PATIENTS with critical illness often display variable hypo- and hypercoagulable sequalae requiring intense monitoring and anticoagulation pharmacotherapy to prevent or treat inappropriate clot formation. Agents like the heparinoids—low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH)—and warfarin are commonly utilized within the intensive care unit (ICU) for the purposes of both prevention and treatment of clots.1 Additionally, patients often present to the ICU with home anticoagulation regimens such as those with the direct oral anticoagulants (DOACs) and determination on the need for reversal of their effects is indicated. The clotting cascade (Figure 1) is the site of interest when identifying possible rationales for a patient's coagulopathy as well as the area in which each anticoagulant exerts its therapeutic effects. When evaluating anticoagulants, clinicians must differentiate and interpret both quantitative and functional data to assess the pharmacodynamic effects the therapy is exerting. The purpose of this narrative review is to evaluate commonly utilized coagulation tests that monitor anticoagulation while in the ICU.
PROTHROMBIN TIME AND INTERNATIONAL NORMALIZED RATIO
Two of the most common conventional coagulation tests utilized for monitoring critically ill patients and those on anticoagulation are the prothrombin time (PT) and international normalized ratio (INR). Both the PT and INR measure the tissue factor and common pathways' clotting factors activity (Figure 1).2 This activation, which is measured in seconds, is what is reported as the PT; INR is similar to PT, though it is standardized to a control measure given analytical variances in tissue factors.3 The PT and INR assess the risk for bleeding and thrombosis as well as the presence of anticoagulants in certain patients. A prolonged PT and INR, defined as a PT 13.5 seconds or more or an INR 1.1 or more, typically indicates patients are at an increased risk for hemorrhage secondary to critical illness or anticoagulants when compared with healthy patients.4
When utilizing warfarin, which inhibits clotting factors II, VII, IX, and X, goal values are determined based upon the disease states being managed.1,5Table 1 highlights common disease states managed with warfarin and the subsequent goal INR values. A higher goal is often targeted for more prothrombotic states such as mechanical mitral valves or antiphospholipid syndromes. Increasing INR values secondary to warfarin increases the risk of spontaneous bleeding events; therefore, routine monitoring is imperative.6
Table 1. -
Common Indications for Warfarin and Goal INR Valuesa
|Indication for Warfarin
||Goal INR Values
|Deep vein thrombosis
Abbreviation: INR, international normalized ratio.
Patients who require warfarin therapy, but with higher stratified risk for major bleeding, will need more frequent monitoring of INR values (at minimum daily monitoring while in the ICU) than those with less risk for hemorrhage. For patients with life-threatening bleeding (eg, intracranial hemorrhage), reversal of warfarin with vitamin K, prothrombin complex concentrates, or fresh frozen plasma can be tracked using INR. An uncorrected INR value in this setting can be a predictor of ongoing hemorrhage, but should be considered a surrogate marker of hemostasis if normalized.7
While PT and INR are useful tools, a limitation is that they may underrepresent the risk of thrombosis in critically ill patients. The PT and INR do not account for the activity of natural anticoagulants like protein C and S, which warfarin inhibits faster than other coagulation factors.5 As such, there is a theoretical risk for an increased prothrombotic state that is not captured by the use of PT and INR alone and, while debated on its necessity, is one of the main rationales for the use of bridging therapy in high-risk patients.8 Additionally, other factors such as diet, drug-drug interactions, or drug-laboratory interactions with warfarin must be considered when evaluating PT and INR values or initiation of new pharmacotherapy. A diet that incorporates leafy green vegetables high in vitamin K content can affect PT and INR values for patients on warfarin within the ICU. Commonly utilized pharmacotherapies administered in the ICU (Table 2) can directly affect warfarin to either enhance or diminish its effects altering the PT and INR value. Additionally, there are drugs which can produce false elevations in PT and INR secondary to laboratory interactions, which could lead to false representation of the patient's true anticoagulation state.9 While other nonwarfarin anticoagulant pharmacotherapies do exert some action on clotting factors, PT and INR are not the ideal laboratory measurements due to unreliability at predicating hemorrhage risk and more targeted testing that is readily available. For instance, factor Xa inhibitors, like apixaban and rivaroxaban, may cause elevation in PT and INR values indicating pharmacodynamic effects at normal or supratherapeutic values, but a normal value does not rule out drug presence.10 Given the minimal limitations, PT and INR remain the gold standard for monitoring warfarin in the ICU.
