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386 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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methods are available to perform these tests. However, an overall lack of standardization across coagulation testing can lead
to considerable variation in test results and their interpretation.
Normal and therapeutic ranges established for one test method
are not necessarily interchangeable with other methods, especially when dierences in endpoint detection or reagents exist.
erefore, it is important to interpret test results based on the
specic performance characteristics of the method used to analyze samples.
Coagulation studies may be used to assess certain bleeding disorders, such as hemophilia A (factor VIII deficiency)
or hemophilia B (factor IX deficiency). These deficiencies,
which are inherited, sex-linked recessive traits, primarily
affect males and cause >90% of hemophilia cases. Other
bleeding disorders include von Willebrand disease—the
most common hereditary bleeding disorder—and deficiencies in fibrinogen or factors II, V, VII, X, XI, XIII, and a
combination of these factors.
Patients with thrombotic disorders may have their hypercoagulability evaluated with specic assays for the following
conditions
•
5,6
:
Antiphospholipid antibody syndrome (APS)—lupus antico-
agulant, anticardiolipin antibody
• AT
• Protein C
• Protein S
• Prothrombin G20210A mutation
•
Activated protein C (APC) resistance mutation (factor V
Leiden)
• Homocysteine polymorphisms
ese tests are oen performed in panels because the presence of more than one predisposition to thrombosis further
increases the risk for thrombosis. Normal reference ranges for
AT and proteins C and S are oen reported as a percent of normal activity, with 100% being the mean normal value. For AT,
the normal activity level is 80% to 130%; for both proteins C and
S, normal activity levels are 70% to 140%. Deciencies can result
in frequent, recurrent thromboembolic events in patients with
these disorders. Because these deciencies are rare, their respective assays are not discussed here in detail. e use for thrombophilia testing is controversial with no clear guidelines on which
patients should be tested.
5,6,34
Negative results may falsely reassure patients and/or clinicians that the risk of recurrent venous
thromboembolism (VTE) is low, leading to discontinuation of
anticoagulants, which may put the patient at risk for thrombosis; positive results may lead to continued anticoagulation due
to overestimation of the risk of recurrent VTE with the specic
thrombophilia, which can put the patient at risk for bleeding.34
Acquired, transient deciencies of any of these inhibitors may
be observed during thrombotic states. erefore, these parameters should not be assessed during the acute phase of thrombosis or while the patient is currently on anticoagulant therapy
because a false-positive result may occur. It is recommended to
test for AT, protein C, protein S, and APC resistance aer the
thrombosis has been resolved when the patient is o heparin or
warfarin for a few weeks or o DOACs for at least ve half-lives6;
the test for prothrombin G20210A mutation and factor V Leiden
is not aected by current anticoagulant therapy6 (Minicase 1).
e results of thrombophilia testing should be used along with
other risk factors for recurrent VTE to help determine whether
a patient should continue anticoagulants.
MINICASE 1
Risk of Recurrent Venous
Thromboembolism
Juan R., a 55-year-old man, presents to the anticoagulation
clinic to discuss the possible continued need for
anticoagulation. He recently completed 3 months of warfarin
therapy for a first event deep vein thrombosis. He reports
that he has started a new job that does not allow him to
readily come in for INR appointments, so he is asking about
converting to a DOAC if he needs to stay on anticoagulant
medication. He weighs 85kg and is 72″ tall with reduced
renal function. Laboratory results 4 weeks after stopping
warfarin are as follows:
LABORATORY
RESULTS
PT 10–13 sec 11.6 sec
INR 0.9–1.1 0.9
Estimated
glomerular
filtration rate
d-dimer <0.5 mcg/mL 1.3 mcg/mL
QUESTION: How should his lab results be interpreted for his
risk of recurrent VTE? Should any additional lab work be
performed? What are his options for future anticoagulation
if needed?
DISCUSSION: The d-dimer is elevated, which means the patient
is at higher risk of recurrent VTE and an extended duration of
anticoagulation can be considered. The patient and clinician
may elect to do a hypercoagulable panel to see if he has any
of the conditions for thrombophilia. Because he has been
off warfarin for 4 weeks, there is less likelihood of a falsepositive result for tests such as protein C deficiency, protein S
deficiency, AT, or APC resistance. This patient can be started
on a DOAC or warfarin if extended duration of anticoagulation
is selected. The patient would need to be counseled on the
benefits and drawbacks of DOACs, including fewer dietary
issues, fewer drug interactions, higher cost, and need for
adherence to therapy due to short half-lives of these agents.
If he decides to stay with warfarin, he may be able to do
patient self-monitoring or PST after the anticoagulation clinic
assesses his ability to perform such care.
NORMAL
RESULTS
>60 mL/min 42 mL/min
PATIENT
RESULTS
CHAPTER 17 • HEmATology: Blood CoAgulATion TEsTs 387
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TABLE 17-7.
TESTS THAT MAY BE
USED FOR QUALITATIVE
ASSESSMENT OF DOACs
DTIs (dabigatran)
TT: prolonged
Factor Xa inhibitors
(apixaban, edoxaban,
rivaroxaban, betrixaban)
Anti-Xa (if not calibrated to a
Source
Activated protein C resistance due to the factor V Leiden
mutation is the most prevalent hereditary predisposition to
venous thrombosis. It is present in approximately 5% of the general white population and is less common or rare in other ethnic groups.6 Prothrombin G20210A mutation is the second most
common hereditary predisposition to venous thrombosis. DNAbased methods, such as polymerase chain reaction–based assay,
are used to determine the presence or absence of a specic mutation at nucleoside position 20210 in the prothrombin gene. A
normal test result would show absence of the G20210A mutation.
