipitate or FFP in the treatment of DIC has been open to debate in the past because of concern that these products merely provide further substrate for ongoing DIC and thus increase the amount of fibrin thrombi formed However, autopsy studies have failed to confirm this concern The goal of blood component therapy is not to produce normal laboratory numbers but rather to produce clinical stability.47 If the serum fibrinogen level is less than 75 to 50 mg/dL, repletion with cryoprecipitate (or fibrinogen concentrate) to raise plasma levels to 100 mg/dL or greater is the goal A reasonable starting dose is bag of cryoprecipitate for every 10 kg of body weight every to 12 hours As cryoprecipitate is not a standardized component (i.e., its content varies from bag to bag), the fibrinogen level should be rechecked after an infusion to assess the increase The amount and timing of the next infusion is then adjusted according to the results Infusions of commercial fibrinogen concentrate are dosed based on the formula included in the manufacturer’s package insert Platelet transfusions also may be used when thrombocytopenia is thought to contribute to ongoing bleeding Many of the fibrin/fibrinogen fragments produced in DIC have the potential to impair platelet function by inhibiting fibrinogen binding to platelets, which may be clinically significant at the concentration of FDPs achieved with fulminant DIC Platelet transfusions in patients with DIC should be considered to maintain platelet counts up to 40,000 to 80,000/mL depending on the clinical specifics of the patient Pharmacologic therapy for DIC has two primary aims: to turn off ongoing coagulation so that repletion of coagulation factors may begin and to impede thrombus formation and ensuing ischemic injury Recombinant activated FVII (rFVIIa), a recombinant hemostatic factor, has been used to treat bleeding in DIC refractory to other therapies as well as in trauma and other medical and surgical causes of severe, life-threatening bleeding.48,49 Most of these studies have demonstrated efficacy in the control of hemorrhage, but most have not demonstrated a decrease in mortality With the exception of patients with acquired inhibitors to FVIII, no controlled trials have been conducted in children rFVIIa has also been shown to correct the hemostatic defect caused by the antiplatelet agents aspirin and clopidogrel Reports have noted that use of rFVIIa may result in an increase in thrombosis and thromboembolic events, although the incidence appears to be small and the severity of most events mild Various synthetic and natural modulators of hemostasis have shown some efficacy in moderating multiorgan dysfunction in the coagulopathy of sepsis.19,20,50 These include anticoagulant molecules (e.g., heparin, ATIII, tissue factor pathway inhibitor [TFPI], APC) and thrombolytic modulators (e.g., tissue plasminogen activator [tPA], TAFI) Although initial reports of the use of recombinant human APC in sepsis demonstrated a benefit on survival 1062 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology in septic adults, there was increased bleeding in the elderly, and the pediatric trial was stopped because of futility and increased bleeding in infants Subsequent reanalysis of data demonstrated no benefit of this agent in the treatment of sepsis; therefore, it was withdrawn from the US market While trials addressing the use of other natural modulators of thrombosis and fibrinolysis have not consistently demonstrated benefit in septic patients, results from ongoing clinical studies (particularly in Japan and Korea) investigating the use of antithrombin and recombinant thrombomodulin either singly or in combination show some benefit on bleeding manifestations in DIC However, effect on mortality has been less consistent HUS, TTP, and thrombocytopenia-associated multiorgan failure are discussed in Chapters 74, 90, and 111, respectively Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome Although neither TTP nor HUS generally produce a coagulopathic state, each is characterized by marked microangiopathy and microvascular thrombosis Despite this similarity, these two entities not represent the same process distinguished by different end-organ effects; the underlying pathoetiology of the two entities is different.44,51,52 HUS is more commonly seen in children and is characterized by a prodrome of fever and diffuse diarrhea (often bloody) Endemic cases of HUS are generally caused by verotoxin-expressing enteropathic strains of Escherichia coli (O157:H7) or Shigatoxinexpressing strains of Shigella Sporadic cases are generally not associated with diarrhea and are