Table 2. -
Common Drug-Drug Interactions With Warfarin Within the ICUa
||Effect on Warfarin Concentrations
||Expected INR Response
Abbreviations: ICU, intensive care unit; INR, international normalized ratio.
ACTIVATED PARTIAL THROMBOPLASTIN TIME AND PARTIAL THROMBOPLASTIN TIME
Similar to the PT and INR, partial thromboplastin time (PTT) and activated PTT (aPTT) measure the time it takes for a clot to form in seconds. The aPTT differs from PTT in that an activator is introduced to the blood sample, expediting the results and increasing the precision of the reference range. These tests measure the contact activation and common pathways' ability to form clot (Figure 1). A normal aPTT or PTT is 25 to 35 seconds.11 Prolonged values indicate increased risk of hemorrhage secondary to clotting factor dysfunction or anticoagulation.
The aPTT has historically been utilized for monitoring IV UFH therapy and its pharmacodynamic effects. For most indications, a goal target of 60 to 100 seconds is reasonable for obtaining therapeutic levels of anticoagulation.12 Due to a high degree of variability in laboratory testing, including reagent utilization, aPTT monitoring for IV UFH has fallen out of favor in lieu of anti-Xa assay monitoring. Additionally, many baseline biological factors can alter the test interpretation. Patients with liver disease, lupus, clotting factor deficiencies, obesity, and advanced age can lead to false aPTT and PTT levels.13 These alterations at baseline can lead to an inability to effectively predict hemorrhage risk in those with the biological factors listed earlier. Several studies have found potential benefits of utilizing anti-factor Xa monitoring compared with aPTT for UFH therapy, including faster time to therapeutic anticoagulation, fewer dose adjustments, less frequent laboratory draws, and a reduction in the dose of UFH need to achieve therapeutic levels.14–16 Current guideline recommendations suggest using aPTT monitoring for UFH in patients with heparin resistance, a prolonged baseline aPTT, or altered heparin responsiveness.17 However, a calibrated UFH anti-Xa assay should be used over aPTT or PTT in the majority of critically ill patients. The aPTT level should be checked every 6 hours until 2 consecutive therapeutic results are obtained, at that point testing can be extended to once daily until the conclusion of therapy or labile values are noted. Unlike with IV UFH use, aPTT monitoring is not routinely performed or recommended for heparin being administered subcutaneously.
Argatroban and bivalirudin are intravenous (IV) direct thrombin inhibitors (DTIs) often utilized in clinical cases where heparin is contraindicated (eg, heparin-induced thrombocytopenia [HIT]). As DTIs block factor II (Figure 1), aPTT is ideal for monitoring their anticoagulant activity and is considered the standard of care.18,19 The goal aPTT while on an IV DTI is typically 1.5 to 3 times the patient's baseline value and should be monitored every 2 hours. As DTIs can elevate the PT and INR at serum concentrations due to laboratory interactions, aPTT remains the gold standard for monitoring in the ICU.20
Routine monitoring of the oral DTI dabigatran is not necessary in the majority of clinical indications; however, aPTT monitoring may be considered where emergent reversal of its anticoagulation affects is warranted such as in major bleeding events. For routine testing, aPTT is considered suboptimal for monitoring due to lack of drug-specific therapeutic ranges; however, in the setting of emergent reversal aPTT may be utilized to qualitatively assess dabigatran presence to determine candidacy for reversal agents.21 Notably, a normal aPTT cannot exclude the presence of dabigatran and should not be the sole criteria utilized to determine whether drug is present within serum samples.
COMPLETE BLOOD COUNT
Patients suffering from critical illness often require frequent blood draws depending on their acuity and disease process. One of the more common laboratory tests that may be ordered for monitoring critically ill patients is the complete blood cell count (CBC). The CBC is a panel of whole blood tests that provide the clinician with valuable information about the concentration of cellular and noncellular blood composition (Table 3).22 One of the more important components of the CBC when monitoring and providing care for patients on anticoagulation is the hemoglobin (Hgb) concentration. Hgb is an iron-rich protein found in red blood cells (RBCs) responsible for the oxygen transport capacity of the blood.22 Minor changes in Hgb values can become significant, as this directly affects patients' ability to transport and oxygenate vital organs. If patients present with a low Hgb, then a transfusion of RBCs, which contains Hgb, is often necessary. Hgb transfusion thresholds have been evaluated in various critically ill patient populations, but in general, most ICU patients will require transfusion when the Hgb value is less than 7 g/dL, with patients with cardiac illness typically transfusing at values of less than 10 g/dL.23 This target is important since there are notable adverse effects associated with blood product administration such as transfusion-associated circulatory overload, transfusion-related lung injury, anaphylaxis, and metabolic disturbances like hyperkalemia and hypocalcemia.
