Prothrombin Time


Article Author:
Rocky Yang


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Leila Moosavi


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Nazia Sadiq
Hajira Basit
Phillip Hynes
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Sandeep Sekhon


Updated:
7/6/2019 6:36:20 PM

Introduction

Prothrombin time (PT) is one of several blood tests routinely used in clinical practice to evaluate the coagulation status of patients. More specifically, PT is used to evaluate the extrinsic and common pathways of coagulation, which would detect deficiencies of factors II, V, VII, and X, and low fibrinogen concentrations.[1][2] PT measures the time, in seconds, for plasma to clot after adding thromboplastin, (a mixture of tissue factor, calcium, and phospholipid) to a patient's plasma sample.[1] Many different preparations of thromboplastin reagents are available which can give different PT results even when using the same plasma. Due to this variability, the World Health Organization (WHO) introduced the international normalized ratio (INR) and has become the standard reporting format for PT results.[3][4] The INR represents to the ratio of the patient's PT divided by a control PT value obtained by using an international reference thromboplastin reagent developed by the WHO.[1][3]

Specimen Collection

Standard laboratory coagulation-based testing has traditionally been used to obtain measurements of PT to ensure reliable results. However, due to the high turnaround time of up to 90 minutes, point-of-care (POC) devices, with a turn-around time of approximately 5 minutes, are becoming more desirable. POC devices are of great value in the emergency and operating room settings where clinical diagnosis and intervention are time-sensitive.[5][6] With increased prescribing of vitamin K-antagonists (VKAs) like warfarin, point-of-care devices have also been more convenient for patients and general practitioners to monitor medication effectiveness. With point-of-care devices, monitoring anticoagulation therapy can take place at thrombosis centers, primary care provider offices, and even by the patients themselves.[4] Although point-of-care devices have been shown to underestimate hemostatic abnormality, point-of-care devices are generally reliable in non-emergency settings.[7] Coagulation tests must be performed using plasma samples and not serum as clotting factors get removed in serum preparations. Standard percutaneous phlebotomy is the recommended method used to collect venous blood samples. However, blood samples may also be obtained from indwelling intravenous lines when necessary.[8]

Procedures

Phlebotomists collect venous blood samples in plastic tubes with a light blue top that contains 3.2% sodium citrate.[9] Sodium citrate serves to chelate the calcium in the blood sample and prevents the activation of the coagulation cascade.[10] This chelation keeps the blood sample in stasis until ready to be tested. Tube filling must be to within 90 percent of the full collection volume with blood to sodium citrate ratio of 9 to 1.[7] The tube is then gently inverted a few times to mix the sodium citrate solution with the blood. The tube should not be shaken to avoid hemolysis that would lead to inaccurate results. Once the blood sample is ready to be tested, calcium chloride is then added to restore the calcium required for coagulation activation.[7] Clot formation can then be detected mechanically or optically depending on the instrumentation used.[10]

Indications

Indications for obtaining PT are:

  • Monitoring vitamin K-antagonists (VKA) such as warfarin is the most common indication for PT
  • Evaluation of unexplained bleeding
  • Diagnosing disseminated intravascular coagulation (DIC)
  • Obtaining baseline value before initiating anticoagulation therapy
  • Assessment of liver synthesis function and to calculate the model for end-stage liver diseases (MELD) score in liver disease

Potential Diagnosis

Causes for a prolonged PT include:

  • Liver disease
    • Liver disease or liver dysfunction leads to a decreased production of most coagulation factors. A decreased production of coagulation factors leads to prolonged PT and physical manifestations that can include petechiae and easy bruising.[4]
  • Vitamin K deficiency
    • Vitamin K is a necessary component in factors II, VII, IX, and X. A deficiency in vitamin K will lead to a decrease in these factors and prolong PT. Potential causes that can lead to decreased vitamin K levels include malnutrition, prolonged antibiotic use, and impairments with fat absorption.[9]
  • Factor deficiency
    • Inherited diseases that lead to a decreased production of factors II, VII, IX, and X will lead to a prolonged PT.
  • Disseminated Intravascular Coagulation (DIC)
    • DIC causes a system-wide activation of coagulation, depleting available coagulation factors leading to an increase in PT.
  • VKA therapy
    • VKA therapy inhibits factors II, VII, IX, and X and causes a prolonged PT.
  • Antiphospholipid antibodies
    • Antiphospholipid antibody syndrome (APS) characteristically presents with recurrent thromboembolic events and/or pregnancy loss along with detected antiphospholipid antibodies (APA).[11][12] APA causes an increased conversion of prothrombin to thrombin in vivo, leading to an overall decrease in prothrombin. Low prothrombin levels can lead to an increased PT result.

