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Anesthesiology Core Review: Part Two Advanced Exam
Chapter 6: Coagulation Monitors
Alan Kim
INTRODUCTION
An accurate assessment of a patient’s hemodynamic status is crucial to a safe anesthetic plan. In the presence of ongoing blood loss, one must quickly
distinguish between surgical bleeding and coagulation derangements. Initially, this risk is assessed preoperatively with several tests assessing
different stages of the clotting cascade. However, given the potential for evolving intraoperative derangements, the clotting ability should also be
assessed perioperatively as well. Certain surgical procedures require the induction of a coagulopathic state, such as necessitating the use of
extracorporeal blood flow machines.
Coagulopathies result from three etiologies: a failure in primary hemostasis, an incompetent coagulation cascade, and excessive fibrinolysis. Primary
hemostasis encompasses platelet plug formation. This process requires functional, circulating platelets and an endothelial defect that exposes
platelet-binding receptors. The coagulation cascade reinforces this platelet plug and simultaneously begins the process of deactivating itself. This
cascade consists of two pathways, the intrinsic and the extrinsic, that overlap in a common pathway. Fibrinolysis is the process through which the clot
breaks down after serving its function in hemostasis.
TESTS OF PRIMARY HEMOSTASIS
The essential elements of primary hemostasis include the concentration and quality of platelets as well as important components that lead to platelet
plug formation. Some have a more historical context and are not easily or commonly employed in perioperative use, while others are a part of a
standard preoperative workup. Platelet function tests are usually employed when there is evidence of coagulopathies.
Complete Blood Count (CBC)
Measurement of the CBC provides a platelet count but does not assay the functional status of each platelet. Perioperatively, both quantitative and
qualitative deficits in platelets contribute to coagulopathies. These deficits are especially prevalent in surgeries involving significant fluid shifts and
requiring extracorporeal blood flow such as in extracorporeal membrane oxygenation or cardiopulmonary bypass. Distinguishing between these
etiologies aids in identifying the appropriate intervention.
Qualitative deficits have a variety of causes: decreased production, splenic sequestration, increased destruction, or dilution. When splenic
sequestration is the underlying cause, platelet levels will often increase in the presence of stressors. In disseminated intravascular coagulation, the
platelets will be rapidly consumed, and provide minimal benefit. The risk-to-benefit ratio of administering these products must be weighed. Repeated
platelet transfusions run the risk of sensitizing a patient to platelet fragments, impeding future transfusions. As such, platelet transfusions should be
reserved for patients with less than 10,000/uL platelets, ongoing blood loss, or invasive procedures.
Bleeding Time
Bleeding time is an older test that can be performed in the absence of a laboratory. There are two variants to this method:
The Ivy bleeding time is determined by placing a blood pressure cuff on the upper arm and inflated to 40 mmHg. A cut is made on the volar surface
of the arm. The cut is blotted every 30 seconds until the bleeding stops. There are devices that standardize the depth and size of the cut. A normal
range is between 2–9 minutes. The time it takes for the bleeding to stop can also be assessed against a nomogram. The time period is assessed as
prolonged, normal, or shortened.
The Duke method changes the location of the cut by using the earlobe. This location is used as the head is more accessible during surgery.
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However, the depth and width of the cut cannot be standardized. Bleeding time may be elevated due to platelet deficit, dysfunction, or vascular
Chapter 6: Coagulation Monitors, Alan Kim Page 1 / 4
abnormalities. A platelet deficit should be investigated as with CBC. Platelet dysfunction can be acquired (medication-induced) or hereditary (von
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Willebrand deficiency) and should be further elucidated.
Perioperatively, bleeding time has a limited utility. Studies comparing bleeding time changes to the increased postoperative bleeding risk have been
The Ivy bleeding time is determined by placing a blood pressure cuff on the upper arm and inflated to 40 mmHg. A cut is made on the volar surface
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of the arm. The cut is blotted every 30 seconds until the bleeding stops. There are devices that standardize the depth and size of the cut. A normal
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range is between 2–9 minutes. The time it takes for the bleeding to stop can also be assessed against a nomogram. The time period is assessed as
prolonged, normal, or shortened.
