Coagulation Issues in the Picu

Robert I. Parker

David G. Nichols

KEY POINTS

Hemostasis is a dynamic process. Once bleeding occurs, clot formation and degradation (fibrinolysis) are also initiated.

Coagulation is an integral part of inflammation, and inflammation may lead to microvascular thrombosis.

A consumptive coagulopathy (DIC) should always be considered in a patient with diffuse or generalized bleeding; however, liver disease and vitamin K deficiency are more common.

Localized bleeding in a trauma or postoperative patient should prompt notification of surgical staff and search for an anatomic source of the bleeding.

Thrombotic events are being recognized with increased frequency in the PICU. Only 60% of children with documented thromboses will have an identifiable hematologic abnormality.

Recombinant factor VIIa has been used to control refractory hemorrhage, but its use has not yet been shown to improve outcome and consequently may not justify accompanying risks.

Neither the prothrombin time nor the International Normalized Ratio (INR) reflect bleeding risk accurately in patients with liver disease.

The presence of a central venous catheter is the most commonly identified thrombotic risk factor in critically ill children.

The coagulopathic conditions frequently encountered in the PICU can be arbitrarily divided into three categories: (1) conditions associated with serious bleeding or a high probability of bleeding, (2) thrombotic syndromes or conditions associated with a higher probability of thrombosis, and (3) systemic diseases associated with selective coagulation factor deficiencies (Table 118.1). These categories are prioritized to suggest their relative importance to the critical care practitioner.

OVERVIEW OF COAGULATION

Traditionally, the process of blood clotting has been presented in a series of discrete functional units, the “intrinsic” (contact activation), “extrinsic” (tissue factor [TF]),^* and “common” pathways, that progress in an orderly nonoverlapping sequence (Fig. 118.1). While simplification of hemostasis facilitates a basic level of understanding, it obscures the fact that, once initiated, clot production and clot destruction (fibrinolysis)

occur simultaneously, and it minimizes an identification of the contributions inflammation, platelets, and the endothelium make in the overall process. Central to this broader understanding is the realization of the primacy of Factor VII (F.VII) and TF. After damage to vascular endothelium, blood comes in contact with TF expressed on fibroblasts and leukocytes. TF triggers both the cellular component of hemostasis (by activating platelets to form a primary platelet plug) and the soluble (protein) component by binding with activated F.VII. The TF-F.VIIa complex unleashes a cascade of protein reactions that ultimately result in the production of fibrin strands, which reinforce the platelet plug.

The “intrinsic” pathway begins with the activation of factor XII (F.XII) to activated factor XII (F.XIIa) through contact with a biologic or foreign surface. Historically, it was believed to be the most important pathway in the initiation of clot formation because deficiencies of downstream factors F.VIII or F.IX produced severe bleeding diatheses (hemophilia A or B, respectively). However, it is now known that the activation of F.X to F.Xa through the action of the F.VIIa/TF complex plays a more central role in coagulation (1,2).

The central role F.X is captured in the term tenase, which is a contraction of “ten” and “-ase” (the suffix used to describe enzymatic action) and illustrates the general principle of concerted action in the coagulation cascade. The term tenase describes the action of F.VIIa/TF complex, along with the F.IXa/F. VIIIa complex on the activation of F.X to F.Xa. The term prothrombinase is another example of concerted action in the coagulation cascade and describes the F.Xa/F.Va complex, which cleaves prothrombin (F.II) to form thrombin (F.IIa).

“Crosstalk,” “positive feedback loops,” and “surface contact” are additional important characteristics of the clotting process. It is now known that crosstalk occurs between the two arms of the clotting cascade, such that F.VIIa (from the extrinsic pathway) enhances the activation of F.IX (to F.IXa) and of F.XI (to F.XIa) (from the intrinsic pathway), further highlighting the central role of F.VIIa and TF in vivo (Fig. 118.2). Furthermore, thrombin initiates various positive feedback loops to enhance the “upstream” activation of the clotting process. The activation of coagulation is initiated from TF, which is found in the subendothelial matrix, on cellular elements (e.g., monocytes) and circulating in plasma as soluble TF. However, clotting does not occur in
free-flowing blood, but rather on surfaces. Platelets, endothelial cells, the subendothelial matrix, and biologic polymers (e.g., catheters, grafts, stents, etc.) provide the surfaces for clot formation.

