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Clinical use of coagulation tests

Clinical use of coagulation tests
Literature review current through: Jan 2024.
This topic last updated: Dec 29, 2023.

INTRODUCTION — Several tests of the coagulation system are available, including the prothrombin time (PT), activated partial thromboplastin time (aPTT), and others; these may be ordered in a variety of clinical settings.

This topic reviews the principles and interpretation of coagulation tests that are routinely available for clinical use.

Additional information regarding the use of these tests in specific clinical settings is presented separately:

Unexplained bleeding – (See "Approach to the adult with a suspected bleeding disorder" and "Approach to the child with bleeding symptoms".)

Preoperative testing – (See "Preoperative assessment of bleeding risk".)

Monitoring anticoagulation:

Warfarin – (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.)

Heparin – (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Dosing and monitoring'.)

Direct oral anticoagulants – (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

Platelet function testing – (See "Platelet function testing".)

ENSURING ACCURACY

Sample collection and handling — Coagulation tests must be performed on plasma rather than serum, because clotting factors are removed during serum preparation, along with the clotted cellular elements.

Accurate coagulation testing requires that the blood sample be collected and handled appropriately. The following parameters are important for ensuring accuracy:

Collection tube – Samples for testing coagulation must be drawn into a tube containing an inhibitor of coagulation that can be removed at the start of the assay. A sodium citrate solution (3.2 percent sodium citrate) in a tube with a light blue top is most commonly used. The amount of citrate solution in the tube is fixed to provide an appropriate ratio of one part citrate solution to nine parts whole blood when the tube is properly filled. Patients with polycythemia require removal of some of the citrate due to a reduced plasma volume. (See 'Sources of interference' below.)

Blood volume – The tube must be filled with enough blood to provide an appropriate ratio of citrate to whole blood. Underfilled tubes can result in artificially prolonged coagulation times. Tubes should not be uncapped as it will result in an incorrect volume of blood being added [1]. Tubes must be filled to within 90 percent of the full collection volume. If the tube is underfilled it may lead to inaccurate results. Improperly filled tubes should be discarded and a new draw requested [2]. Polycythemia effectively reduces the amount of plasma in the tube. (See 'Sources of interference' below.)

Mixing – Because blue top tubes contain a liquid sodium citrate solution, they should be inverted gently a few times as soon as possible after phlebotomy, in order to mix the citrate solution with the blood. The tube should not be shaken as this can cause hemolysis and may lead to inaccurate results.

Elapsed time and temperature – The sample should be tested in a timely manner to avoid degradation of the labile coagulation factors (especially factors V and VIII and protein S); substantial degradation of coagulation factors could lead to artificial prolongation of coagulation times [3]. The total time between phlebotomy and testing should not exceed 24 hours. Primary coagulations tubes cannot be frozen prior to separation of plasma from cells.

Sources of interference — Inaccurate results may occur if the following are present:

Intravenous solutions – Ideally, coagulation specimens should be obtained by percutaneous phlebotomy. A discard tube is not required when drawing blood from percutaneous phlebotomy [4,5]. However, in intensive care unit settings coagulation testing is often obtained from indwelling catheters. The sample must be free of solutions delivered through indwelling intravenous lines, which may dilute the sample and/or introduce heparin. This is especially important for blood obtained from central venous catheters or ports, which are often flushed with heparin or citrate solutions that could lead to artificial prolongation of coagulation times [6-9]. When drawing samples from indwelling lines, the first few milliliters withdrawn are discarded, and the required sample is obtained from a second syringe or tube to avoid contamination with solution in the line.

Anticoagulants – Good medical practice dictates awareness by the laboratory of anticoagulant therapy as this may greatly impact test interpretation and patient care. This may be done by the physician as part of the order entry procedure, by the laboratory personnel checking patient medications in the electronic medical record, or by contacting the ordering physician directly.

Other substances – Other substances present in the sample such as lipids or bilirubin due to lipemia, hyperbilirubinemia, and hemolysis can interfere with determination of clotting times. If it is not possible to avoid such an interference, dilution of the sample may allow an estimate of the clotting time. The need for sample dilution can be assessed by the laboratory at the time of testing.

Polycythemia (eg, hematocrit >55 percent) causes a corresponding reduction of plasma volume in the blood collection tube. Thus, patients with polycythemia require removal of some of the citrate solution to maintain the correct ratio of citrate to whole blood and to prevent artificial prolongation of coagulation times [10]. There are no corresponding recommendations for severe anemia. The best approach to such situations is to be aware of the potential interference and to contact the coagulation laboratory for guidance in proper collection if accurate clotting times are required for patient care.