The Duke method changes the location of the cut by using the earlobe. This location is used as the head is more accessible during surgery.
However, the depth and width of the cut cannot be standardized. Bleeding time may be elevated due to platelet deficit, dysfunction, or vascular
abnormalities. A platelet deficit should be investigated as with CBC. Platelet dysfunction can be acquired (medication-induced) or hereditary (von
Willebrand deficiency) and should be further elucidated.
Perioperatively, bleeding time has a limited utility. Studies comparing bleeding time changes to the increased postoperative bleeding risk have been
unable to demonstrate a strong association. Bleeding time thus is not useful for identifying underlying platelet defects.
Platelet Function Analyzer (PFA-100)
The PFA-100 runs fresh blood run through a sample tube coated with two platelet activating mediums: collagen with epinephrine and collagen with
adenosine diphosphate. It tracks how long it takes for the sample tube to completely occlude from clotting.
This test has a high negative predictive value, is fairly rapid, and does not require any specialized training to run. However, it does have a few
limitations. These include the variable responses due to citrate concentration, collection time, hematocrit level, platelet counts, drug effects, and
abnormal von Willebrand factor levels.
Patients with a normal PFA-100 will generally have an intact primary hemostasis. If this test is abnormal, a formal platelet aggregation test is required.
The PFA-100 is used to identify patients with an aspirin resistance. In patients with aspirin resistance, some respond to higher doses.
Platelet Aggregation Tests
Activated platelets aggregate in two stages. Initially, alpha and dense platelet granules release a host of factors that spur platelet aggregation. Further
aggregation promotes a second irreversible phase of coagulation that utilizes energy-dependent factors such as thromboxane.
These two phases are assessed with the use of a photo-optical instrument that measures the degree of light transmittance through a blood sample.
Each coagulation phase is associated with a relative increase in light transmittance. This is due to the decreased turbidity of the sample when platelet
components aggregate. Since there is more “empty” space in the blood sample, the light is able to transmit more. De-aggregation results in an increase
in platelet particles and increases the turbidity.
Platelet-Mediated Force Transduction
This device assesses both platelet concentration and function. It consists of a sample cup with a tightly fitting upper plate. The upper plate is attached
to a device that senses forces exerted on the plate. A blood sample is placed in between the plate and the cup. As the blood clots, it exerts a force on the
upper plate that is sensed by the device and transduced. The normal values have been established by the device manufacturers. It has shown that high
doses of heparin remove the retraction forces that clotting causes. Furthermore, if protamine is applied to reverse the anticoagulant effects of heparin,
it does not necessarily remove its antiplatelet effects.
TESTS OF THE COAGULATION CASCADE
Standard Coagulation Tests
The coagulation cascade consists of two main tracks: extrinsic and intrinsic. These two tracks measure very different aspects of coagulation, although
they overlap in a common pathway.
Trauma triggers the tissue factor pathway (i.e., extrinsic pathway), which in turn provides a sharp increase in thrombin levels. When the vasculature is
damaged, factor VII leaves the circulation and encounters tissue factor (TF) bearing cells. Factor VII forms a complex with TF, initiating the extrinsic
coagulation pathway. This process is very quick, taking only a few seconds to finish.
The contact activation pathway (i.e., intrinsic pathway) has a minor role in initial clot formation. Instead, it plays a significant part in provoking
inflammation. The final common pathway is the continuation of the prothrombotic state, promoted by activated factors VIII and IX, until negative
feedback curtails these effects.