TABLE 118.1 OVERVIEW OF COAGULATION DISORDERS

Conditions associated with serious bleeding or a high probability of bleeding
Disseminated intravascular coagulation
Liver disease/hepatic insufficiency
Vitamin K deficiency/depletion
Massive transfusion syndrome
Anticoagulant overdose (heparin, warfarin)
Thrombocytopenia (drug induced, immunologic)
Acquired platelet defects (drug induced, uremia)
Thrombotic conditions
Thrombotic thrombocytopenia purpura/hemolytic uremic syndrome
Deep venous thrombosis
Pulmonary embolism
Coronary thrombosis/acute myocardial infarction
Systemic conditions associated with selective coagulation factor deficiencies
Hemophilia (A and B)
Specific factor deficiencies associated with specific diseases
	Amyloidosis-factor X, Gaucher disease-factor IX, nephritic syndrome-factor IX, antithrombin III
	Cyanotic congenital heart disease (polycythemia, qualitative platelet defect)
	Depressed clotting factor levels (newborns)
Laboratory abnormalities not associated with clinically significant bleeding
Lupus anticoagulant
Reactive hyperfibrinogenemia

Platelets not only initiate the clot formation through the formation of a platelet plug, but more importantly, they bring specialized proteins that regulate the clotting response (e.g., F.VIII, inhibitors of fibrinolysis, etc.) to the area of bleeding and provide a surface for the co-localization of clotting factors for efficient clot formation (Fig. 118.3). Under “normal” (unstimulated) conditions, platelets do not adhere to the vascular endothelium, but when the endothelium is mechanically disrupted (e.g., cut) or activated by inflammation, platelets will adhere to the endothelial cell or subendothelial matrix via a von Willebrand factor-dependent mechanism. Once adherent, the platelets become activated and secrete various molecules that further enhance platelet adherence and aggregation, vascular contraction, clot formation, and wound healing (3).

FIGURE 118.1. “Classical” coagulation cascade. Serial activation of serine proteases from zymogen to active form resulting in fibrin clot formation. Those elements in RED represent cofactor for enzymatic steps. HMWK, high-molecular-weight kininogen; PK, prekallekrein; TF, tissue factor; PL, phospholipid; Ca, calcium; Clotting factors: XII, factor XII; XIIa, activated factor XII; XI, factor XI; XIa, activated factor XI; IX, factor IX; IXa: activated factor IX; VIIIa, activated factor VIII; VIIa, activated Factor VII; X, factor X; Xa, activated factor Xa; Va, activated factor V; II, prothrombin; IIa, thrombin; FBGN, fibrinogen; XIIIa, activated factor XIII.

The endothelium is a specialized organ that is integral to the regulation of clot formation (i.e., hemostasis), as it presents a nonthrombogenic surface to flowing blood but enhances clot formation when the endothelium is disrupted by trauma or injured by infection or inflammation (4,5) (Fig. 118.4). The normal endothelium produces inhibitors of blood coagulation and platelet activation and modulates vascular tone and permeability. Endothelial cells also synthesize and secrete components of the subendothelial extracellular matrix, including adhesive glycoproteins, collagen, fibronectin, and von Willebrand factor. When this system is disrupted, bleeding occurs. However, when inflamed, the endothelium often becomes a prothrombotic rather than an antithrombotic organ, and unwanted clot formation may occur.

Interaction of Coagulation and Inflammation

It is believed that the coagulation process developed during evolution as an intrinsic and integral component of human

host defense. Disseminated intravascular coagulation (DIC) illustrates the link between coagulation and inflammation. In DIC, coagulation pathways are activated, natural inhibitory pathways of coagulation are dysfunctional, and the fibrinolytic system is dysregulated. All of these are direct or indirect consequences of the inflammatory response. The natural inhibitory pathways of coagulation are of particular interest in this intersection of coagulation and inflammation, as potential therapies have been based around these biologic processes (6,7). Coagulation may be initiated in the flowing blood, on the endothelial surface, at endothelial lesions, in the perivascular tissues, and in deeper tissues not contiguous to
vascular structures. It may or may not be associated with the formation of fibrin clots (8).

