Editing Prothrombin time (section)

==Laboratory measurement==

The reference range for prothrombin time depends on the analytical method used, but is usually around 12–13 seconds (results should always be interpreted using the reference range from the laboratory that performed the test), and the INR in absence of anticoagulation therapy is 0.8–1.2. The target range for INR in anticoagulant use (e.g. [[warfarin]]) is 2 to 3. In some cases, if more intense anticoagulation is thought to be required, the target range may be as high as 2.5–3.5 depending on the indication for anticoagulation.<ref>{{Cite web|url=https://www2.gov.bc.ca/gov/content/health/practitioner-professional-resources/bc-guidelines|title=BC Guidelines - Province of British Columbia|first=Ministry of|last=Health|website=www2.gov.bc.ca}}</ref>

===Methodology===
[[File:Blue Top.JPG|thumb|Vacutainer tube used for PT and PTT blood tests]]
Prothrombin time is typically analyzed by a laboratory technologist on an automated instrument at 37&nbsp;°C (as a nominal approximation of normal human body temperature).{{citation needed|date=July 2020}}
* Blood is drawn into a [[test tube]] containing liquid [[sodium citrate]], which acts as an [[anticoagulant]] by binding the calcium in a sample. The blood is mixed, then centrifuged to separate blood cells from plasma (as prothrombin time is most commonly measured using [[blood plasma]]). In [[newborn]]s, a capillary whole blood specimen is used.<ref name="fritsma">Fritsma, George A. (2002). "Evaluation of Hemostasis." Hematology: Clinical Principles and Applications . Ed. Bernadette Rodak. W.B. Saunders Company: Philadelphia, 2002. 719-53. Print</ref>
* A sample of the plasma is extracted from the test tube and placed into a measuring test tube (Note: for an accurate measurement, the ratio of blood to citrate needs to be fixed and should be labeled on the side of the measuring test tube by the manufacturing company; many laboratories will not perform the assay if the tube is underfilled and contains a relatively high concentration of citrate—the standardized dilution of 1 part anticoagulant to 9 parts whole blood is no longer valid).
* Next an excess of [[calcium]] (in a [[phospholipid]] suspension) is added to the test tube, thereby reversing the effects of citrate and enabling the blood to clot again.
* Finally, in order to activate the extrinsic / tissue factor clotting cascade pathway, [[tissue factor]] (also known as factor III) is added and the time the sample takes to clot is measured optically. Some laboratories use a mechanical measurement, which eliminates interferences from [[lipemia|lipemic]] and [[icteric]] samples.

===Prothrombin time ratio===
The prothrombin time ratio is the ratio of a subject's measured prothrombin time (in seconds) to the normal laboratory reference PT. The PT ratio varies depending on the specific reagents used, and has been replaced by the INR.<ref>{{Cite journal|last=Bussey|first=Henry I.|date=1992-02-01|title=Reliance on Prothrombin Time Ratios Causes Significant Errors in Anticoagulation Therapy|journal=Archives of Internal Medicine|language=en|volume=152|issue=2|pages=278–82|doi=10.1001/archinte.1992.00400140032009|pmid=1739354|issn=0003-9926}}</ref> Elevated INR may be useful as a rapid and inexpensive [[biomarker|diagnostic]] of infection in people with COVID-19.<ref>{{Cite journal|last1=Thachil|first1=Jecko|last2=Tang|first2=Ning|last3=Gando|first3=Satoshi|last4=Falanga|first4=Anna|last5=Cattaneo|first5=Marco|last6=Levi|first6=Marcel|last7=Clark|first7=Cary|last8=Iba|first8=Toshiaki|date=2020-03-25|title=ISTH interim guidance on recognition and management of coagulopathy in COVID-19|journal=Journal of Thrombosis and Haemostasis|volume=18|issue=5|pages=1023–1026|language=en|doi=10.1111/jth.14810|pmid=32338827|pmc=9906133 |doi-access=free}}</ref>