felt to represent atypical HUS resulting from familial defects in complement FH Complement activation and depletion is the central event in aHUS and also plays a role in the endemic forms of the disease Therapy is supportive, including renal replacement measures when indications exist Although some benefit from plasma exchange has been reported, the role of plasma exchange is unclear However, aggressive treatment with an anticomplement monoclonal antibody (eculizumab) has been reported to be beneficial in patients with aHUS and in some with the endemic form TTP is characterized by the pentad of microangiopathic hemolytic anemia, thrombocytopenia, neurologic symptoms, fever, and renal dysfunction Although only 40% of patients will display the full pentad, up to 75% will manifest a triad of microangiopathic hemolytic anemia, neurologic symptoms, and thrombocytopenia This disorder has been shown to result from the absence of a vWF–cleaving protease (a disintegrin and metalloprotease with thrombospondin motifs 1, type 13 [ADAMTS-13]), resulting in the circulation of unusually large vWF multimers that can induce or enhance the pathologic adhesion of platelets to the endothelium The therapy of choice for TTP is plasma exchange by apheresis Some patients with TTP will also exhibit marked complement activation and depletion similar to that noted in aHUS and may respond to anticomplement therapy (eculizumab) Platelet transfusions are generally not recommended, except in the case of major bleeding, due to the risk of inducing vascular (arterial) occlusion Thrombocytopenia Associated Multiorgan Failure Thrombocytopenia either at the time of or that develops during PICU admission has been shown to confer a poor prognosis regarding mortality and organ failure.53 Thrombocytopenia-associated multiorgan failure (TAMOF) is a recently described entity characterized by clinical signs of sepsis, a microangiopathic blood smear with marked thrombocytopenia, and a clinical course with rapid development of multiorgan failure and poor prognosis.54 The etiology of this disorder is unclear, but the pathophysiology involves consumption of the vWF-cleaving protease ADAMST13 with consequent enhancement of platelet deposition in the microvasculature Plasma exchange to replace the depleted ADAMST13 has been found to reduce morbidity and mortality.55 Abnormal Hemostasis in Liver Disease and Hepatic Insufficiency Liver disease is a common cause of abnormal hemostasis in patients in the ICU, with abnormal coagulation studies or overt bleeding occurring in ,15% of patients who have either clinical or laboratory evidence of hepatic dysfunction (see also Chapter 97) It is a common cause of a prolonged PT or aPTT, with multiple aspects of hemostasis being affected generally without any clinical sequelae.56,57 In liver disease, synthesis of several plasma coagulation proteins—including factors II, V, VII, IX, and X—is impaired Fibrinogen synthesis by the liver is usually maintained at levels that prevent bleeding until terminal liver failure is present FVIII and vWF levels are generally normal to increased in acute and chronic liver disease Additionally, many patients with liver disease, particularly cirrhosis, have increased fibrinolytic activity Increase in fibrinolysis potential is a frequent occurrence in patients who have undergone portacaval shunt procedures The mechanism for this heightened fibrinolytic state is not clear, although increased levels of plasminogen activator have been demonstrated It may be difficult to discern whether fibrinolysis occurs solely because of underlying severe liver disease or as a result of concurrent DIC, as patients with cirrhosis are at increased risk for the development of DIC In liver disease, increased levels of FDPs may result from increased fibrinolysis and by decreased hepatic clearance In the presence of bleeding, it may be impossible to determine whether an increase in fibrinolysis is primarily due to the liver dysfunction or secondary to concomitant DIC Thrombocytopenia is frequently present in patients with hepatic dysfunction and is usually ascribed to splenic sequestration In vitro platelet aggregation is often affected, however Increased plasma concentrations of FDPs are a possible cause of these abnormalities The thrombocytopenia of liver disease is rarely profound but may contribute to bleeding risk in conjunction with other coagulation/hemostatic defects The resultant bleeding may be difficult to manage if all aspects are not addressed Patients with synthetic liver disease may also exhibit decreased synthesis of the vitamin K–dependent anticoagulant proteins PC and