1068 e1 eTABLE 89 6 Platelet Disorders Seen in the Intensive Care Unit Quantitative Increased Destruction Immune • Idiopathic thrombocytopenic purpura • Systemic lupus erythematosus • Acquired immunod[.]
1068.e1 eTABLE Platelet Disorders Seen in the Intensive Care Unit 89.6 Quantitative Increased Destruction Immune • • • • • Idiopathic thrombocytopenic purpura Systemic lupus erythematosus Acquired immunodeficiency syndrome Drugs (gold salts, heparin, sulfonamides, quinidine, quinine) Sepsis Nonimmune • Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome • Mechanical destruction (e.g., cardiopulmonary bypass, hyperthermia) • Consumption (i.e., disseminated intravascular coagulation) Decreased Production Marrow Suppression/Chemotherapy • Viral illness (e.g., cytomegalovirus Epstein-Barr virus, herpes simplex, parvovirus) • Drugs (thiazides, ethanol, cimetidine) Marrow Replacement • Tumor • Myelofibrosis Other Conditions • Splenic sequestration • Dilution (see massive transfusion syndrome) Qualitative Drugs Antiinflammatory Agents • Aspirin (irreversible) • Nonsteroidal antiinflammatory agents • Corticosteroids Antibiotics • • • • Penicillins (e.g., ampicillin, carbenicillin, ticarcillin, penicillin G) Cephalosporins (e.g., cephalothin) Nitrofurantoin Chloroquine, hydroxychloroquine Phosphodiesterase Inhibitors • Dipyridamole • Methylxanthines (e.g., theophylline) Other Drugs • • • • • • • • • • • Antihistamines a-blockers (e.g., phentolamine) b-blockers (e.g., propranolol) Dextran Ethanol Furosemide Heparin Local anesthetics (e.g., lidocaine) Phenothiazines Tricyclic antidepressants Nitrates (e.g., sodium nitroprusside, nitroglycerin) • • • • Uremia Stored whole blood Hypothyroidism Disseminated intravascular coagulation (i.e., FSP-mediated inhibition) Metabolic Causes Inherited • Glanzmann thrombasthenia • Bernard-Soulier FSP, Fibrin split product CHAPTER 89 Coagulation and Coagulopathy 1069 or transfusions at a higher transfusion threshold.92,93 Recent experience in combat trauma suggests that the transfusion of coldstored platelets may have a more prohemostatic effect than that obtained with standard room temperature–stored platelets.94 Consumption of platelets can also cause thrombocytopenia Mechanical destruction invariably occurs during cardiopulmonary bypass, extracorporeal life support, or the use of ventricular assist devices It is not uncommon to note a 50% drop in platelet count postbypass when compared with preoperative platelet levels Platelet counts generally recover toward preoperative levels by 48 to 72 hours after bypass High body temperatures seen in severe hyperthermic syndromes may also destroy platelets, and they are consumed during microvascular coagulation in DIC In many of these circumstances, the thrombocytopenia may be the sole or a contributing cause of significant bleeding Heparin-induced thrombocytopenia is discussed next as well as in Chapter 90 Heparin-Induced Thrombocytopenia Heparin is widely used in ICUs to maintain vascular access or as a therapy for acute thrombosis Exposure to heparin may result in thrombocytopenia; in a small number of cases, this may result in arterial thrombosis Thrombocytopenia may develop upon exposure to heparin in one of two ways Acute nonidiosyncratic thrombocytopenia is seen in 10% to 15% of patients who receive heparin The degree of thrombocytopenia is usually mild and usually remits despite continued use of the drug This has previously been referred to as type I heparin-induced thrombocytopenia (HIT) The thrombocytopenia results from the direct binding of the heparin molecule to the platelet surface, does not involve an immune mechanism, and has no clinical significance Heparin need not be stopped in these patients Idiosyncratic HIT is of much greater clinical consequence Although it is less frequent (typically seen in ,5% of patients who receive heparin), it has a much greater potential for clinical morbidity Arterial thrombosis is the most significant risk of this form of HIT (previously referred to as type II HIT) and may be life threatening, causing myocardial infarction, cerebrovascular accident, pulmonary embolism, or renal infarction The thrombosis is the consequence of the deposition of platelet aggregates in the microcirculation Thrombocytopenia in this disorder involves the formation of platelet aggregates mediated by the binding of a specific antibody, directed against a heparin-platelet factor-4 complex, to platelets in the presence of heparin This results in the activation of platelets and appears to require minuscule amounts of heparin Clinical bleeding is an infrequent problem in these patients Severe thrombocytopenia (i.e., ,15,000–20,000/µL) is unusual in this disorder From a practical perspective, the diagnosis of HIT is usually one of exclusion Clinical scoring systems to assess the probability of HIT have been developed, but they are more useful for identifying those individuals who are less likely to have HIT and are less