SPECIFIC TESTS

Clotting times — Clotting times measure the time it takes plasma to clot when various substances are added. The citrate in the blue top collection tube chelates calcium in the collection tube so that coagulation is unable to proceed, because calcium is required for assembly of coagulation factor complexes on activated cell surfaces or phospholipids. Sufficient calcium to overcome the chelator is added back to the sample at the time of test initiation, along with a source of phospholipid and an initiator (tissue factor for the prothrombin time [PT]; silica or diatomaceous earth for the activated thromboplastin time [aPTT]). The precise composition of PT and aPTT reagents is proprietary and generally not disclosed. PT instrument reagent systems are standardized using the international normalized ratio (INR). (See 'Prothrombin time (PT) and INR' below.)

While the PT and aPTT provide an overall assessment of clot formation, they do not provide information about fibrin crosslinking or clot dissolution and will thus be insensitive to abnormalities of factor XIII function or abnormal fibrinolysis.

Prothrombin time (PT) and INR — The prothrombin time (PT) measures the time it takes plasma to clot when exposed to tissue factor, which assesses the extrinsic and common pathways of coagulation (figure 1). (See "Overview of hemostasis", section on 'Extrinsic pathway' and "Overview of hemostasis", section on 'Thrombin generation'.)

The PT test is performed by recalcifying citrated patient plasma in the presence of tissue factor and phospholipid and determining the time it takes to form a fibrin clot. The formation of a fibrin clot is detected by visual, optical, or electromechanical methods. The result is measured in seconds and reported along with a control value and/or an INR.

The normal range for the PT varies by laboratory and reagent/instrument combination, and local institutional ranges should be used. In most laboratories, the normal range is approximately 11 to 13 seconds.

The INR is dimensionless. It is calculated as a ratio of the patient’s PT to a control PT obtained using an international reference thromboplastin reagent developed by the World Health Organization (WHO), using the following formula [11]:

INR  =  [Patient PT ÷ Control PT]ISI

The control value for the PT is the mean normal PT for the laboratory determined from ≥30 fresh, normal plasmas handled identically to patient material. The ISI (international sensitivity index) is based on an international reference thromboplastin reagent; however, it is useful to have the ISI value confirmed within each laboratory for each PT reagent and instrument to account for effects of handling and equipment performance [12,13].

Unlike the PT, the results of the INR will be similar on a blood sample tested in any laboratory using any thromboplastin reagent/instrument system when calibrated correctly. This allows comparison of the patient’s testing performed at different times and/or locations, which is of great benefit for warfarin monitoring (see "Warfarin and other VKAs: Dosing and adverse effects"). Use of the INR is also extremely valuable for research studies because it allows investigators to compare the degree of anticoagulation of patients from different institutions.

Uses of the PT/INR — Clinical uses of the PT include the following:

Evaluation of unexplained bleeding – (See "Approach to the adult with a suspected bleeding disorder".)

Diagnosing disseminated intravascular coagulation – (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

Obtaining a baseline value prior to initiating anticoagulation – (See "Heparin and LMW heparin: Dosing and adverse effects" and "Warfarin and other VKAs: Dosing and adverse effects".)

Monitoring warfarin therapy – (See "Warfarin and other VKAs: Dosing and adverse effects".)

Assessment of liver synthetic function – (See "Tests of the liver's biosynthetic capacity (eg, albumin, coagulation factors, prothrombin time)".)

As noted above, the INR was developed to allow patients receiving warfarin at steady state to compare values obtained at different times and from different laboratories. The INR is also commonly used as a surrogate for the PT in assessing integrity of the extrinsic and common pathways in bleeding patients (figure 1) and to assess end-stage liver disease as part of the model for end-stage liver diseases (MELD) score.

Causes of prolonged PT — Causes of a prolonged PT include the following (table 1):

Vitamin K antagonists – Vitamin K antagonists such as warfarin interfere with post-translational modifications of procoagulant factors II, VII, IX, and X, resulting in a prolonged PT. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.)

Other anticoagulants – Heparins (unfractionated or low molecular weight) and fondaparinux should in theory prolong the PT because they inhibit thrombin and/or factor Xa. However, most PT reagents contain heparin-binding chemicals (eg, heparinase, polybrene) that block this effect [14]. The PT may become elevated at heparin concentrations above 1 unit/mL, such as after a heparin bolus, due to saturation of the heparin binders. The increase in PT should not be used to guide therapy; monitoring of heparins is discussed separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Laboratory monitoring and dose titration (unfractionated heparin)' and "Heparin and LMW heparin: Dosing and adverse effects", section on 'Laboratory monitoring/measurement (LMW heparins)'.)