PS, as well as ATIII Decreased levels of these natural anticoagulants may increase the risk of thrombosis PT, aPTT, and TT will not be affected by the decreased levels of any of these naturally occurring anticoagulants As indicated previously, the presence of an elevated INR has not been shown to be a sensitive marker to assess bleeding risk in liver disease.24–27,57–59 The lack of correlation of PT (and, consequently, INR) with bleeding risk in patients with liver disease may be explained by the fact that, in contrast to vitamin K antagonist therapy, in which only one pathway involved in hemostasis is affected, liver disease has effects on essentially all phases of hemostasis: primary (platelet-dependent) hemostasis, fibrin clot initiation, coagulation inhibition, and fibrinolysis Of these, the PT/ INR measures only fibrin clot production The net result of these CHAPTER 89 Coagulation and Coagulopathy multiple effects is a rebalancing of hemostasis in patients with liver disease As a consequence, neither the PT nor INR accurately reflects the risk of bleeding in these patients However, patients with liver disease may still experience clinically significant bleeding as a result of severe thrombocytopenia, a qualitative platelet defect resulting from liver disease, or a rebalanced hemostatic system that does not adequately compensate for a decrease in procoagulant clotting factors or increased fibrinolysis Anatomic lesions such as esophageal varices due to portal hypertension also represent a significant risk for upper gastrointestinal hemorrhage in these patients Consequently, the intensive care clinician must carefully and thoroughly assess the patient for these risks However, the role that traditional measures of coagulation (i.e., PT, aPTT) or global thromboelastomeric tests (i.e., TEG, ROTEM) play in this assessment is limited.60 Presentation The hemostatic defect in liver disease is multifactorial; each patient should be approached accordingly The most common scenario is a patient with liver disease and a prolonged PT without overt bleeding in whom the potential for bleeding is a concern In patients with liver disease and impaired synthetic capabilities, particularly those who are critically ill, FVII activity levels are usually the first to decrease due to its short half-life of to hours and increased turnover This causes a prolonged PT and can be noted even when usual markers of hepatocellular injury/hepatic insufficiency remain relatively normal A prolonged TT in the setting of liver disease may indicate the presence of dysfibrinogenemia as a result of altered hepatic fibrinogen synthesis As the severity of liver disease increases, the aPTT may also be affected, reflecting more severely impaired synthetic function In this setting, plasma concentrations of the vitamin K–dependent coagulation proteins decrease, as those of FV (which is synthesized in the liver but not dependent on vitamin K) Although fibrinogen synthesis occurs in the liver, its plasma level is generally maintained until the disease approaches end stage When fibrinogen levels are severely depressed as a consequence of decreased synthesis and not increased degradation (fibrinolysis) or consumption (conversion to fibrin), liver failure has typically reached the terminal phase Severe hypofibrinogenemia (e.g., levels ,75 mg/dL) is associated with an increased risk of bleeding In more severe forms of liver disease, fibrinolysis may complicate clinical management The differentiation between concomitant DIC and fibrinolysis attributable to liver disease alone may be difficult The D-dimer assay result should be normal in the patient who has liver disease, elevated FDPs, and fibrinolysis but no active bleeding because thrombin is not being generated Further clinical distinction usually is not possible and, in practice, it is difficult to distinguish between a patient with fibrinolysis without activation of coagulation and one who has a DIC-like process Management If the patient is not actively bleeding, no specific therapy is required, with certain provisos.56–58 In patients with a prolonged PT who are in a postoperative state or are scheduled for an invasive procedure, correction of the PT may be considered FFP is the component of choice for this purpose However, administration of FFP in these patients has not been shown to decrease procedure-related bleeding, and studies have shown inconsistent and incomplete correction of the PT in liver disease Multiple studies have shown that invasive procedures can be performed 1063 safely without correction of a prolonged PT.59,60 These findings call into question the need to correct