Although routine laboratory monitoring is not indicated
with DOACs, there are some clinical instances when laboratory
assessment could be considered, including a thrombotic or hemorrhagic event, perioperative management, suspicion of overdosage/toxicity, renal/hepatic dysfunction, extremes of body
weight, trauma, questionable adherence to therapy, concomitant
administration with signicant drug interactions, advanced age,
and aer attempted reversal of anticoagulation.35 Although therapeutic concentrations of the actual drug associated with optimal outcomes have not been established for the DOACs, certain
coagulation tests are better suited to assess qualitative (presence
or absence of drug) versus quantitative (estimates of drug levels)
information for specic DOACs, which are discussed in detail
later and summarized in Table17-7.
Careful attention to blood collection technique, sample processing, and laboratory quality control is critical for reliable
coagulation test results. Blood is collected in syringes or vacuum
tubes that contain heparin, EDTA, or sodium citrate. Because
heparin and EDTA interfere with several clotting factors, only
sodium citrate is used for coagulation and platelet tests. Errors
in coagulation can be signicant unless quality assurance is strict
concerning specimen collection, reagents, controls, and equipment. Factors that promote clotting and interfere with coagulation studies are as follows:
• Tissue trauma (searching for a vein)
• Prolonged use of tourniquet
• Small-bore needles
TESTS THAT MAY BE
USED FOR QUANTITATIVE
ASSESSMENT OF DOACs
dTT
TESTS NOT
RECOMMENDED
Anti-Xa: no effect
TT: no effect
dTT: no effect
• Vacuum tubes
• Heparin contamination from indwelling catheters
• Slow blood lling into collection tube
Bleeding risk and test results. e major determinants of
bleeding are the intensity of the anticoagulant eect, the underlying patient characteristics, the use of drugs that interfere
with hemostasis (Tables17-3, 17-6, and 17-8), and the length
of anticoagulant therapy. When evaluating anticoagulation
treatment, one must weigh the potential for decreased thrombosis risk versus increased bleeding risk. Serious bleeding can
occur in patients prone to bleeding, even when the anticoagulant response is in the therapeutic range. e risk of bleeding
is usually higher earlier in therapy (eg, when both heparin and
warfarin are given together, which may be related to excessive
anticoagulation). Also, patients who have a coexisting disease
that elevates PT, aPTT, or both (eg, liver disease) are oen at
much higher risk of bleeding. In these patients, the use and
intensity of anticoagulation that should be employed are controversial. Patient on oral anticoagulants who experience GI
bleeding are more likely to receive a diagnosis of GI cancer.
us, patients on anticoagulation medication who have GI
bleeding should undergo further evaluation to assess possibility of a GI malignancy. More information about these types of
tests can be found in Chapter15.
Prothrombin Time/International Normalized Ratio
Normal range for PT: 10 to 13 seconds but varies based on
reagent-instrument combinations; normal range for INR: 0.8 to
1.1; therapeutic range for INR depends on indication for anti
coagulation; most indications: 2 to 3
e prothrombin time (PT), also called ProTime, test is used to
assess the integrity of the extrinsic and common pathways (factors II, V, VII, X). Deciencies or inhibitors of extrinsic and
common pathway clotting factors results in a prolonged PT;
however, it should be noted that the PT is more sensitive to
deciencies in the extrinsic pathway (factor VII) compared with
the common pathway (factors V, X, II, and brinogen).
38
36,37
-
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Assay performance characteristics, standardization, and
reporting. e PT is dependent on the thromboplastin source
and test method used to detect clotting. romboplastin
reagents are derived from animal or human sources and include
recombinant products. Factor sensitivity is highly dependent
on the source of the thromboplastin and can exhibit variability
between dierent lots of the same reagent. Some thromboplastin reagents are less sensitive to changes in factor activity. is
means that it takes a more signicant decrease in factor activity to produce a prolongation of the PT. Dierences in reagent
sensitivity, combined with the inuence of endpoint detection,
aect clotting time results both in the normal and therapeutic
ranges. Large dierences in factor sensitivity between comparative methods can result in conicting interpretation of results,
both in the assessment of factor deciencies and adequacy of
anticoagulation therapy. Heparin also may prolong PT because
it aects factor II in the common pathway; the addition of a
heparin neutralizing agent to the blood sample can blunt this
eect at heparin concentrations up to 2 units/mL.38 However,
at higher concentrations of heparin—whether due to higher
doses of heparin or sample collection issues—the neutralizing agent may not be enough, and the PT may be prolonged.
ese “crossover” eects may have to be considered when oral
and parenteral anticoagulants are given concomitantly for several days to avoid premature discontinuation of the parenteral
agent. e PT is not as sensitive as the aPTT for dabigatran; PT
levels may be normal or prolonged while a patient is on dabigatran, so this is not a useful test for monitoring or measuring
dabigatran levels. In terms of the oral factor Xa inhibitors, the
PT is more sensitive to rivaroxaban compared with apixaban
or edoxaban; therapeutic doses of rivaroxaban can result in a
normal or prolonged PT level.35 e PT is not sensitive enough
for assessing apixaban or edoxaban therapy.
35
Because PT results can vary widely depending on the thromboplastin source, the INR is the standardized reporting method
for monitoring warfarin therapy. e INR is calculated according to the following equation:
INR = (patient PT/mean normal PT)
ISI
where the International Sensitivity Index (ISI) expresses the
sensitivity of the thromboplastin reagent compared with the
World Health Organization reference standard. e more sensitive or responsive the reagent, the lower the ISI. eoretically, an INR result from one laboratory should be comparable
to an INR result from a dierent laboratory although the PTs
may be dierent. e INR should not be used as a test for
DOAC monitoring because the ISI is specic for vitamin K
antagonists.
35,39
Although the INR system has greatly improved the standardization of the PT, one can still expect dierences in INRs
reported with two dierent methods, particularly in the upper
therapeutic and supratherapeutic ranges. e greater the differences in the ISI values for two comparative methods, the
more likely dierences will be noted in the INR. Laboratories
and anticoagulation clinics should review the performance
characteristics of the PT method used to evaluate their specic patient populations and report changes in methods to
healthcare professionals, particularly those monitoring anticoagulant therapy.