FIGURE 118.2. “Classical” coagulation cascade with crosstalk. Thin lines with “+” indicate enhancement of generation of F.Xia and F.IXa by the F.VIIa/TF complex. HMWK, highmolecular-weight kininogen; PK, prekallekrein; TF, tissue factor; PL, phospholipid; Ca, calcium; Clotting factors: XII, factor XII; XIIa, activated factor XII; XI, factor XI; XI, activated factor XI; IX, factor IX; IXa, activated factor IX; VIIIa, activated factor VIII; VIIa, activated Factor VII; X, factor X; Xa, activated factor Xa; Va, activated factor V; II, prothrombin; IIa, thrombin; FBGN, fibrinogen; XIIIa, activated factor XIII.

FIGURE 118.3. The role of platelets in mediating primary hemostasis at sites of vascular injury. Platelets are initially activated and express specific adhesion receptors on their surface, followed by adhesion to activated endothelial cells and exposed subendothelial components (e.g., collagen, von Willebrand factor). Subsequent platelet aggregation occurs with the development of a primary platelet plug. Coagulation occurs on the developing platelet plug with the creation of a fibrin clot.

During sepsis, TF expression is upregulated in activated monocytes and endothelial cells as a response to endotoxin and other pathogen-associated/pathogen-initiated events. The upregulated TF expression results in the secretion of proinflammatory cytokines and activation of the coagulation cascade including increased thrombin generation. Prior to neutralization by antithrombin III, thrombin plays a central role in coagulation and inflammation through the induction of procoagulant, anticoagulant, inflammatory, and mitogenic responses (9). Thrombin results in the activation, aggregation, and lysis of leukocytes and platelets, as well as the activation of endothelial adhesion molecules and the expression of proinflammatory cytokines (IL-6). Thrombin increases endothelial permeability by causing contraction of endothelial cells; it also stimulates cellular proliferation. The net result of thrombin generation is the production of a procoagulant state, which leads to the formation of fibrin; the activation of factors V, VIII, IX, and XI; the expression of TF and von Willebrand factor; and the aggregation of platelets. Thrombin also has anti-inflammatory effects through the production of activated protein C (APC) (9) (see Fig. 118.4). Concurrent with coagulation activation, two other crucial mechanisms occur during sepsis. One is the depression of natural anticoagulant systems, involving antithrombin and protein C (PC), and the second is the inhibition of fibrinolysis through the production of plasminogen activator inhibitor type-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI) (Figs. 118.4 and 118.5). Other causes of reduced levels of antithrombin III (AT III) and PC include decreased production (impaired liver function), loss from the vascular space (capillary leakage), immaturity (AT III and PC levels are decreased at birth and do not achieve “near-adult” levels until 3-6 months of age), and consumption (conversion of PC to APC).

The Role of the Protein C System

Components of the PC system regulate coagulation (i.e., as natural anticoagulants) such that decreased activity of this pathway results in pathologic thrombosis. Activated protein C
(APC) also possesses intrinsic immunomodulating properties (see Fig. 118.5). In vitro, APC inhibits tumor necrosis factor-α elaboration from monocytes, blocks leukocyte adhesion to selectins, and influences apoptosis (9). The PC pathway is initiated by the binding of thrombin to thrombomodulin and forms a complex on the surface of endothelial cells. The binding of PC to the endothelial cell PC receptor augments PC activation by the thrombin-thrombomodulin complex more than tenfold. PC activation in sepsis and inflammation is downregulated when the exposure to inflammatory mediators and thrombin causes the endothelial cells to shed their PC receptors. The endothelial cell PC receptor (ECPCR) can also translocate from the plasma membrane to the nucleus and redirect gene expression. The translocation of the PC-receptor-APC complex to the nucleus may account for the ability of APC to modulate inflammatory mediator responses in the endothelium (9).