sensitive in their ability to accurately identify adult or pediatric patients with HIT.95,96 Diagnostic markers exist (e.g., heparindependent platelet antibodies, platelet aggregation, or serotonin release), but these tests are best considered confirmatory and not exclusionary An enzyme-linked immunosorbent assay for heparindependent platelet antibodies is the most common test obtained to investigate a possible diagnosis of HIT, but because of a relatively high false-positive rate, it is generally recommended that a more specific heparin-induced platelet injury assay, such as a serotonin release assay, be performed for confirmation The diagnosis may be difficult to recognize because coexisting clinical illnesses with the potential to cause thrombocytopenia also may be present Although HIT may be more likely to be associated with the use of bovine lung heparin, it can occur after exposure to porcine heparin or, much less commonly, LMWH.97 When type II HIT is suspected or confirmed, all exposure to heparin—including heparin flushes, heparin in total parenteral nutrition, and heparincoated catheters—must be removed Anticoagulation with an alternate agent must be initiated because of the risk of delayed thrombosis, which can occur up to 30 days after removal of heparin exposure.98 Patients with type II HIT should receive continued anticoagulation with direct thrombin inhibitors (argatroban, bivalirudin) or with the heparinoid danaparoid (currently not available in the United States) Although anti-Xa agents, such as fondaparinux, may also be used, direct thrombin inhibitors are preferred, as they carry no risk of cross-reacting with the heparindependent antibodies already present Of the members of this class of anticoagulants, bivalirudin is gaining increasing preference for anticoagulation in children at high risk for or with suspected or documented HIT Bivalirudin is largely cleared by proteolysis in the plasma; argatroban is cleared by the liver and lepirudin by the kidney Consequently, the choice and dose of drug may be affected by the presence of hepatic or renal insufficiency Although there are pharmacokinetic and safety data for use in children for bivalirudin and argatroban, there are no similar data pertaining to the use of lepirudin in children Warfarin alone is not adequate therapy for suspected type II HIT because of the risk of thrombosis from depression of PC levels However, warfarin can be used in conjunction with a direct thrombin inhibitor and subsequently continued as a single agent once therapeutic suppression of vitamin K–dependent clotting factors has been achieved Limited reports on the use of the new orally available direct thrombin inhibitors in the therapy of HIT suggest that these agents may become useful as “alternative anticoagulants” when HIT is suspected or confirmed.99 Qualitative Platelet Disorders Many of the drugs frequently used in the ICU have the potential to impair platelet function More seriously ill patients are more likely to be exposed to more drugs and to display underlying pathophysiologic conditions that predispose to bleeding A short list of the drugs that can affect at least in vitro platelet function is presented in eTable 89.6 All unnecessary drugs should be viewed as suspect and discontinued in patients with evidence of qualitative platelet dysfunction or in those in whom it is strongly suspected In most cases, terminating the offending drugs(s) usually restores normal platelet activity Aspirin is a notable exception, as it irreversibly inhibits platelet cyclooxygenase, resulting in a defect that lasts for the duration of the platelet life span (8–9 days) The effect is profound: A single 325-mg aspirin tablet results in a qualitative platelet defect that remains in 50% of the circulating platelets days after its ingestion Ideally, all aspirin ingestion should be avoided for at least days prior to an elective invasive procedure New drugs that target the adenosine diphosphate P2Y12 receptor on the surface of platelets (e.g., clopidogrel, prasugrel, ticagrelor) also produce a prolonged inhibition of platelet reactivity that may last up to weeks following discontinuance of the drug depending on the duration of therapy NSAIDs similarly affect the platelet cyclooxygenase enzyme However, their effects are reversible, and normal platelet function 1070 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology is usually restored within 24 hours of the last dose Under most circumstances, the degree of platelet inhibition produced by these agents is not clinically significant; thus, patients can receive these drugs for analgesia and fever control However, it is reasonable to minimize their use in the bleeding severely thrombocytopenic patient The b-lactam antibiotics can sterically hinder the binding of a platelet aggregation agonist (e.g., adenosine diphosphate) to its specific platelet receptor, resulting in impaired platelet aggregation under circumstances of normal physiologic