Synonyms Protime; PT
Applies to
Argatroban; Common Pathway; Coumadin®; Extrinsic Pathway; Heparin;
Hirudin; INR; International Normalized Ratio; Intrinsic Pathway;
Thromboplastin; Vitamin K
Abstract
The prothrombin time (PT) measures the clotting time from the activation
of factor VII, through the formation of fibrin clot
This test measures the integrity of the extrinsic and common pathways of
coagulation,
Specimen ---Plasma
Container -- Blue top (sodium citrate) tube; 3.2% citrate tubes are now
recommended instead of 3.8% citrate tubes.1
Collection
Routine venipuncture. If multiple tests are being drawn, draw blue top
tubes after any red top tubes but before any lavender top (EDTA), green
top (heparin), or gray top (oxalate/fluoride) tubes.
Immediately invert tube gently at least 4 times to mix.
Tubes must be appropriately filled.
Deliver tubes immediately to the laboratory.
Storage Instructions
Separate plasma from cells as soon as possible. Plasma (or
uncentrifuged specimen) may be stored at room temperature or on ice for
up to 24 hours, otherwise store frozen.1
Causes for Rejection
Specimen received more than 24 hours after collection,
tube not filled,
clotted specimen,
visible hemolysis
Reference Interval
Varies significantly among different reagent-instrument combinations.
The approximate lower limit of normal is 10-12 seconds;
the approximate upper limit of normal is 12-14 seconds.
Newborns normally have prolonged PTs in comparison with adults.
The PT is up to approximately 16 seconds at birth, and the PT gradually
shortens into the adult normal range by the age of 6 months.3 However,
newborns and infants do not normally experience bleeding, because a
balance between procoagulants and natural anticoagulants is maintained.
Critical Values
Longer than 30 seconds is the most commonly used PT panic value in
specialized coagulation laboratories according to the College of American
Pathologists 1999 Survey CG2-C, but the value varies depending on the
reagent-instrument combination and individual laboratory policies.
Use
Screen the integrity of the extrinsic (factor VII
) and common (fibrinogen and factors II, V, and X) pathways of
coagulation; monitor warfarin (Coumadin®) anticoagulation
Methodology
PT reagent is called thromboplastin (phospholipid with tissue factor and
calcium)
. It is added to patient plasma, and the time until clot formation is
measured in seconds.
Tissue factor activates the extrinsic pathway of coagulation. Phospholipid
and calcium are required cofactors in the coagulation cascade.
Citrate in the blue top tube prevents clotting by chelating calcium. PT
reagents contain excess calcium to overcome the citrate
. More recently, point-of-care PT test methods have become available
which use a single drop of whole blood, and these methods are undergoing
evaluation.6
Additional Information
If indicated, a vitamin K trial may be performed in a patient with an
unexplained PT prolongation. If the PT prolongation is due to vitamin K
deficiency, the PT becomes normal or significantly shorter within 12-24
hours after vitamin K administration.
To determine the etiology of an unexplained PT prolongation, a mixing
study is usually the first step (if the PTT is also prolonged, the presence of
heparin or related anticoagulants must first be excluded - see Mixing
Studies). Mixing studies can predict whether the cause of the PT
prolongation is a factor deficiency or an inhibitor. The majority of PT
prolongations are due to factor deficiencies. If the PT mixing study
suggests a factor deficiency, assays for fibrinogen and factors II, V, VII, and
X can be performed to identify the deficient factor(s). Inhibitors that
prolong the PT are rare. Factor VII inhibitors prolong the PT but not the
PTT. Factor II, V, or X inhibitors typically prolong the PTT as well as the PT
(see Coagulation Factor Assays for more information). As mentioned
above, lupus anticoagulants are inhibitors that commonly prolong the PTT,
but uncommonly prolong the PT.
In patients with both a lupus anticoagulant and a prolonged PT, a factor II
assay could be considered, because occasionally lupus anticoagulants cause
decreased factor II due to increased clearance.
Acquired causes of PT prolongations are much more common than
hereditary causes, especially among inpatients (see list below). The liver
synthesizes all of the coagulation factors. Therefore, with liver disease,
multiple factor deficiencies can develop which prolong the PT earlier and
more than the PTT. Coumadin® or vitamin K deficiency impair the
function of factors II, VII, IX, and X, leading to PT and eventually PTT
prolongations. In disseminated intravascular coagulation (DIC), multiple
factor deficiencies may arise due to activation and consumption of factors,
prolonging the PT more often than the PTT.7 Heparin inhibits activated
factors II, X, IX, XI, XII, and kallikrein by enhancing antithrombin activity,
prolonging the PTT more than the PT. Hirudin and argatroban inhibit only
activated factor II (thrombin), prolonging the PT and PTT.