FIGURE 118.4. The interaction of the protein C system with the endothelium. Thrombin bound to thrombomodulin (TM) modifies protein C bound to the endothelial protein C receptor on the cell surface to generate activated protein C (APC). APC acts as a natural anticoagulant by inactivating activated factors V (fVa) and VIII (fVIIIa), modulating inflammation by downregulating the synthesis of proinflammatory cytokines, leukocyte adherence, and apoptosis and enhancing fibrinolysis by inhibiting thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor type-1 (PAI-1). C4Bbp, C4b binding protein; +PS, in the presence of protein S; sTM, soluble thrombomodulin; sEPCR, soluble endothelial cell protein C receptor.

FIGURE 118.5. Inflammation effect on coagulation. Inflammation enhances coagulation through the induction of proinflammatory cytokines that induce tissue factor formation, which in turn decreases activated protein C (APC) formation, leading to enhanced thrombin and fibrin generation. In addition, the decrease in APC allows for greater inhibition of fibrinolysis through the action of plasminogen activator inhibitor type-1 (PAI-1).

The third important property of APC is its influence on fibrinolysis, which is also involved with inflammation. APC is capable of neutralizing the fibrinolysis inhibitors PAI-1 and TAFI. PAI-1 is a 50-kDa glycoprotein of the serine protease inhibitor family. Its primary role in vivo is the inhibition of both tissue- and urokinase-type plasminogen activators. PAI-1 is an acute-phase protein that increases during acute inflammation. In patients with sepsis, increased levels of PAI-1 are
associated with increased levels of various cytokines and acute-phase proteins, abnormal coagulation parameters, increased severity of disease, and poorer outcomes. The regulation of the production of PAI-1 is multifactorial (Fig. 118.6). The 4G/5G insertion/deletion promoter polymorphism of the PAI-1 gene has been shown to affect PAI-1 plasma levels; individuals with the 4G/4G genotype display the highest PAI-1 levels while those with the 5G/5G genotype the lowest (the 4G/5G genotype results in intermediate levels). Differences in PAI-1 levels affect the risk of developing severe complications and death from sepsis. High PAI-1 levels are associated with increased mortality in animal models of sepsis and with increased severity of illness and organ dysfunction scores in septic patients (including children with meningococcal sepsis) (10,11,12). However, the regulation of PAI-1 levels involves more than just the promoters of its synthesis. Activated Protein C stimulates fibrinolysis by forming a tight 1:1 complex with PAI-1 leading to inactivation of PAI-1. High levels of thrombin lead to increased levels of APC, which can complex to PAI-1. This complex is subsequently cleared from the circulation, resulting in PC depletion (11). The increased formation and clearance of these complexes results in PC depletion (11), with the net result being an increased risk for microvascular thrombus formation.

FIGURE 118.6. Plasminogen activator inhibitor type 1 gene polymorphism and sepsis. Genetic and environmental influences on the expression of plasminogen activator inhibitor type 1 (PAI-1) and the importance of PAI-1 in the coagulation and fibrinolysis pathways. TNF-α, tumor necrosis factor-α; APC, activated protein C; TM, thrombomodulin; t-PA, tissue-type plasminogen activator; u-PA, urokinase-type plasminogen activator. (Redrawn from Hermans PW, Hazelzet JA. Plasminogen activator inhibitor type 1 gene polymorphism and sepsis. Clin Infect Dis 2005;41(suppl 7):S453-8.)

Thrombin generation also increases the levels of TAFI, an important negative regulator of the fibrinolytic system. TAFI has been shown to inactivate inflammatory peptides that play a role in the contact activation of coagulation, such as complement factors C3a and C5a. The full role of TAFI in the hemostatic and innate immune response to sepsis is still under investigation. The role of TAFI as a regulator of fibrinolysis appears to be of prognostic significance similar to that of PAI-1, that is, elevated levels, resulting in decreased fibrinolysis, appear to be associated with a poorer outcome in sepsis (13,14,15).