stimulation This, too, is reversed on removal of the drug Fortunately, only a minority of patients exposed to these antibiotics will exhibit clinically significant platelet inhibition In the PICU, the possibility must always be considered that a patient with bleeding suggestive of a platelet defect might have an inherited disorder of platelet function.100 Though rare, these disorders are encountered from time to time and include Glanzmann thrombasthenia (abnormal platelet GPIIb/IIIa), Bernard-Soulier syndrome (abnormal GPIb/IX), Wiskott-Aldrich syndrome, platelet storage pool deficiency (abnormal platelet-dense bodies), and the gray platelet disorder (abnormal platelet a-granules) Individuals with vitamin C deficiency (scurvy) or those with collagen disorders (e.g., Ehlers-Danlos syndrome) will present with mucocutaneous bleeding but have normal platelet number and in vitro function The defect in these conditions is the production of abnormal collagen that is unable to support platelet adhesion, resulting in poor clot initiation and tensile strength Vitamin C deficiency is an acquired defect in collagen structure, whereas Ehlers-Danlos syndrome is congenital Individuals with scurvy typically have hypertrophied purpuric gums, whereas those with Ehlers-Danlos syndrome (and related disorders) have a lifelong history of joint dislocations and poor wound healing Individuals with vWD (either congenital or acquired) frequently present with mucocutaneous bleeding, and many will also have a variably prolonged aPTT as a result of the secondary decrease in FVIII in this disease.34 Management Because many of the adverse drug-related platelet effects are reversible, all unnecessary medications should be discontinued promptly when platelet function seems impaired The more controversial issue is deciding whether platelet transfusions are warranted in a particular patient The relationship of thrombocytopenia to clinical bleeding is relative—that is, it is difficult to identify a specific, arbitrary platelet count (threshold) below which bleeding is likely to occur.102,103 Several conditions, such as massive transfusion syndrome and DIC, may respond to empirical platelet transfusion at counts as high as 80,000 or even 100,000 platelets/mL, although significant bleeding in the presence of a platelet count of 40,000 to 50,000/mL (or greater) is unlikely to be a result of the thrombocytopenia With other causes, such as thrombocytopenia seen with cancer chemotherapy and bone marrow aplasia, prophylactic therapy may not be required (recommended) until counts fall below 10,000 to 20,000/mL.101 Platelet transfusions to treat drug-induced platelet function impairment are of limited benefit until the offending drug has been discontinued and cleared from circulation Recombinant human FVIIa has been used to reverse the hemostatic defect caused by aspirin or clopidogrel The morbidity and mortality related to bleeding increase measurably in patients who undergo aggressive chemotherapy when the platelet count falls below 10,000 to 20,000/mL Empirical administration of platelets to these patients significantly limits both morbidity and mortality This finding has resulted in the administration of prophylactic platelet transfusions to most patients receiving cancer chemotherapy once their platelet count falls below this threshold However, the application of this practice for all other patients with platelet counts in this range irrespective of cause is unclear A major concern that should temper the empirical use of platelet transfusion is the development of alloimmunization to transfused platelets, potentially negating any future benefit from platelet transfusion in a time of need, as well as documented poorer outcome in patients who have received platelet transfusions.91,92 Patients with aplastic anemia appear to have a particularly high incidence of platelet alloimmunization following transfusion Patients with autoimmune disorders associated with increased peripheral platelet destruction, drug-related thrombocytopenia, and disorders causing splenic sequestration are unlikely to benefit from platelet transfusion; thus, routine platelet transfusions should be avoided for these patients An exception is related to planned, invasive procedures with an increased risk of bleeding In this situation, empirical platelet transfusion immediately before the procedure may be reasonable, but benefit from preprocedure platelet transfusions has not been shown.102–105 Defects Associated With Acquired vWF Defects Uremia Uremia is commonly seen in the ICU and is associated with an increased risk of bleeding Uremia has been shown to cause a reversible impairment of platelet function, although the toxin responsible for this defect is not well defined.44 Some studies have demonstrated an impairment of platelet-vessel wall interactions and suggest defects in vWF and/or ECs The degree of platelet impairment appears to be related to the severity of uremia for a given