CAUSES OF PT PROLONGATIONS:
Hereditary:
* Deficiency of factor VII (PTT is normal)
* Deficiency of fibrinogen or factors II, V, or X (PTT
may also be prolonged)
Acquired:
* Liver dysfunction (PT affected earlier and more than
PTT)
* Vitamin K deficiency (PT affected earlier and more than
PTT)
* Warfarin (PT affected earlier and more than PTT)
* Disseminated intravascular coagulation (DIC) (PT
affected earlier and more than PTT)
* Lupus anticoagulants (may or may not prolong the PTT;
PT is rarely prolonged)
* Heparin (PT less affected than PTT, PT may be normal)
* Hirudin or argatroban (PTT also prolonged)
* Specific factor inhibitors (PTT also prolonged except in
the rare case of an inhibitor against factor VII)
The effects of hereditary or acquired factor deficiencies on PT and PTT are
shown in Tables 1 and 2 in Coagulation Factor Assays. Factor half-lives are
summarized in Table 3 in that listing.
Monitoring warfarin: Warfarin is monitored by the international
normalized ratio (INR). The usual therapeutic goal is an INR of 2-3. The
INR is calculated from the PT and is intended to allow valid comparisons
of results regardless of the type of PT reagent used among different
laboratories:
INR = [patient PT / mean normal PT]ISI
The international sensitivity index (ISI) is a measure of the sensitivity of a
particular PT reagent. Different PT reagents have different sensitivities to
factor deficiencies. For example, with an insensitive reagent, the PT will not
become prolonged until the factor levels are very decreased, whereas with
a sensitive reagent, the PT will become prolonged with milder factor
deficiencies. Insensitive reagents have higher ISI values, up to about 3.0.
Sensitive reagents have lower ISI values, down to about 1.0. The ISI for
each reagent is determined by the manufacturer.
During warfarin initiation, the PT/INR is typically checked daily or at least
4-5 times per week until the dose and INR are therapeutic and stable.8 The
interval between PT/INR tests can then be gradually decreased to as
infrequently as every 4 weeks, depending on the stability of the dose and
the PT/INR result.8,9 It takes 4-5 days for warfarin's antithrombotic action
to take effect, because the half-lives of factors II and X are relatively long.
For this reason, patients who need immediate anticoagulation are treated
with an immediate-acting anticoagulant (eg, heparin) while waiting for
warfarin to become therapeutic. Heparin is typically continued until the
INR is in the desired range for two consecutive days.9
To treat warfarin overdose (bleeding), vitamin K or fresh frozen plasma
can be administered.
9
If the INR is >5 without bleeding, vitamin K administration can be
considered. If large doses of vitamin K are administered, patients can
become temporarily warfarin resistant.
Synonyms
APTT; aPTT; Partial Thromboplastin Time; PTT
Applies to
Argatroban; Common Pathway; Extrinsic Pathway; Heparin;
Heparin Resistance; High Molecular Weight Kininogen; Hirudin;
Intrinsic Pathway; Prekallikrein
Abstract
The activated partial thromboplastin time (PTT) measures the
clotting time from the activation of factor XII, through the
formation of fibrin clot
This measures the integrity of the intrinsic and common
pathways of coagulation,
. PTT prolongations are caused by either factor deficiencies
(especially of factors VIII, IX, XI, and/or XII), or inhibitors (most
commonly, lupus anticoagulants, or therapeutic anticoagulants
such as heparin, hirudin, or argatroban).
Specimen
Plasma
Container
One blue top (citrate) tube; 3.2% citrate tubes are now
recommended instead of 3.8% citrate tubes.1
Specimens
drawn from a heparinized line are easily contaminated with
heparin, even when the initial volume drawn is discarded.
Therefore, coagulation tests are best drawn directly from a
peripheral vein, avoiding the arm in which heparin, hirudin, or
argatroban is being infused (if relevant).
Storage
Instructions Separate plasma from cells as soon as possible,
preferably within 1 hour if the PTT is used to monitor heparin,
otherwise, PF4 released from platelets neutralizes heparin and
can falsely lower the PTT value. To minimize the amount of PF4
in specimens, laboratories should ensure that the plasma
contains <10 x 109/L platelets. With or without heparin, plasma
may be stored on ice for up to 4 hours, otherwise, store frozen.
Causes for Rejection
Specimen received more than 4 hours after collection, tubes not
filled, clotted specimens, visible hemolysis
Turnaround Time Less than 1 day; often less than 1 hour if
requested stat. The PT and PTT are the most readily available
coagulation tests.
Reference
Interval Varies significantly among different reagent-instrument
combinations.
The approximate lower limit of normal is 20-25 seconds; the
approximate upper limit of normal is 32-39 seconds.
Newborns normally have prolonged PTTs in comparison with
adults. The PTT is up to 55 seconds at birth, and the PTT
gradually decreases into the adult normal range by the age of 6
months.3 However, newborns and infants do not normally
experience bleeding, because a balance between procoagulants
and natural anticoagulants is maintained.
Critical Values
>100-150 seconds (varies depending on reagent-instrument
combination and laboratory policies)
Use To
screen the integrity of the intrinsic pathway of coagulation
(factors VIII, IX, XI, and XII) and to a lesser extent the common
pathway (fibrinogen and factors II, V, and X).
May detect lupus anticoagulants, but the PTT should not be used
to screen for lupus anticoagulants because the PTT may or may
not be prolonged (depending on the reagents). Also used to
monitor therapeutic heparin, hirudin, or argatroban
anticoagulation.