APPROACH TO THE PATIENT WITH AN ACTUAL OR SUSPECTED COAGULATION DISORDER

Clinical History

Diagnostic assessment begins at the bedside. The medical history, both past and present, may lend some insight into the cause of, or risk for, significant bleeding (16,17). A prior history of prolonged or excessive bleeding or of recurrent thrombosis may direct laboratory investigation and guide emergency therapy. Specific questions should include the occurrence of spontaneous, easy, or disproportionately severe bruising; intramuscular hematoma formation (either spontaneous or related to trauma); spontaneous or trauma-induced hemarthrosis; spontaneous mucous membrane bleeding; problematic bleeding related to surgery (including dental extractions, tonsillectomy, and circumcision); the need for transfusions; the quantity of bleeding during menses; and, finally, current medications.

In spite of the decreased use of aspirin in children, there remain numerous over-the-counter aspirin-containing medications that can potentially interfere with primary (platelet-mediated) hemostasis. Patients (and parents) may not be aware of the aspirin contained in these products. Many other drugs used in the ICU are also associated with bleeding
abnormalities and are discussed below. Additionally, in specific circumstances, herbal medications may contribute to impaired clot formation or abnormal bleeding (e.g., garlic, ginko, senna, cascara). In trauma and surgical situations, it is important to determine the severity of injury relative to the magnitude of bleeding that follows. A prior history of significant thrombosis (e.g., deep venous thrombosis, pulmonary embolus, stroke) suggests the possibility of a hypercoagulable condition. As thrombotic events are uncommon in children, the occurrence of thrombotic events, such as myocardial infarction in young, adult relatives, should cause the clinician to consider a congenital thrombophilic abnormality. These abnormalities include AT III deficiency, PC or protein S deficiency, factor V Leiden R506Q mutation, the prothrombin G20210A polymorphism/mutation, and (possibly) the C677T mutation/polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene (discussed below). In addition, vasculitis associated with an autoimmune disorder such as systemic lupus erythematosus (SLE) must be considered in the evaluation of a child with an unexplained clot. In all cases, the family history is important in attempting to separate congenital from acquired disorders.

In a general sense, defects in primary hemostasis (creation of the platelet plug) or secondary hemostasis (addition of fibrin to the platelet plug) can be separated according to the nature of the bleeding. Patients with primary hemostatic defects tend to manifest “capillary-type bleeding” including oozing from cuts or incisions, mucous membrane bleeding, or excessive bruising. This type of bleeding is seen in patients with quantitative or qualitative platelet defects or von Willebrand disease. In contrast, patients with dysfunction of secondary hemostasis tend to display “large-vessel bleeding,” characterized by hemarthrosis, intramuscular hematomas, and intracranial hemorrhage. This type of bleeding is most often associated with specific coagulation factor deficiencies or inhibitors. Patients with severe platelet-type defects may also manifest this type of bleeding. Consequently, the presence of only mucosal bleeding is more helpful as this would point to a platelet-type defect affecting mainly primary hemostasis rather than an abnormality of fibrin clot formation.

Physical Examination

Development of generalized bleeding in critically ill patients in the ICU presents a special problem. Such bleeding may be a marker for severe major organ dysfunction. Supportive evidence or physical findings of other concurrent organ system dysfunction (e.g., renal failure, liver failure, respiratory failure, and hypotension) often are readily apparent. Common

causes of generalized bleeding in critically ill children include sepsis-related DIC, massive transfusion syndrome (discussed below), severe liver dysfunction, undiagnosed hemophilia, battered child syndrome, and vitamin K deficiency in newborns or older children with malabsorption (18,19,20). In young infants (<3 months of age), the coagulation system is often not yet mature, and prolongation of the prothrombin time (PT) or activated partial thromboplastin time (aPTT) may not reflect an abnormality in hemostasis (21). Consultation with a pediatric hematologist may be indicated when trying to interpret “abnormal” results in this age group.