Table 3. -
Select Complete Blood Count Valuesa
||Males: 4.5-5.9 × 106 cells/μL
||Females: 4.1-5.1 × 106 cells/μL
||Males: 14-17.5 g/dL
||Females: 12.3-15.3 g/dL
||150 000-450 000 cells/μL
Abbreviations: HCT, hematocrit; Hgb, hemoglobin; RBC, red blood cell.
Given the importance of Hgb targets and transfusion thresholds, bedside nurses should be aware of the impact anticoagulants may have on the Hgb value. Critically ill patients who are administered anticoagulants can experience a myriad of outcomes on Hgb values ranging from no effects to major bleeding requiring massive blood transfusions. An important caveat clinicians must be cognizant of is that patients on any form of anticoagulation are at a higher risk of bleeding and potentially requiring blood transfusions than those patients not on anticoagulation.
Before the clotting cascade can be activated and advance with secondary hemostasis, the body must first initiate clot formation and undergo primary hemostasis. Primary hemostasis is the physiologic process that forms the initial platelet plug.24 Platelets produce a plug by becoming exposed to collagen at the site of vascular injury ultimately promoting platelet adherence, activation, and aggregation. Once this process has taken place, secondary hemostasis is activated with goal to produce a fibrin-based clot.
The most common test to examine platelets is the platelet count. The normal range is 150 000 to 450 000 cells/μL.22 This test provides information on the patient's platelet number and/or concentration in a blood sample. Thrombocytopenia, defined as a platelet count less than 150 000 cells/μL, can be a relatively common occurrence in critically ill patients. Some of the most common nonpharmacologic causes of thrombocytopenia include sepsis, renal failure, liver disease, disseminated intravascular coagulation (DIC), and thrombotic thrombocytopenia purpura. Many pharmacotherapies are capable of producing a drug-induced thrombocytopenia. Discontinuing the offending agent is the most important step in management of critically ill patients experiencing drug-induced thrombocytopenia, with platelet counts expected to recover after 4 to 5 half-lives of the responsible medication.25 One exception is thrombocytopenia induced by heparin utilization. HIT produces an immune-mediated response that can linger for up to 3 months after drug administration.26 Monitoring platelet counts while patients are administered heparin products is vital and allows clinicians to differentiate HIT versus other thrombocytopenia etiologies.
Also included in the CBC is the hematocrit (HCT). The HCT determines the percentage of RBCs within a patient's sample.22 An elevated HCT value would indicate low plasma volume, which can produce falsely elevated INR times; therefore, it is important to adjust for elevated HCT values into laboratory assessment with correction factors so as not to overestimate the effects of anticoagulants being measured.27
Another laboratory test that is helpful at predicting critically ill patients' hemorrhage risk is fibrinogen values. The clotting cascade ends with a cross-linked fibrin clot and fibrinogen, commonly referred to as coagulation factor I, serves an important role in this process. Fibrinogen is converted to fibrin by thrombin as a step of the final common pathway (Figure 1). A fibrinogen assay tests for serum concentrations, with the normal range reported at 200 to 400 mg/dL.28 Fibrinogen monitoring is not routine for patients who are on anticoagulation alone, as there are other biomarkers more useful for assessing safety and efficacy; however, patients who receive systemic or local thrombolytics, for stroke or pulmonary embolism, or are experiencing DIC may have frequent fibrinogen values assessed to evaluate hemorrhage risk.
For patients receiving catheter-directed thrombolysis (CDT) for pulmonary embolism or peripheral artery disease, fibrinogen levels have traditionally been used as a surrogate marker for bleeding and used to assist in titrating thrombolytic infusion rates. The most common studied threshold for increased bleeding risk is fibrinogen levels less than 150 mg/dL.29 The PURPOSE study prospectively included 248 patients found no statistically significant difference in major or minor bleeding in patients receiving CDT for peripheral occlusions with fibrinogen levels more than 100 mg/dL or 100 mg/dL or less.30 Lastly, a meta-analysis evaluating 2 randomized clinical trials and 4 cohort studies concluded the predictive value of plasma fibrinogen levels for predicting bleeding complications after CDT inconclusive.31 Although the data are not definitive, fibrinogen levels may aid clinicians and bedside personnel to stratify the hemorrhage risk of a critically ill patient more quickly.