an asymptomatic prolonged PT/INR prophylactically or prior to planned invasive procedures When a correction of the PT is desired, a decrease of the PT to a value seconds or less above the upper limit of normal for the testing lab is considered adequate Supplementation of fibrinogen, in the form of cryoprecipitate or fibrinogen concentrate, is required only if fibrinogen levels are less than 50 to 100 mg/dL or if significant dysfibrinogenemia is documented Vitamin K deficiency is also relatively common in this patient population, and replacement may be necessary In contrast to children with dietary vitamin K deficiency and normal liver function, correction of the PT in vitamin K–responsive critically ill patients typically requires longer than 12 to 24 hours and may be incomplete owing to impaired hepatic protein synthesis Therefore, the immediate use of FFP prothrombin complex concentrates (PCC) is appropriate when rapid correction is necessary With greater impairment of hepatic synthetic function causing marked prolongation of the aPTT or in the presence of significant bleeding, greater volumes of FFP or more specific therapy may be necessary For bleeding patients who fail therapy with FFP (e.g., 10–15 mL/kg body weight given every to hours) use of standard PCC containing measurable amounts of FII, FIX, and FX (3PCC) or 4-factor prothrombin complex concentrates that contain measurable amounts of FVII (4PCC) have been used Currently, 4PCC is preferred although improved control of bleeding of 4PCC over 3-factor PCC (3PCC) has been variable To date, no studies have conclusively shown rFVIIa concentrate to be superior to PCCs for the management of bleeding Currently, rFVIIa is not recommended for the front-line therapy in bleeding patients due to potential thrombotic events and limited survival benefit.61 However, if therapy is designed to replace a known deficiency of a factor not contained in a pooled concentrate (i.e., not factors II, VII, IX, or X), then FFP infusion is indicated Cryoprecipitate or commercial fibrinogen concentrate should be infused for fibrinogen levels of less than 50 to 100 mg/dL Platelet transfusions also may be required if the platelet count is less than 40 to 80,000/µL, depending on the clinical situation Vitamin K should be empirically administered on the presumption that part of the synthetic defect may result from a lack of this cofactor However, a poor response to vitamin K in the presence of severe liver disease should be anticipated Transfusions of packed RBCs may also improve hemostasis by increasing the hematocrit A hemoglobin threshold of less than to g/dL is frequently recommended for packed RBC transfusions, once deemed appropriate by the clinician Vitamin K Deficiency The most common cause of a prolonged PT in the ICU may be acquired vitamin K deficiency.62 Vitamin K is necessary for the g-carboxylation of factors II, VII, IX, and X, without which these factors cannot bind calcium and are not efficiently converted into their activated forms FVII has the shortest half-life of these coagulation proteins; accordingly, the PT is the most sensitive early indicator of vitamin K deficiency Vitamin K deficiency is relatively common in critically ill patients for several reasons, including the use of broad-spectrum antibiotics, poor nutrition preceding or subsequent to ICU admission, and the use of parenteral nutrition without vitamin K supplementation.63 Many of the second- and third-generation 1064 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology cephalosporins directly interfere with vitamin K absorption from the gut lumen Specific metabolites of these antibiotics may also act as competitive inhibitors of vitamin K In addition, these and other antibiotics may kill or inhibit the growth of gut bacteria and limit the amounts of vitamin K that they normally produce and excrete into the gut lumen, which subsequently is absorbed into the bloodstream Although malnutrition also may contribute to the development of vitamin K deficiency, it usually requires to weeks to develop in the complete absence of vitamin K intake However, the use of parenteral alimentation without vitamin K supplementation coupled with antibiotic use may result in rapid vitamin K depletion, and prolongation of the PT can occur within only to days Additionally, vitamin K is fat soluble and not absorbed well in some conditions of biliary tract and intrinsic small bowel disease Fat malabsorption states, including cystic fibrosis, may contribute to the development of vitamin K deficiency Finally, in the setting of surgery, trauma, or critical illness, FVII turnover is increased, further