The physical examination of the patient with a bleeding

disorder should address several basic questions. Is the process localized or diffuse? Is it related to an anatomic or surgical lesion (e.g., bleeding localized to an area of trauma or recent surgical site not associated with generalized bleeding suggests a discrete anatomic cause for the bleeding rather than the presence of a generalized hemorrhagic diathesis)? Is the bleeding primarily muco-cutaneous? Finally, when appropriate, are there signs of thrombosis (either arterial or venous)? The answers to these questions may provide clues to the cause of the problem.

Several specific physical findings may be helpful in determining the etiology of a suspected hemostatic abnormality. For example, the presence of an enlarged spleen coupled with thrombocytopenia suggests splenic sequestration. Splenomegaly accompanied by prolongation of the PT and/or aPTT may be a consequence of underlying liver disease, while splenomegaly in the presence of a normal PT and aPTT may indicate a marrow infiltrative process. Furthermore, evidence of liver disease (e.g., varices, ascites) points to decreased factor synthesis as a possible etiology of a prolonged PT or aPTT. When lymphadenopathy, splenomegaly, or other findings suggestive of disseminated malignancy are detected, acute or chronic DIC should be suspected as the cause of prolonged coagulation times, hypofibrinogenemia, and/or thrombocytopenia. Palpable purpura suggests capillary leak from vasculitis, whereas purpura associated with thrombocytopenia or qualitative platelet defects is generally not palpable. Finally, venous or arterial telangiectasia may be seen in von Willebrand disease and liver disease, respectively. When selective pressure is centrally applied to an arterial telangiectasia, the entire lesion fades, whereas a venous telangiectasia requires confluent pressure across the entire lesion (as with a glass slide) for blanching to occur.

Laboratory Evaluation

Blood Sample Preparation

The importance of correct specimen collection for laboratory evaluation of hemostatic problems must be emphasized. In the PICU, it is common for laboratory samples to be drawn through an indwelling arterial or central venous cannula. Heparin is commonly present in the solutions used to flush these cannulae or as a component of an IV infusion. Depending on the concentration of heparin in the infusing fluid and the volume of blood withdrawn, several tests can be influenced. Heparin presence can cause fibrin degradation products (FDPs) to be falsely elevated and fibrinogen falsely low. Likewise, heparin contamination can spuriously prolong the PT, aPTT, and thrombin time (TT). Therefore, a minimum of 20 mL of blood in adolescents and adults (10 mL of blood in younger children) should be withdrawn through the cannula and either discarded, returned to the patient through a peripheral cannula, or used for other purposes before obtaining a specimen for laboratory hemostasis analysis (22). This practice should minimize any influence of heparin on the results. In young children and infants, it may not be reasonable to withdraw an adequate volume of waste blood, and a peripheral venipuncture may be necessary. Because the aPTT is sensitive to the presence of small amounts of heparin, an unexpected prolonged aPTT obtained through a heparinized catheter should raise the suspicion of sample contamination. In this setting, the TT will also be prolonged but will normalize if the contaminating heparin is neutralized (e.g., with protamine, toluidine blue, or Hepasorb).

Laboratory Results in Suspected Bleeding Disorders

The presence of most suspected bleeding disorders can be confirmed using routinely available tests including the peripheral blood smear (which provides an estimate of platelet number as well as platelet and red blood cell morphology), the PT, the aPTT, the TT, a fibrinogen level, FDPs, and the D-dimer fragment of polymerized fibrin. This latter test is more specific for the fibrinolytic fragment produced when the polymerized fibrin monomer is cleaved by the proteolytic enzyme plasmin. In contrast, the older assays for FDPs or fibrin split products will be positive even if fibrin is not produced and the fragments are the result of proteolytic degradation of native fibrinogen.
In most instances, measurement of the platelet count, fibrinogen level, PT, aPTT, and TT should be sufficient for determining the correct diagnosis. An unnecessary use of laboratory resources may be avoided by using these five screening tests and only ordering further, more specific, testing when a definitive diagnosis is necessary. Several major categories of hemorrhagic disorders and the tests that are characteristically abnormal in each are summarized in Table 118.2.

