1059 e1 eTABLE 89 1 Thrombophilic Factors Inherited Acquired Protein C deficiency Critical illness, trauma Protein S deficiency Central venous catheters Antithrombin deficiency Oral contraceptives (es[.]
1059.e1 eTABLE Thrombophilic Factors 89.1 Critical illness, trauma Protein S deficiency Central venous catheters Antithrombin deficiency Oral contraceptives (estrogen) Elevated factor VIII Pregnancy Dysfibrinogenemia Obesity Factor V Leiden mutation Age (infancy, adolescence) Prothrombin gene mutation (G20210A) Elevated homocysteine Antiphospholipid antibodies (especially, anti-PS, antib2-glycoprotein-1 antibodies) ADP (10 µM) Aggregation (%) ADP (100 µM) p 70 60s c Aggregation (%) A c collagen (3 µg/mL) adrenaline (10 µM) ADP (10 µM) + (1 µM) AR-C67085 p p c ATP secretion (nmol) Acquired p 70 60s ADP (100 µM) c p 60s collagen (1 µg/mL) p p c c c B ATP secretion (nmol) Inherited Protein C deficiency PAR1 (100 àM) c p 60s ãeFig 89.10 Normal platelet aggregation Tracing of platelet aggregation curves measured by light trans- mission aggregometry (LTA) Following exposure to a platelet agonist (e.g., adenosine diphosphate [ADP], epinephrine, collagen, thrombin), light transmission through a suspension is initially decreased (upward deflection in these graphs), reflecting platelet shape change with an increase in cross-sectional diameter Following this brief decrease in light transmission, light transmission through the cuvette increase as platelets aggregate together Degree of platelet response to the agonist is calculated in comparison with the curve to that obtained with “normal” platelets (A) C, normal control aggregation responses to platelet agonists; P, abnormal (patient) responses to platelet agonists (B) Platelet adenosine triphosphate (ATP) secretion in response to ADP (top) or protease-activated receptor (PAR1) (bottom) 1059.e2 eTABLE Variables Measured by TEG and ROTEM 89.2 Variable TEG ROTEM Measurement period – Reaction time Time from start to when waveform reaches mm above baseline R Clotting time Time from mm above baseline to 20 mm above baseline K Clot formation time Alpha angle (degree) , (slope between R and K) , (angle of tangent at mm amplitude) Maximum strength Maximal amplitude Maximal clot firmness Time to maximum strength – MCF-t Amplitude at a specific time A30, A60 A5, A10 Clot elasticity G MCE Maximum lysis - CLF Clot lysis (CL) at a specific time (minutes) CL30, CL60 LY30, LY45, LY60 Time to lysis mm from maximal amplitude CLT; 10% difference from maximum clot firmness CLF, Maximum clot lysis; CLT, clot lysis time; MCE, maximum clot elasticity; ROTEM, rotational thromboelastometry; TEG, thromboelastography 1059.e3 A Thromboelastogram (TEG) Coagulation Fibrinolysis Platelets (MA) Platelet function Clot strength (G) Fibrinogen (K,α) Thrombolysins (Ly30, EPL) Clotting time Clotting kinetics Clot stability Clot breakdown Maximal Lysis (ML) [%] Maximum Clot Firmness (MCF/MA) [mm] 20 mm 60 mm Thromboelastometry (ROTEM) 90 mm Firmness B Enzymatic (R) Clotting time (CT/r) [sec] Clot formation time (CFT/k) [sec] • eFig 89.11 Assessment and interpretation of clot parameters by thromboelastography (TEG) and rota- tional thromboelastometry (ROTEM) (A) TEG: clotting time (R) reflects effect of clotting factors on initiation of clot formation; clot kinetics (k) measures rate of clot formation and reflects generation of fibrin from fibrinogen; maximal amplitude (MA) measures clot firmness related to platelet involvement; clot lysis (Ly) measures fibrinolysis (B) ROTEM: clotting time (CT) is equivalent to TEG R time; clot formation time (CFT) is equivalent to TEG k; maximum clot firmness (MCF) is equivalent to TEG MA; maximum lysis (ML) is equivalent to TEG Ly 1059.e4 eTABLE Hemorrhagic Syndromes and Associated Laboratory Findings 89.3 Clinical Syndrome Screening Tests Supportive Tests Disseminated intravascular coagulation (DIC) Prolonged PT, aPTT, TT; decreased fibrinogen, platelets; microangiopathy (1) FDPs, D-dimer; decreased factors V, VIII, and II (late) Massive transfusion Prolonged PT, aPTT; decreased fibrinogen, platelets prolonged TT All factors decreased; (–) FDPs, D-dimer (unless DIC develops); (1) transfusion history Heparin Prolonged aPTT, TT; prolonged PT Toluidine blue/protamine corrects TT; reptilase time normal Warfarin (same as vitamin K deficiency) Prolonged PT; prolonged aPTT (severe); normal TT, fibrinogen, platelets Vitamin K–dependent factors decreased; factors V, VIII normal Early Prolonged PT Decreased FVII Late Prolonged PT, aPTT; decreased fibrinogen (terminal liver failure); normal platelet count (if splenomegaly absent) Decreased factors II, V, VII, IX, and X; decreased plasminogen; FDPs unless DIC develops Primary fibrinolysis Prolonged PT, aPTT, TT; decreased fibrinogen platelets decreased (1) FDPs, (–) D-dimer; short euglobulin clot lysis time Thrombotic thrombocytopenic purpura Thrombocytopenia, microangiopathy with mild anemia; PT, aPTT, fibrinogen generally within normal limits/mildly abnormal ADAMTS13 deficiency/inhibitor, unusually large von Willebrand factor multimers between episodes; mild increase in FDPs or D-dimer Anticoagulant Overdose Liver Disease ADAMTS13, A Disintegrin And Metalloprotease with Thrombospondin MotifS 1, type 13; aPTT, activated partial thromboplastin time; FDPs, fibrin degradation products; PT, prothrombin time; TT, thrombin time 1060 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology • BOX 89.4 Underlying Diseases Associated With Disseminated Intravascular Coagulation Sepsis Liver disease Shock Penetrating brain injury Necrotizing pneumonitis Tissue necrosis/crush injury Intravascular hemolysis Acute promyelocytic leukemia Thermal injury Freshwater drowning Fat embolism syndrome Retained placenta Hypertonic saline solution Amniotic fluid embolus Retention of dead fetus Eclampsia Localized endothelial injury (aortic aneurysm, giant hematoma, angiography) Disseminated malignancy (prostate, pancreatic) Fibrinolysis invariably accompanies thrombin formation in DIC; thrombin generation or release of the tissue plasminogen activator usually initiates this process Plasmin is generated, which then digests fibrinogen and fibrin clots as they form Plasmin also inactivates several activated coagulation factors and impairs platelet aggregation As such, DIC represents an imbalance between the activity of thrombin, which leads to microvascular thrombi with coagulation factor and platelet consumption, and plasmin, which degrades these fibrin-based clots as they form.35 Therefore, thrombin-induced coagulation factor consumption, thrombocytopenia, and plasmin generation contribute to the presence of bleeding Globally, DIC represents an imbalance between clot formation (coagulation) and clot breakdown (fibrinolysis) Initially, DIC is a thrombotic disorder characterized by microvascular thrombosis, with bleeding occurring only when the consumption of platelets and clotting factors outpaces the ability to replace these critical elements In addition to bleeding complications, the presence of fibrin thrombi in the microcirculation can lead to ischemic tissue injury Pathologic data indicate that renal failure, acrocyanosis, multifocal pulmonary emboli, and transient cerebral ischemia may be related clinically to the presence of such thrombi The presence of fibrinopeptides A and B (resulting from enzymatic cleavage of fibrinogen) leads to pulmonary and systemic vasoconstriction, which can potentiate an existing ischemic injury In a given patient with DIC, either bleeding or thrombotic tendencies may predominate; in most patients, bleeding is usually the predominant problem However, in up to 10% of patients with DIC, the presentation is exclusively thrombotic (e.g., pulmonary emboli with pulmonary hypertension, renal insufficiency, altered mental status, acrocyanosis) without hemorrhage Whether the presentation of DIC is thrombotic, hemorrhagic, or compensated (i.e., laboratory results are consistent with DIC without overt bleeding), endothelial injury and microthrombosis