Role of platelets and von willebrand factor in hemostasis

Platelets not only participate in clot formation through the formation of a platelet plug but also provide an important surface on which clot formation may occur, bring additional procoagulant proteins to areas of injury (e.g., FVIII and von Willebrand factor [vWF]), and provide specific proteins that regulate the clotting response (FVIII, inhibitors of fibrinolysis, etc.) required to limit clot formation to the area of tissue injury and bleeding ( Fig. 89.6 ). Under resting unstimulated conditions, platelets do not adhere to the vascular endothelium, but upon stimulation or when the endothelium is mechanically disrupted (e.g., cut) or activated by inflammation, platelets will become activated and express on their surface vWF mobilized from internal pools and bound from plasma-derived vWF. This binding of vWF to the platelet allows for the efficient binding of platelets to activated ECs and to the subendothelial matrix. Once adherent, activated platelets secrete various molecules that further enhance platelet adherence and aggregation, vascular contraction, clot formation, and wound healing. Platelet adhesion to ECs or to subendothelial matrix can be enhanced or diminished by the amount and structure of vWF. Deficiency or inhibition of the metalloproteinase ADAMTS13 will result an increase in circulating unusually large molecular weight multimers of vWF (UL-vWF) with consequent enhanced platelet adhesion, which is associated with an increased risk of unwanted thrombus formation. Conversely, a decrease in the total amount of vWF in circulation or bound to platelets—or in vivo degradation of vWF, as is seen with certain subtypes of von Willebrand disease (vWD)—is associated with decreased platelet adhesion to areas of injury, with consequent increased bleeding. This bleeding diathesis associated with vWD is further increased by a concomitant decrease in circulating FVIII that occurs in most individuals with vWD owing to an increased in vivo degradation of FVIII not complexed to vWF.

Platelets associate with cells and surfaces by adhesion (platelet to nonplatelet cells and surfaces) and aggregation (platelet to platelet). These contact associations are mediated by specific platelet receptors. The primary receptor for adhesion is the glycoprotein (GP) Ib/IX/V complex that binds von Willebrand factor (vWF). Binding of vWF to this receptor does not require that platelets become activated, although binding of sufficient vWF to platelets can result in platelet activation. Aggregation involves the binding of fibrin (or fibrinogen) to the platelet GP IIb/IIIa (the α ₂ β ₃ integrin receptor). Activation of platelets is required for binding to this receptor. Other important adhesion receptors include those for collagen. Upon activation, platelets secrete both platelet stimulatory and vasoactive molecules that include adenosine diphosphate (ADP), serotonin, and thromboxane A ₂ (TXA2), which enhance hemostasis.

Role of endothelial cells in hemostasis

The endothelium plays a critical role in the regulation of blood coagulation and platelet activation. It also modulates vascular tone and permeability, as detailed later (see also Chapter 25 ).

ECs also synthesize and secrete components of the subendothelial extracellular matrix, including adhesive glycoproteins, collagen, fibronectin, and vWF. ECs ordinarily present a nonthrombogenic surface to flowing blood but enhance clot formation when disrupted by trauma or injured by infection or inflammation. This process involves multiple components of the protein C pathway ( eFig. 89.7 ). When this system is disrupted, the endothelium may become a prothrombotic rather than an antithrombotic organ, and localized thrombosis may occur. When thrombin is generated as a consequence of bleeding, thrombomodulin expressed on the surface of ECs bind thrombin, which then facilitates the conversion of protein C bound to the EC protein C receptor (EPCR) to activated protein C (APC), which, in turn, degrades FVIIIa and FVa, thereby damping down further thrombin formation. However, when ECs are stimulated (e.g., by inflammation), surface expressed TF facilitates the conversion of FVII to FVIIa with resultant generation of FXa, which can catalyze the cleavage of prothrombin (FII) to thrombin (FIIa) on cell (phospholipid) surfaces (e.g., platelets). The balance between the generation of thrombin and APC plays a central role in determining whether a clinical syndrome will be characterized by bleeding or by thrombosis.