Monitoring warfarin therapy. Both the PT and INR may be
reported when monitoring warfarin therapy, although clinically only the INR is used to adjust therapy. Warfarin exerts
its anticoagulant eects by interfering with the synthesis of
vitamin K-dependent clotting factors (II, VII, IX, and X) and
the natural anticoagulant proteins C, S, and Z. Specically,
warfarin inhibits vitamin K-reductase and vitamin K epoxide
reductase (VKOR), which blocks the activation of vitamin K to
its reduced form. Reduced vitamin K is needed for the carboxylation of clotting precursors of factors II, VII, IX, and X. Noncarboxylated clotting factor precursors are nonfunctional, and
thus an anticoagulated state is achieved.40 Warfarin is manufactured as a racemic mixture of (S)- and (R)-enantiomers; the
S-enantiomer is more potent than the R-enantiomer at inhibit-
ing VKOR, which is why the S-enantiomer is responsible for
most of the anticoagulant eects of warfarin. e S-enantio-
mer is metabolized largely by CYP2C9, whereas the R-enan-
tiomer is metabolized mostly by CYP1A2, and CYP3A4; other
CYP enzymes also are involved in the metabolism of warfarin
although to a lesser extent.
Current guidelines from various organizations recom-
mend an INR of 2 to 3 for most indications.
41-43
A higher INR
of 2.5 to 3.5 is recommended for, but not limited to, patients
with mechanical prosthetic heart valves in the mitral position and patients with recurrent thromboembolic events.
44-46
Results below the therapeutic range indicate that the patient is
at increased risk for clotting, and warfarin doses may need to
be increased. Results above the therapeutic range indicate the
patient is at risk for bleeding and warfarin doses may need to
be decreased. Numerous drugs, disease states, and other factors
prolong or shorten the INR in patients receiving warfarin by
various mechanisms of action (Table17-8).
Pharmacogenomics and oral anticoagulant therapy. Genetic
variability in the genes coding for CYP2C9, VKOR complex
subunit 1 (VKORC1), and CYP4F2 can inuence warfarin
dosing by altering its pharmacokinetics and pharmacodynam-
47,48
ics.
CYP2C9 and VKORC1 have a larger inuence compared with CYP4F2. More information regarding CYP2C9
and VKORC1 can be found in Chapter6. e CYP4F2 enzyme
normally plays a role in the conversion of vitamin K to vitamin
KH2, which is needed to carboxylate the clotting factor precursors; patients with the CYP4F2*3 variant may need higher
warfarin dose requirements compared with noncarriers.
48
U.S. Food and Drug Administration–approved warfarin
pharmacogenomics testing devices are available, including one
that is marketed as direct-to-consumer; each one tests for the
CYP2C9*2 and CYP2C9*3 variants, and some may test for the
VKORC1 variants.
29;30
Genetic testing, if used, should be used
along with patient characteristics, clinical considerations, and
continued INR monitoring for optimal outcomes associated
with warfarin use.
Although genetic variants have not been well studied regarding the DOACs, some potential genes may inuence a patient’s
response to these medications. Single nucleotide polymorphisms
CHAPTER 17 • HEmATology: Blood CoAgulATion TEsTs 389
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TABLE 17-8. Select Factors Altering
ANTICOAGULANT EFFECT
POTENTIATED
absorption in fat
Drug interactions Drug interactions
Barbiturates
Azole antifungals
Cephalosporins Colestipol
antibiotics
Macrolide antibiotics
Metronidazole
Sulfa antibiotics
Heart failure exacerbation
Hepatic disease
Source
on the CESI and ABCB1 genes can aect peak and trough levels
for dabigatran, which may be associated with rates of bleeding.49
Genetic variations in ABCB1 and CYP3A4 may alter drug levels
of rivaroxaban, whereas ABCB1 and SULTA1A may alter drug
levels of apixaban.49 Edoxaban was shown to have little interpatient variability due to genetic variations in the factor X, ABCB1,
CYP2C9, and VKORC1 genes.49 Further studies are needed to
elucidate potential genetic inuences in the dosing of DOACs
and associated clinical outcomes.
Activated Partial Thromboplastin Time
Normal range: varies by manufacturer, generally between
25 and 35 sec; therapeutic range for heparin-treated patients
is 1.5 to 2.5 times control aPTT
e activated partial thromboplastin time (aPTT) is used to
screen for deciencies and inhibitors of the intrinsic pathway
ANTICOAGULANT EFFECT
COUNTERACTED
Alcohol (chronic
(factors VIII, IX, XI, and XII) as well as factors in the nal common pathway (factors II, V, and X). e aPTT also is commonly
used as a surrogate assay to monitor UFH and DTIs. e aPTT,
reported as a clotting time in seconds, is determined by adding
an aPTT reagent, containing phospholipids and activators, and
calcium to the patient’s blood sample.
Factor and heparin sensitivity as well as the precision of the
aPTT test depend both on the reagents and instrumentation.
In addition, some aPTT reagents are formulated for increased
sensitivity to lupus anticoagulants. Despite numerous attempts
to standardize the aPTT, little progress has been made. e difculty in part may reect dierences in opinion as to the appropriate heparin sensitivity, the need to have lupus anticoagulant
sensitivity for targeted patient populations, and suitable factor
sensitivity to identify deciencies associated with increased
bleeding risk. Normal and therapeutic ranges must be established for each reagent instrument combination, and ranges
should be veried with changes in a lot of the same reagent.
Laboratory errors may cause either prolongation or shortening of the aPTT; these may include an inappropriate amount
and concentration of anticoagulant in the collection tube, time
between collection of the blood specimen and performance of
the assay, inappropriate collection site (ie, through a venous
catheter, which contains heparin), and inappropriate timing of
blood collection.