likely contribute to the development and progression of multiorgan failure.38,40 Clinical Presentation and Diagnosis DIC is often suspected when there is unexplained, generalized oozing or bleeding; unexplained, abnormal laboratory parameters of hemostasis; or both This usually occurs in the context of a TABLE Laboratory Tests for Diagnosis of Disseminated 89.4 Intravascular Coagulation Test Discriminator Value Platelet count ,80–100,000 or a decrease of 50% from baseline Fibrinogen ,100 mg/dL or a decrease of 50% from baseline Prothrombin time second prolongation above upper limit of normal Fibrin degradation products 80 mg/dL D-dimer Moderate increase suggestive clinical scenario or associated disease.35,37 Although infection and multiple trauma are the most common underlying conditions associated with the development of DIC, certain other organ system dysfunctions predispose to DIC, including hepatic insufficiency and splenectomy Each of these conditions is associated with impaired reticuloendothelial system function and consequent impaired clearance of activated coagulation proteins and fibrin/fibrinogen degradation fragments, which may inhibit fibrin polymerization and clot formation The clinical severity of DIC has traditionally been assessed by the severity of bleeding and coagulation abnormalities Scoring tools that employ a panel of laboratory tests along with severity of illness scores to assess the likelihood and severity of DIC have been proposed to assist in determining prognosis at the time of diagnosis and better direct initial therapy The tests most commonly employed in many of these scoring systems for the diagnosis of DIC are listed in Table 89.4 The more commonly employed scoring systems identify those patients at higher or lesser risk for having DIC based on either a qualitative or quantitative score Each has been validated in adults with DIC, and several have been shown to be useful in the assessment of DIC in pediatric patients.41 Limited studies have shown that early identification of DIC, before the onset of a gross hemorrhagic diathesis, improves survival in critically ill children The combination of a prolonged PT, hypofibrinogenemia, thrombocytopenia, and evidence of microangiopathic hemolysis on peripheral blood smear (i.e., red blood cell [RBC] schistocytes) in the appropriate clinical setting is sufficient to suspect the diagnosis of DIC Severe hepatic insufficiency (with splenomegaly and splenic sequestration of platelets) can yield a similar laboratory profile and must be ruled out In addition to liver disease, several other conditions have presenting findings similar to those of DIC and must be considered in the differential diagnosis, as the specific diagnosis may direct therapies These entities include the coagulopathy of massive transfusion, primary fibrinolysis, thrombotic thrombocytopenic purpura (TTP), atypical hemolytic uremic syndrome (aHUS), heparin therapy, and dysfibrinogenemia.42–44 Although TTP and hemolytic uremic syndrome (HUS) demonstrate findings consistent with a microangiopathy, the coagulation profile noted with these disorders generally does not strongly suggest DIC Conversely, the conditions that may present a coagulation profile suggestive of DIC generally not manifest peripheral blood findings of microangiopathic hemolysis A comparison of the laboratory findings in these disorders is noted in eTable 89.3 ... thrombocytopenic purpura Thrombocytopenia, microangiopathy with mild anemia; PT, aPTT, fibrinogen generally within normal limits/mildly abnormal ADAMTS13 deficiency/inhibitor, unusually large von Willebrand... formation in DIC; thrombin generation or release of the tissue plasminogen activator usually initiates this process Plasmin is generated, which then digests fibrinogen and fibrin clots as they form Plasmin... generalized oozing or bleeding; unexplained, abnormal laboratory parameters of hemostasis; or both This usually occurs in the context of a TABLE Laboratory Tests for Diagnosis of Disseminated 89.4