Platelet-endothelial cell–mediated hemostasis. Protein C (PC) bound to the endothelial protein C receptor (EPCR) in the presence of thrombin (IIa) bound thrombomodulin (TM) is converted to activated PC (APC), which then inactivates activated factor V (Va) and factor VIII (VIIIa) to inactive species, thereby downregulating factor Xa formation via the “tenase” complex (IXa/VIIIa/Ca/phospholipid) and IIa (thrombin) formation via the “prothrombinase” complex (Xa/Va/Ca/phospholipid). Monocytes activated by circulating factors (such as lipopolysaccharide, zymosan, or peptidoglycan) or by tissue factor (TF) generated by injured endothelial cells activate coagulation via FVIIa/TF–mediated factor Xa generation. II, Prothrombin; V, factor V; Va, activated factor V; VII, factor VII; VIIa, activated factor VII; VIIIa, activated factor VIII; IXa, activated factor IX; X, factor X; Xa, activated factor X.

An additional important property of APC is its modulation of fibrinolysis; APC is capable of neutralizing the fibrinolysis inhibitors plasminogen activator inhibitor type-1 (PAI-1) and thrombin activatable fibrinolysis inhibitor (TAFI). PAI-1 is a 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. 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, whereas those with the 5G/5G genotype display the lowest (the 4G/5G genotype results in intermediate levels). Differences in PAI-1 levels have been demonstrated to affect the risk of developing severe complications and death from sepsis, higher PAI-1 levels generally being associated with increased mortality in animal models of sepsis and higher severity of illness and organ dysfunction scores in septic patients, including children with meningococcal sepsis. However, the regulation of PAI-1 levels is complex, involving more than promoters of synthesis. APC can stimulate fibrinolysis by forming a tight 1:1 complex with PAI-1, leading to inactivation of this fibrinolysis inhibitor. 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.

Thrombin generation also increases the levels of TAFI, also known as carboxypeptidase R. TAFI is an important negative regulator of the fibrinolytic system and 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 active investigation. Studies suggest that its role as a regulator of fibrinolysis appears to be of prognostic significance similar to that of PAI-1 (i.e., elevated levels resulting in decreased fibrinolysis appear to be associated with a poorer outcome in sepsis).

Crosstalk between coagulation and inflammation

Evidence exists that the coagulation system developed during evolution as an intrinsic component of the human host defense to infection. Consequently, inflammation, whether induced by infection or noninfectious causes, has the potential to result in activation of coagulation leading to dysregulation of hemostasis. During sepsis, TF expression is upregulated in activated monocytes and ECs as a response to endotoxin and other pathogen-associated/pathogen-initiated events, with both increased secretion of proinflammatory cytokines and activation of coagulation leading to increased thrombin generation. This increase in thrombin generation results in upregulation of coagulation and inflammation through platelet activation and induction of both procoagulant and anticoagulant proteins, and the induction of proinflammatory and antiinflammatory cytokines and mitogenic responses ( eFig. 89.8 ). ^, 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, APC), and the second is the inhibition of fibrinolysis through the production of PAI-1 and TAFI (see Fig. 89.5 ). Components of the PC system have been shown to be major regulators of coagulation (i.e., natural anticoagulants) with decreased activity of this pathway resulting in pathologic thrombosis, and they have been shown to possess intrinsic immunomodulating properties. In vitro, APC inhibits tumor necrosis factor-α elaboration from monocytes, blocks leukocyte adhesion to selectins, and influences apoptosis. Additionally, coincident with activation of coagulation through the contact phase of activation (FXII conversion to FXIIa mediated by high-molecular-weight kininogen and prekallikrein), complement activation is also induced by the conversion of prekallikrein to kallikrein by FXIIa (see eFig. 89.8 ) The presence of systemic inflammatory syndrome and coagulation activation leading to DIC in the setting of sepsis has been shown to result in worse clinical outcomes whether measured by degree of organ dysfunction or mortality. ECs and 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 systems. ^,