All of the available direct acting anticoagulants prolong the PT, including the parenteral direct thrombin inhibitor argatroban and the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban, and edoxaban. However, the degree of prolongation varies by the particular drug and the PT reagent used, and therefore the PT is not reliable for monitoring drug effect. All of the DOACs are approved for use without monitoring. We do not check the PT in an individual receiving a DOAC and we do not make changes to dosing or monitoring of these agents based on the result of the PT, with the possible exception of an individual who has serious bleeding for whom a prolongation of the PT may be taken as evidence of persistent drug effect. These subjects are addressed in separate topic reviews. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Laboratory testing and monitoring (dabigatran)' and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'General considerations for direct factor Xa inhibitors'.)

Vitamin K deficiency – Potential causes include impaired nutrition, prolonged use of broad spectrum antibiotics, or fat malabsorption syndromes. When vitamin K deficiency is mild, only the PT may be prolonged due to a predominant effect on factor VII. However, in severe vitamin K deficiency, both the PT and aPTT may be prolonged. (See "Overview of vitamin K", section on 'Vitamin K deficiency' and "Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects", section on 'Hematologic reactions'.)

Liver disease – Liver disease may be associated with decreased production of both vitamin K-dependent and vitamin K-independent clotting factors. When liver disease is mild, only the PT may be prolonged due to a predominant effect on factor VII. However, in severe and/or chronic liver disease, both the PT and aPTT may be prolonged. Importantly, liver disease is also associated with decreased production of anticoagulant factors. Thus, a prolonged PT does not reflect the overall hemostatic picture. (See "Hemostatic abnormalities in patients with liver disease", section on 'Physiologic effects of hepatic dysfunction'.)

DIC – In disseminated intravascular coagulation (DIC), coagulation factors become consumed and depleted. This may result in prolonged PT and aPTT. Importantly, anticoagulant factors may also be depleted, and the PT does not reflect the overall hemostatic picture. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Clinical manifestations'.)

Factor deficiency – Deficient activity of coagulation factors in the extrinsic pathway may be due to inherited disorders or acquired inhibitors (eg, autoantibodies). This includes deficiency of fibrinogen and factors II, V, VII, or X, or a combined deficiency involving one of these factors. (See "Rare inherited coagulation disorders" and "Acquired hemophilia A (and other acquired coagulation factor inhibitors)".)

Antiphospholipid antibodies – Lupus anticoagulants or antiphospholipid antibodies with specificity for prothrombin (factor II) may cause hypoprothrombinemia and prolongation of the PT; occasionally patients with such antibodies and high antibody titers present with hypoprothrombinemia and bleeding. The combination of high antiprothrombin antibody titers and low prothrombin levels can result in false-negative lupus anticoagulant tests because of a prozone effect [15]. However, isolated prolongation of the aPTT is more common. (See 'Causes of prolonged aPTT' below and "Diagnosis of antiphospholipid syndrome".)

As noted above, polycythemia (hematocrit >55 percent) can artificially prolong the PT if the amount of citrated anticoagulant solution in the collection tube is not appropriately decreased. (See 'Sample collection and handling' above.)

Activated partial thromboplastin time (aPTT) — The activated partial thromboplastin time (aPTT, PTT) measures the time it takes plasma to clot when exposed to substances that activate the contact factors, which assesses the intrinsic and common pathways of coagulation (figure 1). (See "Overview of hemostasis", section on 'Intrinsic or contact activation pathway' and "Overview of hemostasis", section on 'Thrombin generation'.)

The aPTT test is performed by recalcifying citrated plasma in the presence of a thromboplastic material that does not have tissue factor activity (hence the term partial thromboplastin) and a negatively charged substance (eg, celite, kaolin [aluminum silicate], silica), which results in contact factor activation, thereby initiating coagulation via the intrinsic clotting pathway [16]. The thromboplastic material provides a source of phospholipids.

The normal range for the aPTT varies by laboratory and reagent/instrument combination, and local institutional ranges should be used. In most laboratories, the normal range is approximately 25 to 35 seconds.

There is no standardization of the aPTT test across different reagent/instrument systems analogous to the INR for the PT. Thus, aPTT values from different laboratories cannot be compared directly. For heparin monitoring, it is recommended that each laboratory establish the therapeutic range by determining the aPTT range that corresponds to 0.2 to 0.4 units/mL by protamine titration or 0.3 to 0.7 anti-factor Xa units/mL. (See 'Monitoring heparins' below.)

Uses of the aPTT — Clinical uses of the aPTT include the following:

Evaluation of unexplained bleeding – (See "Approach to the adult with a suspected bleeding disorder".)