patient In addition, thrombotic events are also increased in patients with uremia These, too, appear to be multifactorial in etiology but in part may reflect the increased renal loss of ATIII and PS that may occur with nephritic-range proteinuria Several therapeutic approaches may modulate the qualitative platelet defect associated with uremia The primary therapy in this setting is effective dialysis, which has been shown to reduce documented defects in platelet function and plasma vWF parameters Bleeding time is shortened with an increase in hematocrit following transfusion of red cells Cryoprecipitate, 1-deamino-8-D-arginine vasopressin (DDAVP; 0.3 mg/kg, maximum dose 21 mg), and conjugated estrogens (10 mg/day in adult patients) have been shown to improve primary hemostasis in patients with severe uremia Treatment with cryoprecipitate or DDAVP increases the plasma concentration of the large multimeric forms of vWF, thus greatly improving platelet adhesion However, the duration of action of these agents is limited, with peak effect at between and hours Additional doses of DDAVP during the same 24-hour period may result in a diminished response to the drug (tachyphylaxis) with little or no further benefit Patients who exhibit tachyphylaxis to DDAVP may require 48 to 72 hours before responding to this agent again Repeated administration of DDAVP may result in significant hyponatremia, particularly in infants and young children The mechanism of action of the conjugated estrogens is not known In contrast to infusion of cryoprecipitate or DDAVP, the effect of estrogen is more protracted and does not diminish with repeat dosing, although a benefit is frequently not apparent until to days after therapy begins CHAPTER 89 Coagulation and Coagulopathy Thrombocytopenia-Associated Multiorgan Failure As noted earlier, TAMOF is a syndrome characterized by thrombocytopenia and the development of multiorgan failure.54 The pathoetiology of this syndrome is related to a decrease in ADAMST13 resulting in the circulation of ultra-high molecular weight vWF (U-vWF), which has enhanced affinity for its platelet receptor (eFig 89.12) Binding to this receptor causes increased platelet adhesion and aggregation with consequent microvascular thrombi formation Early studies suggest that plasma exchange with replacement of ADAMST13 can arrest the process and reduce the development of organ failure Cardiac-Induced Hemostatic Disorders Cyanotic cardiac disorders have been shown to cause an acquired platelet function defect, characterized by reduced aggregation responses to usual agonists, that remits once the baseline hematocrit is reduced toward normal It is believed that the platelet defect is secondary to exhaustion of platelets in circulation by enhanced interaction with endothelial surfaces A clinically more important defect in vWF has also been described in patients with cardiac lesions that produce increased shear in circulation The presence of increased shear results in changes to both platelet surface receptors and to circulating vWF, with resultant increased binding of vWF to platelets and increased platelet/vWF clearance from circulation Analysis of plasma vWF profile will demonstrate a decrease in high-molecular-weight vWF multimers, suggestive of a type II vWF disorder The abnormality of vWF multimer profile remits once the cardiac lesion is corrected.106 A similar phenomenon can be caused by intravascular ventricular assist devices and with ECMO Systemic Diseases Associated With Factor Deficiencies Patients with amyloidosis, Gaucher disease, or nephrotic syndrome are occasionally admitted to the PICU for the care of a severe acute illness Each may have one or more associated factor deficiencies that may complicate patient management and result in bleeding Patients with either amyloidosis or Gaucher disease may develop FIX deficiency FX deficiency has also been associated with amyloidosis These deficiencies generally result from the adsorption of the specific clotting factor by the abnormal proteins present in each disorder In the nephrotic syndrome, FIX deficiency may develop Although it was originally thought that proteinuria was responsible for the development of FIX deficiency, this does not appear to be the case The deficiency typically remits with corticosteroid therapy Thrombophilia and Immunothrombosis Thrombophilia is the clinical state of being predisposed to developing pathologic clots While fewer than 50% of children who experience a venous or arterial thrombotic event will be found to have an inherited risk factor, most individuals with thrombophilia (i.e., with recurrent such events) will ultimately be found to express an underlying abnormality in hemostasis balance or an anatomic variation that increases the chance of developing a thrombus in a specific region Most of these individuals will develop clots only in the setting of some identified event such as trauma or an acute illness.107,108 Children who carry one of