Coagulation, endothelial cells, complement, and inflammation. Inflammation, coagulation, and immune response are interconnected at various points. Endothelial cell (EC) interactions with leukocytes are important in adaptive immune responses and in modulating the innate immune response via various toll-like receptor (TLR) receptors. In conjunction with ECs and leukocytes, platelets play an important role in host pathogen responses by formation of neutrophil extracellular traps (NETs) and induction of NETosis. Coagulation and inflammation intersect via activation of the complement system, and ECs, leukocytes, and platelets all play roles in wound healing and angiogenesis. APC, activated protein C; EPCR, endothelial cell protein C receptor; ICAM-1, intercellular adhesion molecule 1; NOD, nucleotide-binding oligomerization domain-like receptor; PC, protein C; sTM, soluble thrombomodulin; TM, thrombomodulin; sEPCR, soluble endothelial cell protein C receptor; VCAM1, vascular cell adhesion protein 1.

Clinical history

Diagnostic assessment begins at the bedside. The medical history, both past and present, may provide insights into the risk for significant bleeding. A prior history of prolonged or excessive bleeding or of recurrent thrombosis is important. Specific questions regarding bleeding should investigate the occurrence of any of the following: spontaneous, easy, or disproportionately severe bruising; intramuscular hematoma formation (either spontaneous or related to trauma); spontaneous or trauma-induced hemarthrosis; spontaneous mucous membrane bleeding; prior problems with bleeding related to surgery (including dental extractions, tonsillectomy, and circumcision); the need for unanticipated transfusions in the past; menstrual history; and, finally, current medications.

In spite of the decreased general use of aspirin in children, there remain numerous over-the-counter aspirin-containing medications that can potentially interfere with platelet-mediated primary hemostasis. Patients (and parents) may not be aware of the aspirin contained in these products. High doses of over-the-counter and prescription nonsteroidal antiinflammatory drugs (NSAIDs)—for example, ibuprofen, and naproxen-sodium—may also impair platelet function. However, unlike aspirin, which produces a noncompetitive inhibition of platelets, the inhibition caused by these other NSAIDs is competitive and resolves once the drug is no longer present. Other drugs used in the intensive care unit (ICU) associated with bleeding abnormalities must also be considered. In trauma situations (either surgical or accidental), it is important to determine the severity of injury relative to the magnitude of bleeding that follows. A prior personal history (or strong family history) of significant thrombosis (e.g., DVT, pulmonary embolus, stroke) also suggests the possibility of the presence of a hypercoagulable condition. As thrombotic events are generally uncommon in children, an occurrence in young adult relatives, particularly early cardiovascular events such as myocardial infarction, should cause the clinician to consider the possibility of a congenital thrombophilic abnormality in the patient. These abnormalities include ATIII deficiency, PC or PS deficiency, the presence of the FV Leiden R506Q mutation, the prothrombin G20210A polymorphism/mutation, and hyperhomocysteinemia (discussed later). In addition, vasculitis associated with an autoimmune disorder such as systemic lupus erythematosus (SLE) must always be considered in the evaluation of a child with an unexplained pathologic clot. In all cases, the family history is important in attempting to separate congenital from acquired disorders.

Generally, defects in primary or secondary hemostasis can be separated according to the nature of the bleeding. Patients with primary hemostatic defects tend to manifest capillary-type bleeding characterized by 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 vWD. In contrast, patients with dysfunction of secondary hemostasis (i.e., fibrin clot formation) tend to display large-vessel bleeding characterized by hemarthrosis, intramuscular hematomas, and the like. This type of bleeding is most often associated with specific coagulation factor deficiencies or inhibitors. However, 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 (i.e., a coagulopathy).