exacerbating a deficient state In the ICU, vitamin K deficiency usually results from the interaction of several of these factors and is rarely limited to only one of the conditions mentioned It is the responsibility of the clinician to maintain an awareness of the potential for vitamin K deficiency and to treat accordingly The differential diagnosis of an isolated prolongation of the PT, with or without bleeding, includes both vitamin K deficiency and liver disease The clinical presentation of these patients is often quite similar In fact, the distinction sometimes can be made only on the basis of the response (or lack thereof ) to empirical vitamin K therapy Warfarin administration (either overt or covert) also should be excluded as a cause of a prolonged PT Newer, long-acting vitamin K antagonist rodenticides (so-called “superwarfarin”), which when ingested, produce a profound, prolonged, vitamin K–resistant reduction in vitamin K–dependent clotting factors, may produce an isolated prolongation of the PT initially Treatment of poisoning with these agents requires aggressive, prolonged use of vitamin K and, in the bleeding patient, support with FFP infusions or 4-factor PCC Confirmation of warfarin exposure as the cause of a prolonged PT is possible by toxicologic methods to detect the drug or its metabolites, or detection of the noncarboxylated forms of vitamin K–dependent clotting factors (proteins induced by vitamin K antagonist [PIVKAs]) in plasma In addition, the presence of a specific inhibitor to or congenital deficiency of FVII will also result in an isolated prolongation of the PT Acquired inhibitors of FVII are rare, and homozygous deficiency of FVII has not been described Individuals who are heterozygous for FVII deficiency tend to have FVII levels in the 25% to 35% range and not appear to be at significant increased risk for bleeding Lupus-like anticoagulants that result from inflammation may also produce an isolated prolongation of the PT; these are generally of no clinical significance and are not associated with an increased risk of bleeding Infants who fail to receive vitamin K in the immediate postnatal period may develop a systemic coagulopathy manifested by bruising and gastrointestinal bleeding, generally occurring between and weeks of age The first clinical feature is often prolonged bleeding following circumcision Infants with malabsorption or breast-fed infants who ingest medications that interfere with vitamin K in breast milk may develop similar findings beyond weeks of age The laboratory findings of an isolated vitamin K deficiency, in addition to a prolonged PT, include a normal fibrinogen level, platelet count, and FV level FV is not a vitamin K–dependent protein; therefore, its level should be normal, except in cases of DIC (consumption) or severe liver disease (decreased production) Prolongation of the aPTT from vitamin K deficiency, warfarin therapy, or liver disease is a relatively late event and occurs initially as a result of FIX depletion Management The management of vitamin K deficiency consists primarily of its repletion, usually by IV or subcutaneous routes in critically ill patients Therapy should not await the development of bleeding or oozing but should be administered when PT abnormality is detected and vitamin K deficiency is suspected As with other drugs administered subcutaneously (e.g., insulin), adequate blood pressure and subcutaneous perfusion are necessary to ensure reliable absorption from the soft tissues Concern exists regarding the possibility of anaphylactoid reactions with the IV use of vitamin K This risk is minimized when the drug is given as a piggyback infusion over 30 to 45 minutes in a small volume of fluid rather than as a bolus or slow-push dose; IV-piggyback infusion is the preferred method of drug administration in hemodynamically unstable patients The usual dose of vitamin K in children is to mg IV or subcutaneously (up to 10 mg in larger children) In an otherwise healthy person, the PT should correct within 12 to 24 hours after this dose However, serial dosing of critically ill patients is often used, and the PT may require up to 72 hours to normalize If the PT does not correct within 72 hours after three daily doses of vitamin K, intrinsic liver disease should be suspected Further administration of vitamin K is of no additional benefit in this setting When the patient is actively bleeding, it is not sufficient to give vitamin K alone A more immediate restoration of coagulation is required FFP has traditionally been employed in this setting To restore hemostasis to an acceptable level (30%–50%) of normal enzyme