The risk for symptomatic intracranial hemorrhage (sICH) after administration of IV systemic thrombolytics for acute ischemic stroke ranges between 2% and 7%.32 Patients who experience an sICH postsystemic alteplase for acute ischemic stroke have a mortality rate of approximately 50%, making monitoring and mitigating hematoma expansion vital. In patients with acute ischemic stroke, a reduction in fibrinogen levels more than 25% after alteplase was the best predictor for development of sICH.31 Current guideline recommendations on the management of sICH include administration of antifibrinolytics, such as tranexamic acid, supplementation of 10 U of cryoprecipitate, which contains pooled fibrinogen, and monitoring of fibrinogen levels.33 Additional, cryoprecipitate resuscitation is recommended once levels reach less than 150 mg/dL; however, some data suggest an even more liberal threshold of less than 200 mg/dL.34 The majority of sICHs occur within 8 hours of administration of systemic thrombolytics. Guidelines recommend obtaining a fibrinogen level if sICH occurs, but the frequency at which it should be monitored remains to be determined and it is not unreasonable to resuscitate with cryoprecipitate early if an expedited level is not available.33
There are several novel coagulation laboratory tests that can be used to monitor anticoagulation in the ICU. The most widely available is anti-factor Xa activity assays (or “anti-Xa”). This test can be used to measure the functional activity of UFH, LMWH, and fondaparinux, though a separate calibration curve is required for each medication.12,35 Chromogenic anti-factor Xa assays calibrated to rivaroxaban and apixaban have also been described to guide reversal of anticoagulation, but are not routinely used.36 It measures the activity of heparin against the activity of activated coagulation factor X.34 As LMWHs have a greater inhibitory effect on factor Xa relative to thrombin compared with UFH, a higher reference range is detected (Table 4).35
Table 4. -
Anti-Factor Xa Monitoring by Medicationa
|Anti-factor Xa activity
|UFH: 0.3- 0.7 U/mLLMWH:
Fondaparinux: 0.8-1.2 U/mL
Abbreviations: LMWH, low-molecular-weight heparin; UFH, unfractionated heparin.
From Vandiver et al,12
Wei and Ward,34
and Gehrie and Laposata.35
Anti-factor Xa activity monitoring has several advantages over conventional monitoring with aPTT, including that it is not impacted by diurnal variation, citrate concentration, or underfilling of collection tubes.12 Importantly, coagulopathy, including alterations in fibrinogen, antithrombin deficiency, liver disease, consumptive disease, and coagulation factor deficits, does not alter the assay. Given coagulopathy occurs in up to a third of critically ill patients, anti-factor Xa monitoring may prove a more reliable test compared with aPTT.37
A recent study including 103 patients requiring temporary mechanical circulatory support (ventricular assist devices and extracorporeal membrane oxygenation life support [ECMO]) demonstrated a lower rate of bleeding with anti-factor Xa activity monitoring relative to activated clotting time-based monitoring.38 Similar results were observed in another recent study of 41 ECMO patients comparing anti-factor Xa activity with aPTT.39 Finally, in patients with coronavirus disease-2019 (COVID-19) coagulopathy on UFH, anti-factor Xa activity more reliably predicted therapeutic range UFH relative to serum fibrinogen concentration.40
Conventional coagulation testing modalities, such as PT, INR, and aPTT, are utilized for their quantitative assessment while viscoelastic modalities, such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM), provide data on the functional qualities of the patient's clotting cascade.41 For example, a patient who presents with an INR of 1.5 and a known history of severe cirrhosis will likely not produce the same degree of functional coagulopathy as an otherwise healthy patient who is admitted due to a traumatic injury with the same value. While the INR values are quantitatively the same, it does not consider rebalanced hemostasis that the patient with cirrhosis above may display and this can explain the functional variances seen within each patient's hemostatic profile.42
The testing mechanics differ between both ROTEM and TEG, but the basic principle is that in a normal blood sample it becomes stagnant, which increases blood viscosity and elasticity, which is being measured by both tests. Each can be used to measure the following: clotting factor activation, clot strength, platelet and fibrinogen activity, and the degree of fibrinolysis.41 These tests run in real time, generating an electronic tracing within minutes that provides measurement of the patient's hemostatic profile. Figure 2 is an example of a generated computer tracing and the corresponding areas of measurement.