TABLE 118.2 COAGULATION DISORDERS AND ASSOCIATED LABORATORY FINDINGS

▪ CLINICAL SYNDROME	▪ SCREENING TESTS	▪ SUPPORTIVE TESTS
Disseminated intravascular coagulation	Prolonged PT, aPTT, TT; decreased fibrinogen, platelets; microangiopathy	(+) 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); (+) transfusion history
Anticoagulant overdose 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
Liver disease
Early	Prolonged PT	Decreased Factor VII
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	(+) 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	ADAMTS-13 deficiency/inhibitor, unusually large von Willebrand factor multimers between episodes; mild increase in FDPs or D-dimer
Hemolytic uremic syndrome	Microangiopathic hemolytic anemia, ± thrombocytopenia; PT, aPTT generally within normal limits	Renal insufficiency; FDPs and D-dimer generally (−)
PT, prothrombin time; aPTT, activated partial thromboplastin time; TT, thrombin time; FDPs, fibrin degradation products.

Patients who present with a thrombotic event will generally not display abnormalities of usual “clotting” studies; that is, their PT, aPTT, TT, and fibrinogen will usually be within normal ranges. The finding of a shortened PT or aPTT is not necessarily indicative of a prothrombotic or thrombophilic process

being present. While hyperfibrinogenemia (>400 mg/dL) and persistent elevations of F.VIII (>400%) have been associated with an increased risk of thrombosis in adults, both may be elevated by acute inflammation. Consequently, the finding of elevations of these clotting factors in a patient who has experienced an unexpected thrombotic event may not necessarily indicate that the cause of the event was an elevation in either factor. Without prior samples, it is impossible to determine if the elevation is the consequence of the thrombosis or was present prior to its development and potentially causative.

Several inherited or acquired abnormalities place an individual at increased risk for thrombosis and should be investigated when a thrombotic event is suspected or documented. Prior to the initiation of anticoagulation, plasma levels of protein C (antigen and activity), protein S (antigen and activity; total and free), and antithrombin III (antigen and activity) should be obtained. In addition, PCR analysis for mutations in the F.V (F.V Leiden; R506Q), and prothrombin (G20210A) genes should be performed. A serum homocysteine level may be obtained as the thrombosis risk of the MTHFR mutation may be related to elevations of homocysteine caused by alterations in the metabolism of folic acid rather than the mutation per se. Whether the MTHFR C677T polymorphism/mutation can cause thrombosis in the absence of an elevated serum homocysteine has been questioned recently (23,24,25). None of the known thrombophilic risk factors are found in up to 40% of adults who present with thrombosis and the incidence is likely lower in children (26,27,28). It is likely that the percentage in children who are negative for these abnormalities is at least as high or higher. The intensive care physician must look for confounding clinical conditions, such as dehydration (in cerebral venous sinus thrombosis), indwelling catheters, vascular compression (e.g., cervical ribs), and type II heparin-induced thrombocytopenia (see below) in evaluating a children with thrombosis.

CONDITIONS ASSOCIATED WITH SERIOUS BLEEDING, A HIGH PROBABILITY OF BLEEDING, OR SERIOUS HEMOSTATIC SEQUELAE

Disseminated Intravascular Coagulation

Pathogenesis

Because it often occurs in conjunction with other life-threatening disorders, DIC is one of the most serious hemostatic abnormalities seen in the PICU. DIC is caused by an abnormal activation of blood coagulation leading to excessive thrombin generation, a widespread formation of fibrin thrombi in the microcirculation and the consumption of clotting factors and platelets. Ultimately, this consumption of clotting factors and platelets is responsible for significant bleeding
when consumption exceeds production (29). The conditions associated with DIC are generally the same in adults and children and include the wide variety of disorders with the ability to initiate coagulation (Table 118.3). The mechanisms involved in these conditions either activate procoagulant proteins enzymatically or cause the release of TF, which then triggers coagulation.