50
Causes of aPTT prolongation. In addition to reagent specic
issues impacting aPTT responsiveness, hereditary diseases or
other acquired causes may prolong aPTT test results. Causes of
aPTT prolongation include the following
2,51
:
Hereditary causes
1. Deciency of factor VIII, IX, XI, XII, prekallikrein, or high-
molecular weight kininogen (PT is normal)
2.
Deciency of brinogen or factor II, V, or X (PT also is
prolonged)
Acquired causes
1. Lupus anticoagulant (PT usually normal)
2. Heparin (PT less aected than aPTT; PT may be normal)
3. Bivalirudin, or argatroban (PT usually also prolonged)
4.
Dabigatran (less accurate at higher dabigatran concentrations)
5. Liver dysfunction (PT aected earlier and more than aPTT)
6.
Vitamin K deciency (PT aected earlier and more than
aPTT)
7. Warfarin (PT aected earlier and more than aPTT)
8. DIC (PT aected earlier and more than aPTT)
9. Specic factor inhibitors (PT normal except in the rare case
of an inhibitor against brinogen, factor II, V, or X)
Use of aPTT to monitor heparin. Although used to detect
clotting factor deciencies, the aPTT is used primarily for
monitoring therapeutic heparin therapy and may be used
to qualitatively monitor dabigatran therapy. e generally
accepted therapeutic range of heparin is an aPTT ratio of 1.5
to 2.5 times the control value.40 Given the interpatient and
intrapatient variability that can result from aPTT reagents,
alternative means of monitoring heparin therapy are being
390 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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scrutinized. is 1.5 to 2.5 aPTT ratio corresponds to the following concentrations39:
•
A plasma heparin concentration of 0.2 to 0.4 units/mL by
assay using the protamine titration method
•
A plasma heparin concentration of 0.3 to 0.7 units/mL by
assay using the inhibition of factor Xa
Unfractionated heparin should be given by continuous IV
infusion or subcutaneous injection, with exact dosing depen
dent on the indication. e aPTT should be drawn at baseline, 6 hours aer continuous IV heparin is begun, and 6 hours
aer each subsequent dosage adjustment because this interval
approximates the time to achieve steady-state levels of heparin.
Institutions may have their own specic heparin dosing nomogram or base their nomogram on one used in clinical studies;
using a nomogram also allows quick ne-tuning of anticoagulation by nurses without continuous physician input.
Activated partial thromboplastin time determinations
obtained earlier than 6 hours, when a steady-state concentration
of heparin has not been achieved, may be combined with heparin
concentrations for dosage individualization using non–steadystate concentrations. is approach has been demonstrated to
reduce the incidence of subtherapeutic aPTT ratios signicantly
during the rst 24 hours of therapy.
52,53
is nding is important
because the recurrence rate of thromboembolic disease increased
when aPTT values were not maintained >1.5 times patient baseline aPTT during the rst 24 hours of treatment.
54,55
Heparin concentration measurements may provide a target
plasma therapeutic range, especially in unusual coagulation situations such as pregnancy, in which the reliability of clotting studies is questionable. In this setting, shorter-than-expected aPTT
results in relation to heparin concentration measurements may
be indicative of increased circulating levels of factor VIII and
increased brinogen levels.56 Patients may have therapeutic heparin concentrations measured by whole blood protamine sulfate
titration or by the plasma anti-Xa heparin assay. However, they
may have aPTTs not signicantly prolonged above baseline. is
dierence has been referred to as a dissociation between the
aPTT and the heparin concentration.57 Many of these patients
have short pretreatment aPTT values.
Current recommendations for patients with decreased aPTT
results on heparin are that such patients be managed by monitoring heparin concentrations using a heparin assay to avoid
unnecessary dosage escalation without compromising ecacy.
ese patients, referred to as pseudoheparin resistant, may be
identied as having a poor aPTT response (to an adequate
heparin concentration >0.3 units/mL via plasma anti-Xa assay)
despite high doses of heparin (>50,000 units/24 hours; usual
dose is 20,000 to 30,000 units/24 hours). When higher doses of
heparin (>1,500 units/hour) are required to maintain therapeutic aPTT values, high concentrations of heparin-binding protein
or phase reactant proteins bind and neutralize heparin. Additionally, thrombocytosis, or AT deciency, may exist.
Another use for the aPTT is to demonstrate both ecacy and
safety with LMWH, which have several indications. However,
clinically, the anti-Xa levels are more routinely used for this class
of medications. LMWH has a pharmacokinetic and pharmacodynamic prole, which makes routine monitoring unnecessary
in most circumstances. Exceptions include special populations,
such as those patients with renal failure or severe obesity who are
at risk for being overdosed when weight-adjusted regimens are
used. Both PT and aPTT times are not signicantly prolonged
at recommended doses of LMWHs. However, both ecacy and
safety can be demonstrated by assaying anti-Xa levels.
Decreased aPTT levels. Although most attention has been
-
focused on causes of prolonged aPTT levels, there is growing
evidence of adverse events associated with decreased aPTT
levels, including VTE, myocardial infarction (MI), hyperthyroidism, diabetes, spontaneous abortion, and death.58 Clotting factors of the intrinsic pathway, as well as vWF levels and
activity, have been elevated in some patients presenting with
decreased aPTT levels, which provides some evidence that
patients with decreased aPTT levels are hypercoagulable.59
ere is no denitive answer whether a shortened aPTT is a
cause, a consequence, or just an association with these other
conditions. To rule out whether a shortened aPTT is due to
a laboratory error, such as inappropriate specimen collection,
repeat testing should be performed.
Heparin alone has minimal anticoagulant eects; when it is
combined with AT (normal range: 80% to 120%), the inhibitory
action of AT on coagulation enzymes is magnied 1,000-fold,
resulting in the inhibition of thrombus propagation. Patients who
are AT decient (<50%) may be dicult to anticoagulate, as seen
with DIC (Minicase 2). e DIC syndrome is associated not only
with obvious hemorrhage but also occult diuse thrombosis.
