From: Elizabeth M. Van Cott, M.D., and Michael Laposata, M.D., Ph.D., "Coagulation." In: Jacobs DS et al, ed. The Laboratory Test Handbook, 5th Edition. Lexi-Comp, Cleveland, 2001; 327-358.
Index of Tests
Thrombin Time [CO004600]
Applies to Fibrinopeptide A; Fibrinopeptide B
Abstract Measures clotting time of the last step in the coagulation
cascade, which is the conversion of fibrinogen into fibrin by thrombin.
Useful for diagnosis of dysfibrinogenemia. Very sensitive to low
amounts of heparin, hirudin, or argatroban anticoagulants.
Container One blue top (sodium citrate) tube
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 may be stored on ice for up to 4 hours; otherwise,
Causes for Rejection Specimen received more than 4 hours
after collection, tube not filled, clotted specimens
Turnaround Time Less than 1 day
Reference Interval Approximately 10-13 seconds or 16-24 seconds,
depending on thrombin concentration and ionic strength of the reaction
Use Performed together with Reptilase® time to diagnose
dysfibrinogenemia in patients undergoing evaluation for hypercoagulability
and/or a bleeding tendency. Often performed only if an initial panel
of tests excludes more common disorders, because dysfibrinogenemia
is uncommon. The thrombin time is an older method for detecting
heparin contamination in specimens; direct heparin neutralizing
methods are now available for this purpose. The thrombin time has
occasionally been used to monitor heparin therapy in patients for
whom the PTT could not be used,1 but now antifactor Xa
assays are available for such situations. The thrombin time is often
too sensitive to monitor heparin anticoagulation, and the assay
is not standardized for this purpose.
Methodology Thrombin is added to patient plasma and the clotting
time is measured in seconds. Thrombin cleaves fibrinogen, releasing
fibrinopeptide A and fibrinopeptide B from fibrinogen and converting
fibrinogen into fibrin clot. Assays use bovine or human thrombin.
Some laboratories use the thrombin time to detect unexpected heparin
contamination in specimens. Even small amounts of heparin prolong
the thrombin time, because heparin inhibits thrombin. If the thrombin
time is prolonged, patient plasma can be mixed with an equal volume
of normal plasma. The thrombin time of the mixture remains prolonged
if the prolongation is due to heparin, fibrin degradation products
(FDP), hirudin, argatroban, or other thrombin inhibitors. If the
thrombin time of the mixture is normal, then the etiology of the
prolongation is decreased fibrinogen or dysfibrinogenemia. The Reptilase®
time is not prolonged by heparin. Many laboratories now use direct
heparin neutralizing methods to detect heparin contamination rather
than the thrombin time (see Heparin
Additional Information The thrombin time is prolonged when
fibrinogen is decreased or dysfunctional, or when a thrombin inhibitor
is present. Dysfibrinogenemia is an uncommon hereditary or
acquired condition characterized by dysfunctional fibrinogen. Many
different mutations are known to cause hereditary dysfibrinogenemia.
Dysfibrinogenemia mutations can cause bleeding, thrombosis, or both,
or they may be clinically asymptomatic. If bleeding is present it
is usually mild, but severe bleeding has been reported. Dysfibrinogenemia
has an estimated prevalence of 0.8% in patients with venous thrombosis.2 Arterial thrombosis is less frequent than venous thrombosis in these
patients. Most patients with hereditary dysfibrinogenemia are heterozygous.
Rare homozygous cases have been reported. The thrombin time and
Reptilase® time, which measure the clotting time during the
conversion of fibrinogen into fibrin, are often prolonged in dysfibrinogenemia
because fibrinogen is dysfunctional. Assays that measure fibrinogen
function show lower levels than assays that measure fibrinogen quantity
(immunological or "antigen" assays), because fibrinogen function
is impaired but fibrinogen quantity is not. The PT and PTT may be
prolonged in dysfibrinogenemia.2,3,4 Causes of acquired
dysfibrinogenemia include liver disease, hepatoma,4 or
or acute phase reactions with generation of high levels of fibrinogen.5 The bleeding and thrombosis risk with acquired dysfibrinogenemia
is uncertain. See Fibrinogen.
The thrombin time can be prolonged in disseminated intravascular
coagulation (DIC) or thrombolytic therapy due to high levels of
FDP and decreased fibrinogen. However, the thrombin time is not
a necessary test for DIC diagnosis because fibrinogen and FDP can
be measured directly. Prolongation of the thrombin time and Reptilase®
time has been commonly observed with amyloidosis due to inhibition
of fibrinogen conversion to fibrin.6 Patients exposed
to bovine thrombin may develop thrombin inhibitors that prolong
bovine-based thrombin times, and if the antibody cross-reacts against
human thrombin, human-based thrombin times can also be prolonged
(see Factor Inhibitors). The
Reptilase® time is normal with these inhibitors. Rarely, heparin-like
anticoagulants have been reported in patients with malignancies
or other disorders, with prolonged thrombin times and normal Reptilase®
1. Ray MJ, Perrin EJ, Smith IR, et al, "A Proposed Model to Monitor
Heparin Therapy Using the Concentrated Thrombin Time Which Allows
Standardization of Reagents and Improved Estimation of Heparin Concentrations,"Blood
Coagul Fibrinolysis, 1996, 7(5):515-21.
2. Haverkate F and Samama M, "Familial Dysfibrinogenemia and Thrombophilia.
Report on a Study of the SSC Subcommittee on Fibrinogen,"Thromb
Haemost, 1995, 73(1):151-61.
3. Cote HC, Lord ST, and Pratt KP, "gamma -Chain Dysfibrinogenemias:
Molecular Structure-Function Relationships of Naturally Occurring
Mutations in the gamma Chain of Human Fibrinogen,"Blood,
4. Galanakis DK, "Fibrinogen Anomalies and Disease. A Clinical
Update,"Hematol Oncol Clin North Am, 1992; 6(5):1171-87.
5. Galanakis D, personal communication, 1999.
6. Gastineau DA, Gertz MA, Daniels TM, et al, "Inhibitor of the
Thrombin Time in Systemic Amyloidosis: A Common Coagulation Abnormality,"Blood,
Olson JD, Arkin CF, Brandt JT, et al, "College of American Pathologists
Conference XXXI on Laboratory Monitoring of Anticoagulant Therapy.
Laboratory Monitoring of Unfractionated Heparin Therapy,"Arch
Pathol Lab Med, 1998, 122:782-98.