activity, 10 to 15 mL/kg body weight of FFP is typically required A similar approach is used in patients who were previously given warfarin Four-factor PCCs that contain significant amounts of FVII (along with factors II, IX, and X) are effective in correcting both PT and aPTT values in these patients and have become the treatment of choice to correct a patient with vitamin K deficiency or warfarin overdose–associated bleeding rFVIIa (15–20 mg/kg) has been used with success to reverse the bleeding noted in vitamin K deficiency and warfarin overdose Circulating Anticoagulants An acquired antibody directed against a specific component required for in vitro clot formation may also produce a prolonged PT and/or aPTT Additionally, heparin contamination of a blood specimen will also result in a prolonged aPTT The clinician can narrow down the likely clotting factors involved in the test result by consulting the simple clotting cascade (see Fig 89.2) When a circulating inhibitor is suspected, the first test to obtain is a mixing study Failure to obtain a substantial shortening of the PT or aPTT, generally into the lab normal range, suggests that the patient plasma contains an inhibitor to a critical component Heparin will prolong the aPTT and TT, while only antibodies to thrombin (FIIa) may cause prolongation of the TT Isolated prolongation of the PT raises the possibility of anti–FVII antibodies, while an isolated prolongation of the aPTT suggests inhibitors to factors XII, XI, IX, or VIII Prolongation of both the PT and aPTT could indicate the presence of an inhibitor to FX, FII (prothrombin), or FIIa (thrombin).64 Antibodies to prothrombin have CHAPTER 89 Coagulation and Coagulopathy 1065 been described in a large percentage of adult patients with SLE, and antithrombin antibodies have been described in patients previously exposed to bovine thrombin used to promote clot formation postsurgery or trauma Patients with antithrombin antibodies will also exhibit a prolonged TT in addition to prolonged PT and aPTT Patients with antiprothrombin antibodies are at increased risk for bleeding (if hypoprothrombinemia is present) or for thrombosis Except for deficiency of FXII, a critically low value of any of the other clotting factors may result in an increased risk of bleeding As stated earlier, LACs will also produce a prolongation of the PT and/or aPTT depending on where in the clotting cascade their primary action is directed LACs are antiphospholipid antibodies and produce an in vitro effect Phospholipid provides a surface on which clots may form in vivo and form part of the tenase complex (along with FIXa and FVIIIa) that catalyzes the conversion of FX to FXa, and the prothrombinase complex (FXa along with FVa) that catalyzes the conversion of FII (prothrombin) to FIIa (thrombin) While phospholipid is a rate-limiting substrate in vitro, it is ubiquitous in vivo and no amount of antibodies can neutralize its participation in clot formation Consequently, LACs represent a laboratory phenomenon and not a risk for bleeding However, the lupus-induced antibodies to prothrombin or to fibrinogen produce a potential risk for bleeding, as they result in hypoprothrombinemia from enhanced clearance of prothrombin or in poor fibrin clot formation caused by inhibition of fibrin polymerization.65,66 Iatrogenic Coagulopathy Massive Transfusion Syndrome Transfusion of large quantities of blood can result in a multifactorial hemostatic defect The genesis of this problem is related to the washout of plasma coagulation proteins and platelets, and it may be exacerbated by the development of DIC with consequent factor consumption, hypothermia, acidosis, or, rarely, by citrate toxicity or hypocalcemia These variables often act in combination to cause a coagulopathic state.67,68 A washout syndrome can result from the transfusion of large amounts of stored blood products that are devoid of clotting factors and platelets It develops exclusively in patients who receive large volumes of packed RBCs (e.g., trauma victims, patients with massive gastrointestinal hemorrhage or hepatectomy, or those undergoing cardiopulmonary bypass) without also receiving FFP and platelets FV and FVII have short shelf half-lives and are often deficient in blood that has been banked longer than 48 hours In addition, a qualitative platelet defect can be demonstrated in whole blood within hours of its storage, especially if an acid-citrate-dextrose solution is used Consequently, transfusion of large quantities of stored whole blood may produce limited improvement in the bleeding that results from decreased clotting factors and platelets Limited data