Physical examination

Development of generalized bleeding in critically ill patients in the ICU presents a special problem. Such bleeding is often a marker of severe underlying multiorgan system dysfunction. Correction of the coagulopathy usually requires improvement in the patient’s overall clinical status. Supportive evidence or physical findings of other concurrent organ system dysfunction (e.g., renal failure, respiratory failure, hypotension) often are readily apparent. With the exception of massive transfusion syndrome (discussed later), generalized bleeding in critically ill children and infants is often caused by sepsis-related DIC. However, the clinician must also consider in the differential diagnosis the coagulopathy of severe liver dysfunction, undiagnosed congenital bleeding disorders (e.g., hemophilia, vWD), nonaccidental injury, or vitamin K deficiency in newborns or older children with malabsorption. In young infants (<3 months of age), the coagulation system is often not yet mature, and prolongation of the PT or aPTT may not reflect an abnormality in hemostasis. Consequently, the intensivist must also take this into consideration when interpreting abnormal results. In these cases, consultation with a pediatric hematologist may be indicated.

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? Is the bleeding primarily mucocutaneous? 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 (primary vs. secondary hemostatic dysfunction).

During the general examination, particular attention should be paid to the presence of several specific physical findings that may be helpful in determining the etiology of a suspected hemostatic abnormality. For example, the presence of an enlarged spleen coupled with thrombocytopenia suggests that splenic sequestration may be a contributor to the observed thrombocytopenia. Splenomegaly accompanied by prolongation of the PT or aPTT may be a consequence of underlying liver disease, whereas splenomegaly in the presence of normal PT and aPTT may indicate that a marrow infiltrative process may be present. Further, evidence of liver disease (e.g., portal hypertension, ascites) points to decreased clotting 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, or thrombocytopenia. Purpura spots that are palpable suggest capillary leak from vasculitis. In contrast, purpura spots associated with thrombocytopenia or qualitative platelet defects are generally not elevated and cannot be distinguished by touch. Finally, venous and arterial telangiectasia may be seen in vWD 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.

Basic tests of hemostasis

A listing of commonly available and used tests of hemostasis is provided in eBox 89.3 . In the general ICU population, the most common tests obtained are PT, aPTT, and fibrinogen. The INR is reported out with the PT, as it is calculated from the PT taking into account the sensitivity of the thromboplastin reagent employed by the testing lab. The INR was developed to allow clinicians to assess and monitor the intensity of anticoagulation employing a vitamin K antagonist (e.g., warfarin) when the PT was obtained in laboratories using different thromboplastin reagents. As the INR is calculated from the PT, it is often used as a surrogate for the INR in which the clinician need not know the control PT from the testing lab. However, the INR has been standardized and validated for the unique derangements in plasma clot formation induced by vitamin K inhibitors; subsequent application to all conditions that may cause a prolongation in PT is conjectural. Indeed, studies investigating the ability of the INR to predict bleeding in numerous clinical settings other than in the presence of warfarin anticoagulation have not demonstrated a clear association, although there may be an association between preoperative INR and postoperative bleeding. That being said, an elevated INR can be assumed to indicate that the PT is also prolonged.

The standard tests to assess the status of the coagulation system use the conversion of fibrinogen to fibrin as their end point in one way or another. Consequently, they can be considered to be functional assays. While prolongation of the PT/INR or aPTT are interpreted as indicating a hypocoagulable state (i.e., decreased rate of clot formation), neither test is sensitive to conditions that result in an increase in the rate of clot formation (i.e., a hypercoagulable state). Correct interpretation of the PT and aPTT in neonates, particularly premature infants, requires that the clinician recognize two factors that cause normal values for the PT and aPTT to be longer than those for older children. First is that, at birth, plasma levels of many of the clotting proteins are low. While some studies demonstrate a slow increase into early adolescence, these levels generally reach near normal adult levels by 3 months of age, at which time the results may be accurately interpreted using the normal age range. The second is that the normal hematocrit for neonates is greater than that for older children, resulting in a reduced plasma volume. When the hematocrit is 55% or greater, this reduced plasma volume may result in an “over-anticoagulation” of a specimen collected into a typical commercial tube. Consequently, if the result is high, a repeat specimen obtained in a tube with reduced citrate should be obtained for confirmation of the abnormal results. This adjustment may also be appropriate when obtaining specimens from older children with elevated hematocrit secondary to cyanotic heart disease.