Oral anticoagulant eect on aPTT. Although warfarin mildly
elevates aPTT, aPTT is not used to monitor warfarin therapy.
erefore, if warfarin is started in a patient receiving heparin,
the clinician should expect some elevation in aPTT. e aPTT
provides qualitative information on dabigatran but not quantitative information; clinicians should note that a normal aPTT
does not mean there is no clinically important dabigatran
activity occurring in a patient.40 e aPTT is even less sensitive
than PT for the oral factor Xa inhibitors and thus cannot be
recommended for either qualitative or quantitative assessment
for these agents.
35,60
Activated Clotting Time
Normal range: 70 to 180 seconds but varies
Activated clotting time (ACT), also known as activated coagulation
time, is frequently used to monitor heparin or DTIs when high
doses are required, such as during invasive procedures like
cardiopulmonary bypass gra surgery, percutaneous transluminal
coronary angioplasty, PCI extracorporeal membrane oxygenation,
valve replacements, and carotid endarterectomy. In most cases,
an ACT is obtained from a POC machine using whole blood;
thus, it may be run directly in the operating room as well as at the
bedside when rapid heparinization is required (eg, hemodialysis
unit, operating room, and cardiac catheterization laboratories).
Activated clotting time responsiveness remains linear in proportion to an increasing dose of heparin, whereas the aPTT has a
log-linear relationship to heparin concentration. Corresponding
ACT values up to 400 seconds demonstrate this dose-response
relationship, but ACT lacks reproducibility for values in excess
CHAPTER 17 • HEmATology: Blood CoAgulATion TEsTs 391
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• Sample temperature
MINICASE 2
• Heparin potency
• Platelet count and function
A Case of Disseminated
Intravascular Coagulation
• Factor deciencies
• Hypothermia
e main indication for using ACT over aPTT involves
Teresa G., a 36-year-old woman in her third trimester of
pregnancy, is hospitalized with clinical suspicion of DIC
because of acute onset of respiratory failure, circulatory
collapse, and shock. The following laboratory values for her
are obtained:
patients receiving high-dose heparin or DTIs. e DOACs
prolong the ACT, but reproducibility is poor for the factor Xa
inhibitors, and sensitivity is low for dabigatran; thus, this test is
not recommended for qualitative or quantitative measurements
of these agents.
LABORATORY
RESULTS
PT 10–13 sec 16 sec
aPTT 25–35 sec 59 sec
TT 25–35 sec 36 sec
Hgb 12.3–15.3 g/dL 9.8 g/dL
Hct 36% to 45% 27.7%
Platelet count 150,000–450,000/µL 64,000/µL
MPV 7–11 fL 17 fL
FDP (latex) <10 mcg/mL 120 mcg/mL
AT 80% to 120% 57%
d-dimer <0.5 mcg/mL 2.04 mcg/mL
QUESTION: What laboratory tests are used to determine
if a patient is experiencing DIC? What are the expected
laboratory results for these tests?
DISCUSSION: Laboratory findings of DIC may be highly
variable, complex, and difficult to interpret. Scoring systems
have been developed to aid in diagnosing DIC.
and aPTT should be prolonged (and they are prolonged
in this patient), but this may not always occur. Therefore,
the usefulness of both PT and aPTT determinations may
be helpful in making the diagnosis. TT is prolonged as
expected. The platelet count is typically and dramatically
decreased. Her MPV is inversely related to her decreased
platelet count as expected, suggesting a hyperdestructive
phenomenon versus a hypoproliferative state. Although FDPs
are elevated, this rise is not solely pathognomonic for DIC.
Increased d-dimer levels are strongly suggestive of DIC. AT
determination reveals a considerable decrease consistent
with DIC. Decreased AT is useful and reliable for diagnosis
of DIC in the absence of d-dimer testing ability.
NORMAL
RANGE
PATIENT
RESULTS
70-73
Both PT
of 600 seconds as well as low concentrations of heparin. ACT
test results can be inuenced by the following factors61:
• Testing device
• Testing technique
Anti-Xa
Normal range: varies based on specic anticoagulant used for
treatment of existing VTE; heparin: 0.3 to 0.7 International
Units/mL; LMWH: 0.5 to 1 International Units/mL (twice daily
therapeutic dosing); 1 to 2 International Units/mL (once daily
therapeutic dosing); 0.2–0.5 International Units/mL (prophylactic dosing); fondaparinux, rivaroxaban, apixaban, edoxaban,
betrixaban: not established
e anti-Xa level may be used to monitor LMWH when given
in therapeutic doses; however, routine monitoring is not
usually done because LMWH has a more predictable doseresponse relationship than UFH. is assay is recommended to
be drawn 4 hours aer administration of a therapeutic weightadjusted dose of LMWH, when anti-Xa activity has peaked. An
eective plasma concentration range is approximately 0.5 to
1.1 plasma anti-Xa units/mL for twice-daily therapeutic subcutaneous dosing of LMWH, or 1 to 2 International Units/
mL for once-daily therapeutic dosing of LMWH. e target
range for prophylactic dosing is not as well dened as for therapeutic dosing, but 0.2 to 0.5 International Units/mL has been
suggested.62 When ordering an anti-Xa test, it is imperative
that the correct calibrator is used to ensure correct results; for
example, the LMWH calibrator cannot be used to measure
anti-Xa activity of fondaparinux. e anti-Xa level may be used
as a quantitative assessment for the oral factor Xa inhibitors as
long as the specic drug calibrator is used; if the specic calibrator is not used, the anti Xa level can only serve as a qualitative assessment test. Dabigatran has no eect on anti-Xa levels.
Currently, some laboratories may not have specic calibrators
for the oral factor Xa inhibitors, which limits the usefulness of
this test (Minicase 3).