from combat trauma suggests that the use of fresh whole blood may improve hemostasis.69 The development of a washout coagulopathy is directly dependent on the volume of blood transfused relative to the blood volume of the patient As a general rule, residual plasma clotting activity after single-blood-volume exchange falls to 18% to 37% of normal; after a double-bloodvolume exchange, residual activity is only 3% to 14% of normal; and after a triple-blood-volume exchange, less than 5% of normal clotting function remains The patient who is bleeding as a consequence of massive transfusion or washout presents with diffuse oozing and bleeding from all surgical wounds and puncture sites Laboratory abnormalities include prolonged PT, aPTT, and TT Fibrinogen levels and platelet counts are typically decreased; FDPs are not usually increased unless concurrent DIC is present The likelihood that the clinicolaboratory picture is a direct result of the massive transfusion can be estimated from the amount of bleeding that has occurred and the blood volume that has been administered relative to the patient’s blood volume (i.e., the number of blood volume equivalents that have been transfused) The more stored blood (e.g., packed RBCs) transfused relative to the patient’s blood volume, the greater the chance of the development of coagulopathy due to massive transfusion Management Children with severe trauma frequently present with massive bleeding and acidosis secondary to hypoperfusion Prospective identification of those at risk to develop a coagulopathy from massive transfusion is important When the magnitude of the insult and the anticipated need for blood are large, both platelets and FFP should be given before a coagulopathy develops; the exact ratio of packed RBCs to other blood components (i.e., platelets, plasma, or cryoprecipitate) to prevent the development of massive transfusion coagulopathy has not been established Traditionally, for children weighing more than 30 to 40 kg (or body surface area 1 m2), half of a unit of apheresis-collected platelets (generally equivalent to 4–5 U of platelets derived from whole blood donation) and U of FFP have to be given for each U of whole blood or packed cells transfused In smaller children, 10 mL/kg of platelets and 10 to 15 mL/kg FFP must be given for each 40 to 50 mL/kg of blood transfused These amounts should prevent washout and its attendant bleeding However, based on data from military hospitals and adult civilians, more aggressive transfusion support through the implementation of a formal transfusion protocol that would provide multiproduct support with RBCs, plasma, and platelets in a set ratio closer to 1:1:1 (or 1:1:2) has been hypothesized to improve the outcome in these children Recent retrospective analyses have shown improved survival in patients who received a higher ratio of blood products, but prospective studies have not clearly demonstrated an improvement in outcome with this approach.70,71 While the reasons for this are unclear, some studies have suggested that the criteria established in adults to identify those patients who will require massive transfusion may not be appropriate for children While blood product use and blood bank–related costs have been shown to be less with such transfusion regimens, there remains some concern over an increase in side effects (e.g., transfusion-related acute lung injury [TRALI]) with more plasma-rich transfusion regimens.72,73 The use of solvent-detergent processed plasma may reduce the risk of TRALI Some centers have investigated the use of rotational elastometry to guide blood product transfusion in trauma patients, but these methods have not yet been widely accepted in clinical practice.74 Anticoagulant Overdose The possibility of errors in administration of prophylactic or therapeutic anticoagulant therapy in critically ill children always exists Methods of prophylactic anticoagulant use, systemic anticoagulation, and thrombolytic therapy are sometimes poorly standardized and may lead to overdose ... correct within 12 to 24 hours after this dose However, serial dosing of critically ill patients is often used, and the PT may require up to 72 hours to normalize If the PT does not correct within... the full pentad, up to 75% will manifest a triad of microangiopathic hemolytic anemia, neurologic symptoms, and thrombocytopenia This disorder has been shown to result from the absence of a vWF–cleaving... sepsis, a microangiopathic blood smear with marked thrombocytopenia, and a clinical course with rapid development of multiorgan failure and poor prognosis.54 The etiology of this disorder is unclear,