Based upon their mechanisms of action, agents like LMWH, DOACs, argatroban, fondaparinux, warfarin, and bivalirudin are all expected to produce prolonged clotting factor times; however, use of viscoelastic testing in monitoring of UFH has been evaluated most extensively. Using these modalities might be ideal in situations where UFH is being utilized for complicated pathology, such as COVID-19 hypercoagulability, because it allows for stratification of coagulopathy caused by the disease versus pharmacotherapy with introduction of heparinase solutions to the test, which neutralizes any heparins within the sample, and highlights the hemostatic profile of the disease state only.43 Additional benefits of viscoelastic testing have been demonstrated with their use in monitoring UFH in patients requiring ECMO where patients have had a shorter length of stay, reduced heparin doses, and in some data sets less bleeding events.44
The COVID-19 pandemic has presented many anticoagulation and hypercoagulability clinical dilemmas. Management of severe COVID-19 initially included larger anticoagulant doses of heparinoids, bivalirudin, and argatroban than are traditionally utilized, which labeled patients as “anticoagulant resistant,” but viscoelastic testing was able to determine whether there were additional antithrombotic therapies, like antiplatelet agents, that would aid in preventing inappropriate clot formation.45 Larger amplitudes may indicate the need for antiplatelet therapy given robust platelet activity or quantity, depending on the underlying clinical condition, such as with COVID-19 or acute ischemic stroke; however, there remains limited data on viscoelastic testing guiding initiation or dose-adjusting antiplatelet regimens.46 It is important to note that patients being treated with antiplatelet regimens can present with falsely normal or elevated amplitudes with standard viscoelastic testing. Additional viscoelastic modalities, measured outside the standard testing, may be utilized to determine true functionality. Functionality of antiplatelet regimens on the arachidonic (aspirin) and P2Y12 (ticagrelor and clopidogrel) receptors can be determined with these additional viscoelastic tests; however, there remains a paucity of evidence on validated algorithms for treatment based upon these tests.47
Viscoelastic testing is not without its limitations. First, as this veers from the conventional coagulation monitoring, robust education is needed on the appropriate testing procedures and interpretation of data. Second, the machine that runs the viscoelastic test typically requires more maintenance than conventional coagulation tests. Finally, viscoelastic testing does not account for variables such as hypocalcemia and acidosis, which can affect patients' hemostasis.
PLATELET FUNCTION TESTS
Similar to viscoelastic testing, aspirin and P2Y12-specific assays can aid in predicting hemorrhagic risk by interpreting the functional activity of platelets in critically ill patients. These tests are primarily utilized in patients receiving antiplatelet therapy to determine clinical response and hemorrhage risk in cardiothoracic, neurological, and trauma patients.48 While they can provide valuable information and allow for pharmacotherapy modification with dose reductions or escalation, they remain infrequently utilized in the majority of ICUs given their frequent false-positive rates.
WHOLE BLOOD COAGULATION TEST
Whole blood coagulation test (WBCT) has been available for a number of years, but is not widely used in hospital settings. The World Health Organization recommends its use to diagnose coagulopathy following snakebite envenoming, as it may predict the need for antivenom therapy; however, a meta-analysis demonstrated that it has similar efficacy to INR.49 Ciraparantag, a novel anticoagulant reversal, is under development for reversal of Xa DOACs and LMWH and utilizes WBCT to determine efficacy, so it may be more widely used in the future.50
The thrombin time (TT), also known as thrombin clotting time, measures the conversion of fibrinogen to fibrin in the final step of the coagulation cascade.51 If fibrinogen is low or the patient is receiving an anticoagulant that inhibits thrombin (eg, UFH, LMWH, and DTI), TT will be prolonged.51,52 It is not widely available in hospital settings and thus is limited mostly to research.
ECARIN CLOTTING TIME
Ecarin clotting time is a test that activates prothrombin into meizothrombin (an intermediate in the conversion to thrombin), which will then cleave fibrinogen to result in clot formation.53,54 Ecarin is derived from the viper venom and has been available for several decades. While it can be used to assess DTI (eg, bivalirudin, argatroban and dabigatran), it is not widely available in most hospital settings.
Monitoring anticoagulant utilization in the critically ill patient remains a challenge for clinicians. Appropriate test selection, including need for quantitative versus functional results, is crucial to providing the most appropriate data needed to assess thrombosis and hemorrhage risk. Common conventional testing with PT, INR, aPTT, PTT, and CBC remains the gold standard for most institutions; however, there is a growing movement evaluating the use of more viscoelastic testing modalities, such as TEG and ROTEM, to monitor anticoagulation in the critically ill. Critical care nurses are vital to ensure that the appropriate test and interpretation occurs within the ICU.
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