Methodology
PTT reagent (phospholipid with an intrinsic pathway activator
such as silica, celite, kaolin, ellagic acid) and calcium are added
to patient plasma, and the time until clot formation is measured
in seconds. Phospholipid in the PTT assay is called "partial
thromboplastin" because tissue factor is not present.
Tissue factor is present with phospholipid in (complete)
thromboplastin reagents that are used for PT assays.
Tissue factor activates the extrinsic pathway of coagulation,
which is not measured in PTT assays.
Phospholipid and calcium are required cofactors in the
coagulation cascade. Citrate in the blue top tube prevents
clotting by chelating calcium.
When the PTT test is ready to be performed, excess calcium is
added to overcome citrate.
More recently point-of-care PTT test methods have become
available which use a single drop of whole blood, and these
methods are undergoing evaluation.5
Causes of PTT Prolongations
Hereditary:
* Deficiency of factor VIII, IX, XI, XII,
prekallikrein, or HMWK (PT is normal)
* Deficiency of fibrinogen or factor II, V, or X
(PT is also prolonged)
Acquired:
* Lupus anticoagulants (PT usually normal)
* Heparin (PT less affected than PTT, PT may
be normal)
* Hirudin or argatroban (PT usually also
prolonged)
* Liver dysfunction (PT affected earlier and
more than PTT)
* Vitamin K deficiency (PT affected earlier and
more than PTT)
* Coumadin®(PT affected earlier and more
than PTT)
* Disseminated intravascular coagulation (DIC)
(PT affected earlier and more than PTT)
* Specific factor inhibitors (PT normal except in
the rare cases of an inhibitor against
fibrinogen, factor II, V, or X)
Monitoring heparin: Low-dose, subcutaneous, prophylactic
unfractionated heparin (eg, 5000 units two or three times daily)
is typically not monitored with coagulation tests. Platelet counts
should be followed to ensure that if heparin-induced
thrombocytopenia develops, the diagnosis will be made promptly.
These low levels of unfractionated heparin usually do not affect
the PTT. Full-dose, therapeutic levels of unfractionated heparin
should be monitored, and the platelet count also followed. The
PTT is the most commonly used assay for unfractionated heparin
monitoring because it is inexpensive, automated, and usually
available 24 hours a day. The therapeutic range is the PTT range
that corresponds to an antifactor Xa level of 0.3-0.7 units/mL.
Each laboratory determines its own therapeutic range, but it is
often a PTT range that is about 1.5-2.5 times the mean of normal
PTT. Therapeutic levels of heparin are most often administered
as an initial intravenous bolus followed by a continuous
intravenous infusion. The PTT is measured every 6 hours during
the first day of unfractionated heparin therapy and 6 hours after
any dosage change. If the PTT is therapeutic, it can be checked
once daily while patients are on heparin. A less common
approach is to administer therapeutic unfractionated heparin
doses subcutaneously twice daily, drawing the PTT 6 hours after
injection.7,8 Peak levels are reached 2-4 hours after subcutaneous
injection, although this is variable. If patients on unfractionated
heparin are started on Coumadin,® heparin is continued until
the INR is therapeutic for 2 days. With some PT reagents,
heparin can prolong the PT (and therefore the INR) to some
extent. Conversely, the PTT can be prolonged somewhat by
Coumadin.® Low-molecular weight heparin (LMWH) usually
does not significantly prolong the PTT, therefore, the PTT is not
used to monitor LMWH. Antifactor Xa assays can be used to
monitor LMWH, when indicated.
Heparin resistance is a condition in which the PTT does not
prolong as much as expected despite high doses of heparin. This
is commonly due to an acute phase reaction, because many acute
phase reactant proteins bind and neutralize heparin.
Additionally, factor VIII becomes elevated during acute phase
reactions, which shorten the PTT. Rarely, heparin resistance is
due to antithrombin deficiency. Mild decreases of antithrombin
commonly occur as a result of heparin therapy, but mild
decreases do not cause significant heparin resistance. Thus, if a
patient has heparin resistance, indices of an acute phase reaction
may be ordered (eg, fibrinogen, factor VIII), and a heparin assay
(antifactor Xa assay) may be helpful.
Monitoring hirudin (lepirudin, RefludanTM): Hirudin is a direct
thrombin inhibitor that is commonly used as an anticoagulant for
the treatment of thrombosis in patients with heparin-induced
thrombocytopenia. Hirudin treatment should be monitored with
the PTT. The usual therapeutic dose of hirudin in patients with
normal kidney function is 0.4 mg/kg intravenous bolus followed
by 0.15 mg/kg/hour continuous intravenous infusion. The dose
has to be significantly reduced when the creatinine is >1.6
mg/dL. The PTT is performed 4 hours after starting hirudin and 4
hours after any dosage change. If the PTT is in the desired
therapeutic range (1.5-2.5 times mean of normal PTT), the PTT
can be checked once daily while on hirudin. Note: See
Coagulation Factor Assays for the use of chromogenic factor X
assays to monitor Coumadin® in patients receiving hirudin or
argatroban.
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