Fibrinogen Assay
Normal range: 200 to 400 mg/dL (5.8 to 11.8 mmol/L)
Although the PT and aPTT are used to screen for deciencies in the intrinsic, extrinsic, and common pathways, the
brinogen assay is most commonly used to assess brinogen
concentration. Fibrinogen assays are performed by adding a
known amount of thrombin to a dilution of patient plasma.
e brinogen concentration is determined by extrapolating the patient’s clotting time to a standard curve. Elevated
brinogen levels may be related to pregnancy or acute phase
reactions and may be associated with an increased risk of cardiovascular disease.63 Decreased brinogen is associated with
DIC and hepatic cirrhosis; PT and aPTT levels also may be
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MINICASE 3
Direct Oral Anticoagulant
Monitoring
Genevieve H., a 67-year-old woman, is hospitalized with
reports of chest pain and must undergo emergency surgery.
Her home medications include rivaroxaban, metoprolol,
atorvastatin, and lisinopril.
The following laboratory parameters are obtained prior to
surgery:
LABORATORY
STUDY
PT 10–13 sec 35.6 sec
INR 0.9–1.1 1.28
aPTT 21–45 sec 69 sec
TT 17–25 sec 23 sec
QUESTION: What specific test result(s) can be used to
assess this patient’s DOAC therapy? What are the expected
results for these tests if a patient is taking a DOAC such as
rivaroxaban?
NORMAL
RANGE
PATIENT
RESULTS
Thrombin Time
Normal range: 17 to 25 seconds but varies according to
thrombin concentration and reaction conditions
e thrombin time (TT), also known as thrombin clotting time,
measures the time required for a plasma sample to clot aer the
addition of bovine or human thrombin and is compared with
that of a normal plasma control. Deciencies in both the intrinsic and extrinsic systems do not aect TT, which assesses only
the nal phase of the common pathway or essentially the ability
to convert brinogen to brin.
Prolongation of TT may be caused by hypobrinogenemia,
dysbrinogenemia, heparin, DTIs, or the presence of FDPs.
e TT is ultrasensitive to heparin and dabigatran; therefore,
it only is useful to show whether these drugs are present in the
blood sample—not as a monitoring test or to quantify drug levels; a normal TT can exclude the presence of dabigatran. With
thrombolytic therapy, laboratory monitoring may not prevent
bleeding or ensure thrombolysis. However, some clinicians recommend measuring TT, brinogen, plasminogen activation,
or FDPs to document that a lytic state has been achieved. Typically, TT is >120 seconds 4 to 6 hours aer “adequate” thrombolytic therapy.
e dilute thrombin time (dTT) is a test that compensates
for the extreme sensitivity of the TT to heparin and dabigatran
by diluting the patient’s blood sample with normal plasma. Neither TT nor dTT is a useful monitoring test for the oral factor
Xa inhibitors.
DISCUSSION: She shows elevations in her PT, INR, and aPTT,
while her TT is within normal limits. The PT can be used as
a qualitative measurement for rivaroxaban; results may be
normal to elevated if rivaroxaban is present in this patient’s
system. An anti-Xa level calibrated for rivaroxaban is the
only test that can quantitatively assess how much drug is
in the patient’s system. The INR, although slightly elevated,
is noncontributory to this patient’s findings given she is not
on a vitamin K antagonist. The aPTT is also elevated, but
this test has not been shown to be a reliable indicator of
either qualitative or quantitative assessments of oral factor
Xa inhibitors such as rivaroxaban. The TT is normal given
this test is not affected by oral factor Xa inhibitors; the TT
assesses the ability to convert fibrinogen to fibrin and is not
affected by issues in the extrinsic or intrinsic pathways of
the coagulation system.
increased due to decreased brinogen levels, and patients may
have symptomatic bleeding. Additionally, supratherapeutic
heparin concentrations >1 unit/mL may result in falsely low
brinogen concentration measurements. TT (discussed later)
is the most sensitive test for brinogen deciency, and it is
prolonged when brinogen concentrations <100 mg/dL. However, the actual brinogen concentration occasionally must
be determined. Fibrinogen levels are usually drawn as part
of a DIC panel, to further explore reasons for an elevated PT
or aPTT level, or to further evaluate unexplained bleeding in
a patient.
Ecarin Clotting Time
e ecarin clotting time (ECT) test is a specic assay for thrombin generation. It is used to monitor parenteral DTIs and can
be used as a quantitative assessment for dabigatran (Table17-7).
Ecarin is a type of snake venom that can activate prothrombin; it
is added to plasma, which cleaves prothrombin to meizothrombin, a serine protease similar to thrombin. Ecarin is a type of
snake venom that can activate prothrombin.35 DTIs inhibit
meizothrombin so the ECT can quantify the amount of DTI in
the body by measuring the time for meizothrombin to convert
brinogen into brin. us, a longer ECT corresponds to higher
drug concentrations. ECT is not aected by other anticoagulants
such as warfarin, heparin, or factor Xa inhibitors.
Clot Degradation Tests
Clot degradation tests are useful in assessing the process of brinolysis. ese tests include FDPs and -dimer, which can be
used to diagnose DIC or thrombosis and monitor the safety and
ecacy of thrombolytic therapy. rombolytics (eg, alteplase,
reteplase, and tenecteplase) are exogenous agents that lyse clots
already formed. ey are used in the treatment of acute cerebrovascular accidents, MI, VTE, and peripheral arterial occlusion.
e mechanism by which they activate brinolysis can variably impact circulating proteins (hence, the necessity for close
monitoring to minimize bleeding complications and ensure ecacy). Numerous laboratory parameters have been evaluated for
this purpose, including PT, aPTT, BT, brinogen, FDPs, and
-dimer. ese laboratory parameters are discussed throughout
this chapter and in Minicase 4.