The thrombin time (TT) tests the conversion of fibrinogen to fibrin. Prolongation of the TT may reflect low fibrinogen levels (hypofibrinogenemia); presence of an inhibitor to thrombin (commonly, heparin contamination of the specimen); or the presence of an abnormal, poorly clottable, fibrinogen (dysfibrinogenemia). Fibrinogen levels <75 to 100 mg/dL are generally considered to represent a risk of bleeding. Elevated fibrinogen (hyperfibrinogenemia) is frequently seen in critically ill patients, as fibrinogen is an acute phase reactant. Consequently, finding a low-normal fibrinogen should cause the clinician to consider a process in which fibrinogen is being consumed (i.e., a consumptive coagulopathy). In this setting, one may consider obtaining a measure of fibrinogen/fibrin degradation (i.e., marker for the presence of fibrinolysis). While there are assays for both fibrin(ogen) split products, the D-dimer assay is generally considered to be more specific for the detection of fibrin degradation products that form following the generation of polymerized fibrin ( eFig. 89.9 ). While traditional fibrin split products (FSPs)/fibrin degradation products (FDPs) identify all proteolytic fragments of both native fibrin monomer and polymerized fibrin, the D-D fragment (D-dimer) is only produced following cleavage of fibrinogen by thrombin to form fibrin monomer, which then has (spontaneously) polymerized to form fibrin polymer. The finding of an elevated D-dimer requires that thrombin generation had occurred. However, trauma and surgery will result in increased D-dimer levels resulting from bleeding and response to bleeding.

Generation of fibrin degradation products (FDPs), fibrin split products (FSPs), and D-dimer fragments. Fibrin monomers are formed following cleavage of fibrinopeptides from a fibrinogen molecule by thrombin. These fibrin monomers spontaneously polymerize by interaction of uncovered D-domains of two different monomers. When polymerized fibrin is lysed by plasmin, fragments consisting of 2 D domains (D-dimers) are formed (among other fragments). In contrast, when native fibrinogen is acted upon by plasmin, only X, Y, D, and E—but no D-D—fragments are formed. Ca ²⁺ , Calcium ion; FXIIIa, activated factor XIII.

The mixing study, also referred to as an inhibitor screen , is a useful next step when evaluating a prolonged PT or aPTT. If the prolongation is the result of a critical deficiency of a specific clotting factor(s), mixing of the patient specimen 1:1 with normal plasma will result in correction of the PT or aPTT into the normal range. Failure to demonstrate a meaningful correction suggests the presence of an inhibitory substance (e.g., an antibody) that impairs fibrin formation.

Currently, the assessment of an increased risk of pathologic clot formation relies on identification of myriad clinical and laboratory risk factors; numerous factors with the strongest association with thromboembolic events (TEs) are listed in eTable 89.1 . The role that other factors—such as ABO type, platelet cytoadhesion receptors, fibrinolysis regulatory proteins, and blood lipids—may play in TEs is currently uncertain.

The presence of antibodies directed against phospholipids may result in an artifactual prolongation of the PT and/or aPTT. These are referred to as lupus anticoagulants (LACs), as they were first described in patients with SLE. Prolongation of PT or aPTT caused by LAC does not reflect an increased risk of bleeding but rather can indicate a risk for thrombosis. While LAs are not inherently a risk for TEs, the specific antiphospholipid antibodies (APAs) are. Specifically, antibodies directed against phosphatidylserine and β ₂ -glycoprotein-1 have been shown to represent strong risk factors for TEs. ^,