===International normalized ratio===
The result (in seconds) for a prothrombin time performed on a normal individual will vary according to the type of analytical system employed. This is due to the variations between different types and batches of manufacturer's tissue factor used in the reagent to perform the test. The INR was devised to standardize the results. Each manufacturer assigns an ISI value (International Sensitivity Index) for any tissue factor they manufacture. The ISI value indicates how a particular batch of tissue factor compares to an international reference tissue factor. The ISI is usually between 0.94 and 1.4 for more sensitive and 2.0–3.0 for less sensitive thromboplastins.<ref>{{cite journal|pmid=14995988|year=2004|last1=Houdijk|first1=W. P.|title=International multicenter international sensitivity index (ISI) calibration of a new human tissue factor thromboplastin reagent derived from cultured human cells|journal=Journal of Thrombosis and Haemostasis|volume=2|issue=2|pages=266–70|last2=Van Den Besselaar|first2=A. M.|doi=10.1111/j.1538-7836.2004.00434.x|s2cid=20151897}}</ref><ref>{{cite journal|pmid=15917425|pmc=1770687|year=2005|last1=Poller|first1=L|title=European Concerted Action on Anticoagulation. A multicentre calibration study of WHO international reference preparations for thromboplastin, rabbit (RBT/90) and human (rTF/95)|journal=Journal of Clinical Pathology|volume=58|issue=6|pages=667–9|last2=Keown|first2=M|last3=Chauhan|first3=N|last4=Van Den Besselaar|first4=A. M.|last5=Tripodi|first5=A|last6=Shiach|first6=C|last7=Jespersen|first7=J|doi=10.1136/jcp.2004.019810}}</ref><ref name=mayolabs>{{Cite web|url=https://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9236|title=Test ID: PT Prothrombin Time, Plasma}}</ref>

The INR is the ratio of a patient's prothrombin time to a normal (control) sample, raised to the power of the ISI value for the analytical system being used.

:<math>
\text{INR}= \left(\frac{\text{PT}_\text{test}}{\text{PT}_\text{normal}}\right)^\text{ISI}
</math>

PT<sub>normal</sub> is established as the geometric mean of the prothrombin times (PT) of a reference sample group.<ref name="pmid9365404">{{cite journal| author=D'Angelo A, Galli L, Lang H| title=Comparison of mean normal prothrombin time (PT) with PT of fresh normal pooled plasma or of a lyophilized control plasma (R82A) as denominator to express PT results: collaborative study of the International Federation of Clinical Chemistry. IFCC Working Group Standardization of Coagulation Tests. | journal=Clin Chem | year= 1997 | volume= 43 | issue= 11 | pages= 2169–74 | pmid=9365404 | doi= | pmc= | url=https://pubmed.ncbi.nlm.nih.gov/9365404  }} </ref>

===Interpretation===
The prothrombin time is the time it takes [[blood plasma|plasma]] to clot after addition of [[tissue factor]] (obtained from animals such as rabbits, or recombinant tissue factor, or from brains of autopsy patients). This measures the quality of the ''extrinsic pathway'' (as well as the ''common pathway'') of [[coagulation]]. The speed of the ''extrinsic pathway'' is greatly affected by levels of functional [[factor VII]] in the body. Factor VII has a short [[half-life]] and the [[carboxylation]] of its [[glutamate]] residues requires [[vitamin K]]. The prothrombin time can be prolonged as a result of deficiencies in vitamin K, [[warfarin]] therapy, [[malabsorption]], or lack of intestinal colonization by bacteria (such as in [[newborn]]s). In addition, poor factor VII synthesis (due to [[liver disease]]) or increased consumption (in [[disseminated intravascular coagulation]]) may prolong the PT.{{citation needed|date=July 2020}}