Prothromboplastin (PTT) values track the intrinsic coagulation cascade. Normal PTT values are in the range of 28–32 seconds. The test uses a
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phospholipid matrix to emulate the interaction of factor XII and the platelet membrane. PTT values are extremely sensitive to even small amounts of
Chapter 6: Coagulation Monitors, Alan Kim Page 2 / 4
heparin. As a result, it is often used as a way to track the efficacy of a heparin dose. Given the
©2021 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility variable responses to heparin dosing, a patient’s
response to standard dosing is factored into further titrating to a therapeutic level.
coagulation pathway. This process is very quick, taking only a few seconds to finish.
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The contact activation pathway (i.e., intrinsic pathway) has a minor role in initial clot formation. Instead, it plays a significant part in provoking
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inflammation. The final common pathway is the continuation of the prothrombotic state, promoted by activated factors VIII and IX, until negative
feedback curtails these effects.
Prothromboplastin (PTT) values track the intrinsic coagulation cascade. Normal PTT values are in the range of 28–32 seconds. The test uses a
phospholipid matrix to emulate the interaction of factor XII and the platelet membrane. PTT values are extremely sensitive to even small amounts of
heparin. As a result, it is often used as a way to track the efficacy of a heparin dose. Given the variable responses to heparin dosing, a patient’s
response to standard dosing is factored into further titrating to a therapeutic level.
Prothrombin time (PT) values reflect the extrinsic pathway. PT values are measured by adding recombinant tissue factor (factor III) to a sample of
plasma. The speed at which this sample coagulates is the PT value. Factor VII has the greatest effect on the speed at which this occurs. PT values can
differ significantly based on the specific system used to calculate its value. As such, the international normalized ratio (INR) value is calculated to
standardize the values across different systems. INR = (PT sample/PT normal)ISI, where ISI is the international sensitivity index that will vary depending
on the system employed in its measurement.
Anti-Xa Activity
Anti-Xa activity is ordered to track the effects of low molecular weight heparin (LMWH) or unfractionated heparin (UFH). The effect of LMWH such as
enoxaparin is lost in the PT/PTT/INR tests. It requires a separate test of the heparin Xa levels to judge its effects. As such when giving a therapeutic dose
of enoxaparin, heparin Xa levels can be followed closely.
Reptilase Time
Reptilase time measures deficiencies in fibrinogen. Reptilase mimics thrombin activity in cleaving fibrinopeptides, but only cleaves the A variant, while
thrombin cleaves both A and B variants to release fibrin. Unlike thrombin, reptilase is poorly inhibited by antithrombin III (AT-III). As such,
anticoagulants that rely on AT-III activity, such as heparin, hirudin, and argatroban, do not prolong reptilase time.
Ecarin Clotting Time
Ecarin clotting time (ECT) is used to track hirudin-based anticoagulant effects. Ecarin activates prothrombin. Direct thrombin inhibitors such as hirudin
inhibit this activation pathway. ECT is unaffected by warfarin administration.
Specific Factor Testing
In the presence of specific factor deficiencies such as hemophilia A (factor VIII) and hemophilia B (factor IX), these factors can have their levels tested
directly. Hemophiliac A patients require at least 30% factor VIII activity prior to proceeding to a minor surgery. These same patients require 100% factor
VIII levels when undergoing major surgeries. These levels should be assessed shortly prior to the start of surgery. If levels are deficient, surgeries
should be delayed until restored. In an emergency, they should be run through the case.
Disseminated intravascular coagulation (DIC) is another test in which specific factor levels, as well as factor degradation byproducts, are indicative of a
pathologic state. The assessment of fibrinogen levels and fibrin split products, coupled with clinical signs of excessive bleeding, are hallmarks of
ongoing DIC.
Activated Coagulation Time (ACT)
ACT is a widely used assay of heparin activity. Whole blood is added to an activator that triggers the intrinsic coagulation pathway. There is a manual
and automated version of this test. The manual version relies on the visual confirmation of clot formation as the endpoint. The automated version
relies on the clot retracting force to trigger the endpoint. A normal time is generally between 80 and 120 seconds.
There are two main automated ACT machines (Hemochron and HemoTec systems). Although the individual mechanics differ, the objective is the same.