TABLE 118.3 CONDITIONS ASSOCIATED WITH DISSEMINATED INTRAVASCULAR COAGULATION

Sepsis	Retained placenta
Liver disease	Hypertonic saline abortion
Shock	Amniotic fluid embolus
Penetrating brain injury	Retention of a dead fetus
Necrotizing pneumonitis	Eclampsia
Tissue necrosis/crush injury	Localized endothelial injury
Intravascular hemolysis	(aortic aneurysm, giant hemangiomata, angiography)
Acute promyelocytic leukemia	Disseminated malignancy (prostate, pancreatic)
Thermal injury
Freshwater drowning
Fat embolism syndrome

FIGURE 118.7. Fibrinolysis. Thrombin, generated from prothrombin by the action of the Xa/Va prothrombinase complex activates endothelial cells to produce plasminogen activators. These, in turn, cleave plasminogen to form plasmin, which degrades fibrin (formed by the action of thrombin on fibrinogen) to D-dimer fragments and other fibrinogen degradation products. Inhibitors of fibrinolysis (in diamonds) include PAI-1, which inhibit the actions of tPA and uPA, and α₂AP, α₂M, and TAFI, which inhibit plasmin. Thrombin, when bound to thrombomodulin on the surface of endothelial cells, activates TAFI to its active form and produces activated Protein C an important vitamin K-dependent protein with anticoagulant and anti-inflammatory properties. α₂AP, alpha-2-antiplasmin (alpha-2-plasmin inhibitor); α₂M, alpha-2-macroglobulin; tPA, tissue-type plasminogen activator; uPA, urine-type plasminogen activator; PAI-1, plasminogen activator inhibitor type-1; FDPs, fibrin degradation products; Xa, activated factor X; Va, activated factor V; aPC, activated Protein C; TAFI, thrombin-activatable fibrinolysis inhibitor; TAFIa, activated TAFI.

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 clotting factors and platelets. Thrombin generation and/or release of tissue plasminogen activator (tPA) initiate fibrinolysis (Fig. 118.7), which invariably accompanies thrombin formation in DIC (29). Tissue plasminogen activator converts plasminogen to plasmin, which then digests fibrinogen and fibrin clots as they form. Plasmin also inactivates several activated coagulation factors and impairs platelet aggregation. Therefore, thrombin-induced coagulation factor consumption, thrombocytopenia, and plasmin generation contribute to the presence of bleeding.

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 DIC, either bleeding or thrombotic tendencies may predominate. In most patients with DIC, bleeding is the predominant problem. However, 10% may have a presentation that is exclusively thrombotic (e.g., pulmonary emboli with pulmonary hypertension, renal insufficiency, altered mental status, acrocyanosis).
Whether the presentation of DIC is thrombotic, hemorrhagic, or “compensated” (that is, laboratory results consistent with DIC without bleeding), microthrombosis likely contributes to the development and progression of multiorgan failure.

Clinical Presentation and Diagnosis of DIC

The suspicion that DIC is present usually stems from one of two conditions: (a) unexplained, generalized oozing or bleeding or (b) unexplained, abnormal laboratory parameters of hemostasis. This usually occurs in the context of a suggestive clinical scenario or associated disease (see Table 118.3). While infection and multiple trauma are the most common underlying conditions associated with the development of DIC, multiple organ system dysfunction syndrome (MODS) and acute respiratory distress syndrome are associated with severe forms of DIC (18,20).

DIC has traditionally been assessed by the severity of bleeding and coagulation abnormalities. Scoring tools are available that use laboratory tests and severity of illness scores to diagnose and determine the severity of DIC. The laboratory tests used in the diagnosis of DIC and in these scoring systems are listed in Table 118.4. While no data exist for children, these scoring systems may have prognostic value for patients with sepsis (30,31,32). Limited studies suggest that early identification of DIC before the onset of a gross hemorrhagic diathesis may improve survival in critically ill children (6,33).

The triad of a prolonged PT, hypofibrinogenemia, and thrombocytopenia in the appropriate clinical setting is sufficient to suspect DIC. Severe hepatic insufficiency (with splenomegaly and splenic sequestration of platelets) can yield a similar laboratory profile and must be ruled out. Other conditions can present similar to DIC and must be considered in the differential diagnosis including massive transfusion syndrome, primary fibrinolysis, thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS

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