CHAPTER 17 • HEmATology: Blood CoAgulATion TEsTs 393
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MINICASE 4
A Patient on Thrombolytic Therapy
Alfred F., a 44-year-old man, has clinical signs and symptoms and
electrocardiogram findings consistent with acute anterior-wall
MI requiring PCI. However, he presents to a hospital without PCI
capabilities. He receives reteplase between the transit time to the
nearest hospital with PCI capability. Subsequently, he is started
on a heparin infusion. The following pretherapy and posttherapy
coagulation laboratory results are obtained:
LABORATORY
STUDY
PT 10–13 sec 12.2 sec 17 sec
aPTT 25–35 sec 35 sec 69 sec
Fibrinogen 200–400
FDP (latex) <10
d-dimer <0.5
Plasminogen 80% to
NORMAL
RESULTS PRETHERAPY POSTTHERAPY
300 ng/mL 22 ng/mL
mg/dL
<10 mcg/mL >160 mcg/mL
mcg/mL
<0.5 mcg/mL <0.6 mcg/mL
mcg/mL
70% 22%
120%
QUESTION: What might explain the elevated FDP? What accounts
for the fall in the plasminogen level on completion of the lytic
therapy? Finally, why is the d-dimer concentration not elevated in
proportion to the greatly elevated FDP concentration?
DISCUSSION: The elevated posttherapy PT and aPTT are
consistent with heparin therapy after receiving reteplase. The
FDP concentration is elevated because reteplase resulted in
fibrinogenolysis. Many FDPs are generated in this setting. By
the nature of thrombolytic therapy, plasminogen is converted to
plasmin, accounting for the decline in the plasminogen percentage.
Because thrombolytic therapy was unsuccessful in full clot lysis
(with predominate fibrinogenolysis), the d-dimer concentration is
not greatly elevated. For this assay to have been more elevated,
degradation products arising from cross-linked fibrin (fibrinolysis)
would have had to be present. Fibrinogen concentrations should
be followed periodically in patients receiving thrombolytic
agents.
DIAGNOSTIC FOLLOW-UP: If TT, PT, or aPTT is prolonged and if
circulating inhibitors or bleeding disorders are suspected, further
tests are usually performed. These tests may include assays
for specific clotting factors to determine if a specific deficiency
exists. For example, hemophilia or autoimmune diseases may be
associated with inhibitors such as antifactor VIII and the lupus
anticoagulant.
Fibrin Degradation Products
Normal range: <10 mcg/mL or <10 mg/L but varies with assay
Excessive activation of thrombin leads to overactivation of the
brinolytic system and increased production of brin degra-
dation products (FDPs). Excessive degradation of brin and
brinogen also increases FDPs. is increase can be observed
with DIC or thrombolytic drugs. FDPs can be monitored during
thrombolytic therapy, but they may not be predictive of clot lysis.
False-positive reactions may occur in healthy women immediately before and during menstruation and in patients with
advanced cirrhosis or metastatic cancer.
D-Dimer
Normal range: <0.5 mcg/mL (<3 nmol/L) but varies with
specic assay
-dimer is a marker of thrombotic activity and is formed when
thrombin initiates the transition of brinogen to brin and activates factor XIII to cross-link the brin formed; when plasmin
digests the cross-linked brin, -dimer is formed. e -dimer
test is specic for brin, whereas the formation of FDPs (discussed previously) may be either brinogen or brin derived
following plasmin digestion (Figure17-6).
e -dimer is oen used to help diagnose or rule out
thrombosis in the initial assessment of a patient suspected of
having acute thromboembolism; results are typically elevated
if a patient is positive for VTE. However, -dimer is a sensitive
but nonspecic marker for VTE because other causes such as
malignancy, DIC, infection, inammation, and pregnancy also
can elevate the -dimer levels.
64,65
us, a positive result does not
necessarily conrm a diagnosis of VTE, but a negative result can
help rule out VTE. Clinical correlation is essential, and further
diagnostic workup is warranted with a positive test result to rule
out other disorders as causes for abnormal levels. Various guidelines recommend using -dimer as one possible diagnostic aid
in patients with a low or moderate probability for rst event VTE
as determined by calculating the pretest probability through a
validated scoring system such as the Wells or Geneva score; if
the -dimer result is positive, further testing, including imaging
studies, is recommended.
66,67
-dimer levels can increase by age
and some studies have suggested using a dierent cut-o point
for patients ≥50 years old. Using this approach, the cut-o for
patients <50 years old remains <0.5mcg/mL, but for patients ≥50
years old the cut-o would be 10 times the patient’s age.
65,68,69
Using the age-adjusted cut-os may increase the diagnostic ecacy and specicity of the -dimer without losing its sensitivit y.65 In patients who have a high pretest probability for VTE, the
-dimer test is not recommended, and patients should have an
imaging test done instead.
64,66,67
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ENDOTHELIAL DAMAGE
COLLAGEN
XII
XIIa
PREKALLIKREIN
KININOGENS
AG-AB COMPLEXES
ENSOTOXIN
TISSUE DAMAGE
PLATELET DAMAGE
ADP
RED CELL DAMAGE (RELEASE)
THROMBOPLASTIN
ACTIVITY
+ VII
PHOSPHOLIPIDS
X
XI
XIa
THROMBIN
KALLIKREIN
PLASMINOGEN
Xa
PROTHROMBIN
P.F. 1+2
FIBRINOGEN
FIBRIN
KININS
PLASMIN
COMPLEMENT
ACTIVATION
FDP
D-DIMER
FIGURE 17-6.Source
Semin Thromb Hemost.
Publications, Inc.
In addition, to diagnose or rule out VTE, -dimer has been
used for its predictive value for recurrent thromboembolism in
patients treated for rst event idiopathic VTE. Recurrent VTE
risk prediction models, such as DASH, Vienna, and HERDOO 2,
include the -dimer test into their calculations.65 Patients with
normal levels of -dimer 1 month aer stopping anticoagulation therapy for a rst-event idiopathic VTE have a lower
risk for VTE recurrence, whereas elevated levels of -dimer
put patients at higher risk of VTE recurrence.65 Thus,
in patients with elevated levels of -dimer, an extended
duration of anticoagulation therapy could be considered
(Minicase 1).