The INR is typically used to monitor patients on warfarin or related oral anticoagulant therapy.  The normal range for a healthy person not using warfarin is 0.8–1.2, and for people on warfarin therapy an INR of 2.0–3.0 is usually targeted, although the target INR may be higher in particular situations, such as for those with a [[artificial heart valve|mechanical heart valve]]. If the INR is outside the target range, a high INR indicates a higher risk of bleeding, while a low INR suggests a higher risk of developing a clot. In patients on a vitamin K antagonist such as warfarin with supratherapeutic INR but INR less than 10 and no bleeding, it is enough to lower the dose or omit a dose, monitor the INR and resume the vitamin K antagonist at an adjusted lower dose when the target INR is reached.<ref name=Farinde2019>{{cite journal|url=https://emedicine.medscape.com/article/2172018-overview|title=Warfarin Overanticoagulation |website=Medscape|date=2019-04-18|author=Abimbola Farinde}}</ref> For people who need rapid reversal of the vitamin K antagonist – such as due to serious bleeding – or who need emergency surgery, the effects of warfarin can be reversed with vitamin K, [[prothrombin complex concentrate]] (PCC), or [[fresh frozen plasma]] (FFP).<ref name=Ag2012>{{cite journal | vauthors = Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G | title = Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e44S–e88S | date = February 2012 | pmid = 22315269 | pmc = 3278051 | doi = 10.1378/chest.11-2292 }}</ref>
{{further|Warfarin#Overdose}}

===Factors determining accuracy===
[[Lupus anticoagulant]], a circulating inhibitor predisposing for thrombosis, may skew PT results, depending on the assay used.<ref>{{cite journal |vauthors=Della Valle P, Crippa L, Garlando AM, etal |title=Interference of lupus anticoagulants in prothrombin time assays: implications for selection of adequate methods to optimize the management of thrombosis in the antiphospholipid-antibody syndrome |journal=Haematologica |volume=84 |issue=12 |pages=1065–74 |date=December 1999 |pmid=10586206 |url=https://www.haematologica.org/cgi/reprint/84/12/1065 |format=PDF |access-date=7 February 2022 |archive-date=2 October 2011 |archive-url=https://web.archive.org/web/20111002154117/http://www.haematologica.org/cgi/reprint/84/12/1065 |url-status=dead }}</ref> Variations between various thromboplastin preparations have in the past led to decreased accuracy of INR readings, and a 2005 study suggested that despite international calibration efforts (by INR) there were still statistically significant differences between various kits,<ref>{{cite journal |vauthors=Horsti J, Uppa H, Vilpo JA |title=Poor agreement among prothrombin time international normalized ratio methods: comparison of seven commercial reagents |journal=Clin. Chem. |volume=51 |issue=3 |pages=553–60 |date=March 2005 |pmid=15665046 |doi=10.1373/clinchem.2004.043836 |doi-access=free }}</ref> casting doubt on the long-term tenability of PT/INR as a measure for anticoagulant therapy.<ref name=Jackson>{{cite journal |vauthors=Jackson CM, Esnouf MP |title=Has the time arrived to replace the quick prothrombin time test for monitoring oral anticoagulant therapy? |journal=Clin. Chem. |volume=51 |issue=3 |pages=483–5 |date=March 2005 |pmid=15738512 |doi=10.1373/clinchem.2004.045393 |doi-access=free }}</ref> Indeed, a new prothrombin time variant, the Fiix prothrombin time, intended solely for monitoring warfarin and other vitamin K antagonists has been invented<ref>Gudmundsdottir BR, Francis CW, Bjornsdottir AM, Nellbring M, Onundarson PT.
Thromb Res. 2012 Oct;130(4):674-81. doi: 10.1016/j.thromres.2011.12.013. Epub 2012 Jan 4.PMID 22225856</ref> and recently become available as a manufactured test. The Fiix prothrombin time is only affected by reductions in factor II and/or factor X and this stabilizes the anticoagulant effect and appears to improve clinical outcome according to an investigator initiated randomized blinded clinical trial, The Fiix-trial.<ref>Onundarson PT, Francis CW, Indridason OS, Arnar DO, Bjornsson ES, Magnusson MK, Juliusson SJ, Jensdottir HM, Vidarsson B, Gunnarsson PS, Lund SH, Gudmundsdottir BR.
Lancet Haematol. 2015 Jun;2(6):e231-40. doi: 10.1016/S2352-3026(15)00073-3. Epub 2015 May 25.
PMID 26688233 Clinical Trial.</ref> In this trial thromboembolism was reduced by 50% during long-term treatment and despite that bleeding was not increased.