Platelet function testing

While platelets participate in clot formation and deficiencies in platelet number or function increase the risk of bleeding, platelet function is not measured in the traditional plasma-based clotting studies. Platelet function testing has traditionally been performed in a plasma-free system in which aggregation of platelets is measured following addition of a specific platelet agonist ( eFig. 89.10 ). The pattern of responsivity gives clues to the specific functional defect, which is diagnostic at times. ^, This test is time intensive, requires a generous blood sample, and does not reflect the interaction of platelets with other cells and its role on clot strength and stability. Consequently, in an acute setting, these tests are of minimal usefulness. The template bleeding time assesses the role of platelets in initiating platelet clot formation in vivo (i.e., primary hemostasis). However, it is a manual test and poorly standardized. Consequently, many hospital laboratories no longer offer the test. A commercial test developed as an in vitro bleeding time (PFA-100) was touted as a substitution for the template bleeding time. However, it has not demonstrated the specificity required to be clinically useful and has fallen out of favor by many hematologists. There are flow cytometry–based tests measuring platelet activation, but these have not yet been incorporated into general laboratory platelet testing. Platelet function assessment by platelet mapping obtained from global measures of hemostasis have been developed; however, these also lack specificity and sensitivity and are not generally available.

Normal platelet aggregation. Tracing of platelet aggregation curves measured by light transmission 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 1 (PAR1) (bottom) .

vWF is a multimeric adhesive glycoprotein found in plasma, the extracellular matrix, ECs, and platelets. It is required for efficient adhesion of platelets to ECs and extracellular matrix and circulates in complex with FVIII. In this state, it protects FVIII from proteolytic cleavage. vWD is the most common inherited bleeding disorder, affecting 1% of the population. Acquired vWD has been documented in various lymphoproliferative, myeloproliferative, and autoimmune disorders. It has also been documented in a variety of congenital and acquired cardiac conditions characterized by an increase in blood flow shear rates. Such shear-induced acquired vWD has also been demonstrated with intravascular ventricular assist devices in adults and with extracorporeal membrane oxygenation (ECMO). The etiology of shear-induced vWD is related to promotion of self-association of vWF and increased activity of the vWF cleaving protease ADAMTS13 with consequent decrease of high-molecular-weight vWF multimers in circulation causing decreased platelet adhesion. This phenomenon may be more pertinent to children with critical illness. The diagnosis of vWD relies on three types of measurements: quantitative antigenic measurement of plasma vWF, a functional platelet adhesion/aggregation assay (ristocetin cofactor assay), and determination of plasma vWF multimeric profile. FVIII activity is also obtained, as the absence of vWF results in low FVIII activity due to in vivo proteolytic degradation. The type of inherited vWD will determine the pattern of results noted. In conditions of acquired vWD due to increased shear stress, one would expect to see both decreased total vWF and a loss of the largest vWF multimers in circulation.

Thromboelastography and thromboelastometry

Tests that measure thromboelastic characteristics of clot formation and dissolution in real time have been used to obtain more precise information regarding abnormalities in hemostasis and to guide hemostatic support measures. These tests include thromboelastography (TEG) and rotational thromboelastometry (ROTEM). The primary difference in test technique is that TEG employs a system in which a probe placed into a cuvette containing whole blood is rotated around the pin while clot formation occurs while ROTEM involves rotating the pin in the blood contained within the cuvette. Additionally, the probe (pin) is a torsion wire in TEG and an optical probe in ROTEM. Both provide information regarding rate of clot formation, maximal strength of the clot, and the timing of fibrinolysis ( eTable 89.2 and eFig. 89.11 ). To date, studies evaluating the superiority of these tests compared with traditional plasma-based clotting studies are inconclusive.

eTABLE 89.2

Variables Measured by TEG and ROTEM

Variable	TEG	ROTEM
Measurement period	–	Reaction time
Time from start to when waveform reaches 2 mm above baseline	R	Clotting time
Time from 2 mm above baseline to 20 mm above baseline	K	Clot formation time
Alpha angle (degree)	< (slope between R and K)	< (angle of tangent at 2 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	2 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.

Assessment and interpretation of clot parameters by thromboelastography (TEG) and rotational 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.