Normal and Critical Findings

The reference ranges for PT vary by laboratory since different facilities use reagents or instruments. However, in most laboratories, the normal range for PT is 10 to 13 seconds.[10] The normal INR for a healthy individual is 1.1 or below, and the therapeutic range for most patients on VKAs is an INR of 2.0 to 3.0.[4] An increased PT/INR for patients on VKAs may suggest a super-therapeutic level and will require medication dose adjustments to prevent bleeding.

Interfering Factors

  • Polycythemia with a hematocrit greater than 55%[10]
    • Elevated hematocrit greater than 55% leads to a decrease in plasma of the blood sample, thereby reducing the coagulating factors available. The sodium citrate levels must be readjusted to prevent artificially prolonged PT measurements, to account for this decreased plasma
  • Underfilled tubes
    • Similar to polycythemia, underfilled tubes also will lead to an artificially prolonged PT measurement.
  • Samples obtained from indwelling catheters may suffer contamination as these lines often require a flush with heparin or other solutions that would artificially prolong coagulation times[8]
  • Anticoagulants
    • All direct acting anticoagulants prolong PT[13]
      • Argatroban
      • Dabigatran
      • Rivaroxaban
      • Apixaban
      • Edoxaban
  • Storage and temperature
    • Blood samples for PT testing are only acceptable if stored for less than 24 hours at either room temperature or 4 degrees Celsius[1]
    • Prolonged cold storage at 4 degrees Celsius or lower can activate Factor VII, which can lead to shortened PT results[10]
  • High lipid levels
    • Patients with hypercholesterolemia or hypertriglyceridemia have a shorter PT measurement due to more elevated fibrinogen and factor VII levels[14]

Complications

  • Standard percutaneous phlebotomy to obtain blood samples can cause localized pain, bleeding, and bruising.
  • A decreased PT/INR suggests[7][1][7]:
    • Increased intake of supplements that contain vitamin K
    • High intake of vitamin K-rich foods
    • Fasting may reduce factors II, VII, and X, subsequently decreasing PT

Patient Safety and Education

As the use of VKAs increases, it is vital to educate patients on the importance of routine monitoring of PT/INR. Proper monitoring will allow for medication adjustments and prevention of adverse events. If patients are self-monitoring with POC devices, sufficient education and training is necessary for the patient and/or family members who will assist the patient. The cognitive capacity of patients must also be evaluated to ensure the proper use of POC devices.[4]

Clinical Significance

PT, along with INR, are important measurements to monitor patient coagulation status, especially patients who are on VKAs. However, although PT/INR is useful in monitoring coagulation status, they are rarely used alone. PT/INR use is typically in conjunction with activated partial thromboplastin time (aPTT), which evaluates the intrinsic and common pathways of coagulation. PT/INR and aPTT results together can help in diagnosing various hematologic disorders.


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Prothrombin Time - Questions

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Deficiency of which of the following does not prolong prothrombin time?



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What does prothrombin time (PT) measure?



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A 27-year-old man with a history of inflammatory bowel disease comes for a follow-up visit to review his recently obtained laboratory results. He has no family history of bleeding disorders and is not taking any medications currently. His only complaints today are of minor abdominal pain and greasy stools for the past few years. He tries to maintain a healthy diet but admits to eating mostly fried foods. His laboratory results show a prothrombin time of 27 seconds. What is the most likely cause of his abnormal prothrombin time?



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Which of the following is a normal prothrombin time (PT)?



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Which is true about the international normalized ratio (INR)?



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The prothrombin time test does NOT measure deficiencies in which of the following factors?



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A 65-year-old homeless man with a history of hypertension, chronic alcohol use, and chronic hepatitis C presents to the emergency department for fatigue, poor appetite, yellowing of the eyes, a rash on his legs and easy bruising. He describes the rash as tiny, circular, red-purple patches that he noticed in the past week. He denies any recent travel out of the country and does not recall having insect bites. He recently finished a 5-day course of antibiotics for a sinus infection. His only current medication is occasional acetaminophen for headaches. Laboratory results show alanine aminotransferase 86 U/L (7 - 55 U/L), aspartate aminotransferase 191 U/L (8 - 48 U/L), alkaline phosphatase 100 U/L (40 - 129 U/L), total bilirubin 3.2 mg/dL (0.1 - 1.2 mg/dL), albumin 2.3 g/dL (3.5 - 5.0 g/dL), prothrombin time 27 sec (10 - 13 sec). What is the most likely cause of this patient's rash?