-dimer is also a common test used as an aid to diagnose
and evaluate patients with DIC. Several scoring systems for
DIC based on clinical and laboratory data have been developed,
which include specic laboratory measurements such as platelet
counts, PT, brinogen, and FDPs.
70-73
e clinical and laboratory
results are given specic scores, and when added up, indicate
whether a patient is likely to have DIC. Although a -dimer
test is not specically mentioned in some scoring systems, it is
oen used as a brin degradation marker, and it is a simple and
quick test to perform. Table17-9 provides a list of the labora-
tory parameters, including the -dimer, used to diagnose DIC
(Minicase 4).
Near-Patient or Point-of-Care Testing Devices
Several point-of-care testing (POCT) devices are available for
dierent coagulation tests, such as PT/INR, ACT, -dimer, and
platelet function tests. More information about POCT can be
found in Chapter4. POCT uses whole blood, a sample that may
be more physiologically relevant and result in a more accurate
assessment of true coagulation potential.
Point-of-care coagulation testing oers specic clinical
advantages, especially when used to monitor antithrombotic
therapy because test results can be combined with clinical presentation to make more timely decisions regarding therapeutic
intervention. is is especially signicant in emergency departments, cardiac catheterization laboratories, surgical settings,
and critical care units, in which immediate turnaround time is
essential to patient care decisions. With newer antithrombotic
options, these technologies will become increasingly relevant
and may aid in making decisions for major bleeding events and
prior to emergency surgery. Although many of the newer drugs
do not require routine monitoring, the availability of rapid interventional testing may be critical to the selection of certain therapies for target patient populations, particularly when these drugs
have a long half-life or cannot be completely reversed. Concomitant therapy is being used increasingly in cardiac patients,
especially during cardiac intervention; thus, the potential for
CHAPTER 17 • HEmATology: Blood CoAgulATion TEsTs 395
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TABLE 17-9.
MONITORING PARAMETER DIC PRIMARY FIBRINOLYSIS TTP CHRONIC LIVER DISEASE
FDP
PT
aPTT
Fibrinogen
Platelet count
LFTs
↓ = decreased; ↑
thrombotic or hemorrhagic problems may be increased without
the ability to rapidly conrm coagulation status, both at the initiation of therapy and at the conclusion of a procedure.
In outpatient settings, POCT may be not only clinically benecial but also more cost-eective and convenient than central
laboratory testing, particularly in oral anticoagulation clinics
and home healthcare settings. Patients can be informed of their
INR results and subsequent dosing instructions within minutes,
which is an obvious time-saving element. Certain patient variables may limit the accuracy of results obtained from the currently available POC devices for INR monitoring. ese include
↑ ↑ ↑ ↑
↑ ↑
↑ ↑
↑ ↑
↓ ↓
↓
↑
↑
Variable
↓ ↓
↑
↑
↑
especially for patients who live far away from testing facilities, who have diculty with scheduled appointments, or who
frequently travel.67 Appropriate patient selection is essential
for PST/PSM to be eective; ideal patient candidates or their
caregivers should have manual dexterity, have visual acuity,
demonstrate competency to perform the test, have the condence and ability to responsibly participate in self-care, and
have the ability to complete a structured training course.
e American Society of Hematology and the Anticoagulation Forum both endorse PST and/or PSM for appropriate
patients.
74;75
concurrent use of LMWH or UFH, presence of antiphospholipid antibodies, and Hct levels above or below device-specic
SUMMARY
boundaries.
Patient self-testing (PST) and patient self-management
(PSM) for INR are options for properly selected and trained
patients on long-term warfarin therapy. PST is when a patient
tests their own INR but rely on a clinician for interpretation
of results and any modications to the current regimen. PSM
is when patients test their own INR and adjust their own therapy, usually based on an algorithm, which oers more patient
autonomy and control over their own dosages. Benets seen in
both PST and PSM include lower VTE recurrence, increased
time in therapeutic range, and increased patient satisfaction;
additionally, there was a mortality benet seen in PSM but not
PST.74 Although there are benets to a PST/PSM model of care,
including increased convenience to the patient, there also are
issues that limit the widespread use of PST and PSM in the
United States. ese include reimbursement from insurance
companies, lack of large-scale randomized trials using a U.S.
population, low levels of awareness or understanding among
healthcare practitioners and patients about these options, and
areas with limited resources.67 Additionally, the cost-eectiveness of PST/PSM is not well dened. Higher costs are associated
with the cost of the test strip as well as increased testing frequency, but this may be oset by the convenience of PST/PSM,
Many factors contribute to normal hemostasis, including interactions among vascular subendothelium, platelets, coagulation
factors, natural anticoagulant proteins C and S, and substances
that promote clot degradation, such as tissue plasminogen activator. In the clinical setting, the impact of these and other considerations must be evaluated. Disorders of platelets or clotting
factors can result in bleeding, which may necessitate the monitoring of specic clotting tests.
Coagulation tests such as aPTT, ACT, and PT/INR are used
to monitor heparin and warfarin therapies. Laboratory monitoring for DOACs is an emerging area with certain tests used
for qualitative versus quantitative assessments of these agents.
In general, coagulation tests are used for patients receiving anticoagulants, thrombolytics, and antiplatelet agents. e availability of rapid diagnostic tests to manage LMWH, DTIs, and
platelet inhibitor drugs may inuence the selection of these
newer therapies. Other indications for routine use of these tests
include primary coagulopathies and monitoring of drugs that
may cause bleeding abnormalities. Finally, other available tests
(eg, -dimer and AT level determinations) may improve diagnostic assessment of patients with DIC and ensure appropriate
treatment selection.
74,75
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