When a reliable clot forms, the machine triggers a time. The results of the two tests are not interchangeable as statistically different measurements
have been conducted at both low and high heparinization levels. A single type should be used over the duration of a case.
This test is often used to confirm adequate heparinization prior to initiating cardiopulmonary bypass. A level of 300–400 seconds is generally
considered safe for cardiopulmonary bypass. Institution- and service-dependent thresholds may vary. A level of 400 and above is considered adequate
in an emergency situation as long as additional anticoagulation is administered and assessed over the course of the surgery.
There are several limitations with the use of ACT:
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Chapter 6: Coagulation Monitors, Alan Kim Page 3 / 4
ACT levels do not correlate with plasma heparin levels. In cardiopulmonary bypass, the addition of an extracorporeal circuit causes hemodilution,
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which can theoretically lower ACT values. Hypothermia increases ACT in a dose-dependent fashion. These two effects are limited to heparinized
blood samples. The ACT values of unheparinized samples are not affected by hypothermia or hemodilution.
have been conducted at both low and high heparinization levels. A single type should be used over the duration of a case.
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This test is often used to confirm adequate heparinization prior to initiating cardiopulmonary bypass. A level of 300–400 seconds is generally
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considered safe for cardiopulmonary bypass. Institution- and service-dependent thresholds may vary. A level of 400 and above is considered adequate
in an emergency situation as long as additional anticoagulation is administered and assessed over the course of the surgery.
There are several limitations with the use of ACT:
ACT levels do not correlate with plasma heparin levels. In cardiopulmonary bypass, the addition of an extracorporeal circuit causes hemodilution,
which can theoretically lower ACT values. Hypothermia increases ACT in a dose-dependent fashion. These two effects are limited to heparinized
blood samples. The ACT values of unheparinized samples are not affected by hypothermia or hemodilution.
Platelet levels and function influence ACT as well. Thrombocytopenia with platelet levels below 50,000/uL can prolong ACT. Platelet function
inhibitors such as aspirin and prostacyclin will also prolong ACT times.
Platelet lysis will actually shorten ACT values by releasing platelet factor 4 (PF-4). PF-4 neutralizes heparin which in turn shortens the ACT time.
Both anesthesia and surgery will cause a hypercoagulable state, shortening the ACT as well.
Inadequate rises in ACT in response to therapeutic doses of heparin should be investigated thoroughly. However, the most likely etiology is a
deficiency in functional AT-III levels. Heparin activates AT-III as the initial step of its anticoagulant activity. Although it also neutralizes several
coagulation factors, the bulk of its function relies upon the presence of functional AT-III.
When adequate ACT levels are not achieved, even after significant heparin doses, AT-III deficiency should be considered as a possible etiology.
Patients will have a wide range of responses to the same heparin dose, depending on the levels of innate antiheparin factors that are present in them.
Heparin dose response (HDR) curves are used to account for this variability. Thus, based on the patient’s initial response to the heparin bolus, the
automated HDR curves will inform the need for any additional heparin.
TESTS OF FIBRINOLYSIS
The thromboelastogram (Chapter 7) is one of the most commonly used perioperative assays to assess both coagulation and fibrinolysis. Alternative
measurements of fibrinolysis are discussed below.
Fibrin Degradation Products
Fibrin degradation products are various byproducts of fibrin breakdown by plasmin. Antibody assays detect their presence, and any elevation in their
levels is indicative of increased fibrinolytic activity. The D-dimer is one of these fibrin degradation products. Although its presence is often sought
during a diagnosis of deep vein thrombosis, pulmonary embolism, or disseminated intravascular coagulation, they can be elevated in a variety of other
conditions.
Euglobulin Lysis Time
The euglobulin lysis time measures the time it takes for the euglobulin fraction of a plasma sample to break down a clot. The time is shorter when
fibrinolysis is more active, longer when not. As with other tests, there are both automated and manual versions of this test.
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Chapter 6: Coagulation Monitors, Alan Kim Page 4 / 4
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