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A 25-year-old woman, gravida 2, para 0, abortus 2, comes to the clinic for a follow-up visit 1 week after having her second miscarriage within the last year. She has a depressed mood and has had difficulty concentrating. She has also lost interest in her favorite hobbies of reading and writing and prefers to lay in bed for most of the day. Since her miscarriage, she has been eating only one meal per day that consists of crackers and vegetable soup. Her medical history is significant for hospitalization 1 year ago for pulmonary embolism. She does not take any medication except for a prenatal vitamin. Laboratory results show a prothrombin time of 27 seconds. What is the most likely cause of this patient's increased prothrombin time?



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A 10-year-old boy is brought to the emergency department with fever, a productive cough with green phlegm and easy bruising. He has had daily fevers for the past seven days with only mild alleviation with acetaminophen and ibuprofen. His medical history is significant for meconium ileus shortly after birth and was diagnosed with cystic fibrosis. He has had oily and greasy stools all his life and has recurrent sinopulmonary infections requiring antibiotics 3-4 times per year. Coagulation study reveals prothrombin time 25 sec (ref. 10 - 13 sec) and activated partial thromboplastin time 35 sec (ref. 25 - 40 sec). Which of the following coagulation factors is most likely to be abnormal in this patient?



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A 65-year-old man comes to the clinic for evaluation of fatigue, headache, and itching, especially after taking warm baths. He has a history of hypertension and diabetes mellitus type 2, both being managed by diet alone. He does not take any medications and has not had any recent illness. Laboratory results showed a hematocrit 59% (ref. 40 - 54% for men) and prothrombin time of 24 secs (ref. 10 - 13 sec). Which of the following is likely responsible for this patient's abnormal lab values?



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Prothrombin Time - References

References

Levy JH,Szlam F,Wolberg AS,Winkler A, Clinical use of the activated partial thromboplastin time and prothrombin time for screening: a review of the literature and current guidelines for testing. Clinics in laboratory medicine. 2014 Sep;     [PubMed]
Triplett DA, Coagulation and bleeding disorders: review and update. Clinical chemistry. 2000 Aug;     [PubMed]
van den Besselaar AM,Chantarangkul V,Tripodi A, Thromboplastin standards. Biologicals : journal of the International Association of Biological Standardization. 2010 Jul;     [PubMed]
Barcellona D,Fenu L,Marongiu F, Point-of-care testing INR: an overview. Clinical chemistry and laboratory medicine. 2017 May 1;     [PubMed]
Stein P,Kaserer A,Spahn GH,Spahn DR, Point-of-Care Coagulation Monitoring in Trauma Patients. Seminars in thrombosis and hemostasis. 2017 Jun;     [PubMed]
Ebner M,Birschmann I,Peter A,Spencer C,Härtig F,Kuhn J,Blumenstock G,Zuern CS,Ziemann U,Poli S, Point-of-care testing for emergency assessment of coagulation in patients treated with direct oral anticoagulants. Critical care (London, England). 2017 Feb 15;     [PubMed]
Bolliger D,Tanaka KA, Point-of-Care Coagulation Testing in Cardiac Surgery. Seminars in thrombosis and hemostasis. 2017 Jun;     [PubMed]
Hinds PS,Quargnenti A,Gattuso J,Kumar Srivastova D,Tong X,Penn L,West N,Cathey P,Hawkins D,Wilimas J,Starr M,Head D, Comparing the results of coagulation tests on blood drawn by venipuncture and through heparinized tunneled venous access devices in pediatric patients with cancer. Oncology nursing forum. 2002 Apr;     [PubMed]
Kamal AH,Tefferi A,Pruthi RK, How to interpret and pursue an abnormal prothrombin time, activated partial thromboplastin time, and bleeding time in adults. Mayo Clinic proceedings. 2007 Jul;     [PubMed]
Winter WE,Flax SD,Harris NS, Coagulation Testing in the Core Laboratory. Laboratory medicine. 2017 Nov 8;     [PubMed]
Della Valle P,Crippa L,Garlando AM,Pattarini E,Safa O,Viganò D'Angelo S,D'Angelo A, 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. Haematologica. 1999 Dec;     [PubMed]
Kremers RMW,Zuily S,Kelchtermans H,Peters TC,Bloemen S,Regnault V,Hemker HC,de Groot PG,Wahl D,de Laat B, Prothrombin conversion is accelerated in the antiphospholipid syndrome and insensitive to thrombomodulin. Blood advances. 2018 Jun 12;     [PubMed]
Hellenbart EL,Faulkenberg KD,Finks SW, Evaluation of bleeding in patients receiving direct oral anticoagulants. Vascular health and risk management. 2017;     [PubMed]
Kim JA,Kim JE,Song SH,Kim HK, Influence of blood lipids on global coagulation test results. Annals of laboratory medicine. 2015 Jan;     [PubMed]

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