the inherited risk factors are less likely to develop pathologic clots than are older adults, likely due to the lack of acquired risk factors such as obesity or hypertension and because their endothelium is generally 1071 healthier However, children with acute critical illness and those with chronic disorders characterized by chronic inflammation are at risk Overall, the incidence of thrombosis in children is lower than in adults In critically ill children, several risk factors have been found that identify those children at greatest risk These include infants, adolescents (older than 13–15 years), obesity, elevated FVIII activity, and the presence of a percutaneous central venous catheter (CVC) The presence of a CVC represents the greatest risk, and thrombi associated with the CVC are the most commonly identified Extrapolation from data obtained on populations including adolescents and young adults would suggest that individuals who have chronic or severe acute inflammation would also be at risk for thromboembolic events Studies to assess whether the presence of an identified thrombophilic risk factor increases the risk of developing a CVC-related thrombus have shown at most a weak association.109 Immunothrombosis is the term given to microvascular thrombi that develop as a result of a prothrombotic environment created by the interplay of coagulation and immune activation/inflammation This process involves platelets through their role in the development of intracellular neutrophil extracellular traps (NETs) and NETosis.110 In critically ill children, the presence of inflammation and infection appears to play a strong role in the development of pathologic thrombi As studies have increasingly shown the role that platelets play in host responses to pathogens, the concept of immunothrombosis—in which the crosstalk between coagulation and immune systems creates an environment that facilitates thrombus formation—has gained acceptance.3,111,112 While studies have shown that the development of a venous thrombosis in PICU patients prolongs length of stay and increases morbidity and mortality, the issue of who in the PICU requires prophylactic anticoagulation has not yet been adequately studied to justify institution of broad treatment guidelines Consequently, clinicians must use their best judgment regarding this issue Summary Critically ill children are at risk for developing secondary issues of unbalanced hemostasis manifested by either bleeding or unwanted clotting The intensivist must be aware of this possibility and take appropriate measures to address these issues before they become major factors in patient management and outcome To accomplish this goal, the intensivist must first be aware of what can happen and have sufficient understanding of the elements involved in normal hemostasis to be able to formulate an initial diagnostic and therapeutic plan, and to know when consultation with hematology is warranted Key References Bonar RA, Lippi G, Favaloro EJ Overview of hemostasis and thrombosis and contribution of laboratory testing to diagnosis and management of hemostasis and thrombosis disorders Methods Mol Biol 2017; 1646:3-27 Chima RS, Hanson SJ Venous thromboembolism in critical illness and trauma: pediatric perspectives Front Pediatr 2017;5:47 Colling ME, Bendapudi PK Purpura fulminans: mechanism and management of dysregulated hemostasis Transfus Med Rev 2018;32(2): 69-76 Fortenberry JD, Nguyen T, Grunwell JR, et al Thrombocytopenia-Associated Multiple Organ Failure (TAMOF) Network Study Group Therapeutic plasma exchange in children with thrombocytopenia-associated 1071.e1 Blood flow ADAMTS13 GPIb Normal hemostasis vWF No ADAMTS13 Vessel wall TAMOF • eFig 89.12 Thrombocytopenia-associated multiorgan failure (TAMOF): von Willebrand factor (vWF) and platelet adhesion/aggregation vWF binds to platelets and endothelial cells via the glycoprotein Ib/IX/V complex (GPIb) on the platelet surface, enabling platelet adhesion to endothelial cells and platelet-to-platelet aggregation In the presence of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motifs 1), unusually large vWF multimers (ULvWF) are cleaved (shortened), limiting their ability to support adhesion In the absence of ADAMTS13, ULvWF persist in circulation and platelet adhesion is enhanced, with consequent initiation of microvascular occlusion/thrombosis ... mortality This finding has resulted in the administration of prophylactic platelet transfusions to most patients receiving cancer chemotherapy once their platelet count falls below this threshold... platelet count falls below this threshold However, the application of this practice for all other patients with platelet counts in this range irrespective of cause is unclear A major concern that... intensivist must be aware of this possibility and take appropriate measures to address these issues before they become major factors in patient management and outcome To accomplish this goal, the intensivist