Diagnosing disseminated intravascular coagulation (DIC) – (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

Obtaining a baseline value prior to initiating anticoagulation – (See "Heparin and LMW heparin: Dosing and adverse effects" and "Warfarin and other VKAs: Dosing and adverse effects".)

Monitoring therapy with unfractionated heparin (for individuals with a normal baseline aPTT) – (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Laboratory monitoring and dose titration (unfractionated heparin)'.)

Monitoring therapy with parenteral direct thrombin inhibitors (eg, argatroban, hirudin) – (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Parenteral direct thrombin inhibitors'.)

Of note, low molecular weight (LMW) heparins often do not prolong the aPTT. If necessary, monitoring can be performed by testing for anti-factor Xa activity. However, laboratory monitoring is generally not necessary in nonpregnant patients, because the anticoagulant response to a fixed dose of LMW heparin is highly correlated with the patient's body weight. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Laboratory monitoring/measurement (LMW heparins)'.)

Causes of prolonged aPTT — Causes of a prolonged aPTT include the following (table 1):

Heparin – Heparin is an indirect thrombin inhibitor that complexes with antithrombin (AT), converting AT from a slow to a rapid inactivator of thrombin (factor IIa), factor Xa, and, to a lesser extent, factors IXa, XIa, and XIIa. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Laboratory monitoring and dose titration (unfractionated heparin)'.)

Heparin in the blood sample (eg, due to testing from an indwelling venous catheter) can falsely elevate the aPTT. Re-testing is indicated if this is thought to be the reason for the aPTT prolongation. In more complex cases (eg, unable to obtain peripheral sample, suspected surreptitious use of heparin), the reptilase time can be used to determine if heparin is the cause of the aPTT prolongation. (See 'Reptilase time (RT)' below.)

Direct thrombin inhibitors and direct factor Xa inhibitors – Direct thrombin inhibitors and direct factor Xa inhibitors both can cause prolongation of the aPTT, although there is not a well-defined correlation between the degree of prolongation and the degree of anticoagulation for the oral agents. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

Other anticoagulantsFondaparinux may cause mild prolongation of the aPTT. (See "Fondaparinux: Dosing and adverse effects".)

Warfarin has a weak effect on most aPTT reagents, but supratherapeutic warfarin doses may increase the aPTT, and warfarin will increase the sensitivity of the aPTT to heparin effect [17].

Liver disease – When liver disease is mild, only the PT may be prolonged due to a predominant effect on factor VII. However, in severe and/or chronic liver disease, both the PT and aPTT may be prolonged. Importantly, liver disease is also associated with decreased production of anticoagulant factors. Thus, a prolonged aPTT does not reflect the overall hemostatic picture. (See "Hemostatic abnormalities in patients with liver disease", section on 'Physiologic effects of hepatic dysfunction'.)

DIC – As noted above, coagulation factors become consumed and depleted in patients with disseminated intravascular coagulation (DIC). This may result in prolonged PT and aPTT. Importantly, anticoagulant factors may also be depleted, and the aPTT does not reflect the overall hemostatic picture. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Clinical manifestations'.)

von Willebrand disease – von Willebrand disease (VWD) can cause prolongation of the aPTT because von Willebrand factor is the carrier (and stabilizer) of factor VIII. If factor VIII levels are sufficiently low, the aPTT may become prolonged. Other patients with VWD may have a normal aPTT. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Laboratory testing'.)

Hemophilia A or B – Hemophilia A (hereditary deficiency of factor VIII) and hemophilia B (hereditary deficiency of factor IX) cause prolongation of the aPTT in individuals with severe or moderate factor deficiencies (eg, ≤15 percent activity). Some individuals with mild disease may have a normal aPTT. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Laboratory findings'.)

Other inherited factor deficiencies – Additional inherited factor deficiencies that can cause a prolonged aPTT include the following:

Hereditary factor XI deficiency (sometimes called hemophilia C), which is common in Ashkenazi Jews. (See "Factor XI (eleven) deficiency".)

Hereditary factor XII deficiency, which is not associated with clinical bleeding. (See "Overview of the causes of venous thrombosis", section on 'Factor XII deficiency'.)

Hereditary deficiencies of factors X, V, prothrombin (factor II), fibrinogen, or combined vitamin K-dependent factor deficiency. (See "Rare inherited coagulation disorders", section on 'Laboratory findings' and "Disorders of fibrinogen", section on 'Diagnostic testing'.)

Factor inhibitors – The most common factor inhibitors are to factor VIII. These may be alloantibodies (eg, in patients with severe hemophilia A who develop an immune response to transfused human factor VIII) or autoantibodies. Autoantibodies to factor VIII may be associated with autoimmune disease, other systemic illnesses, or present with bleeding with no apparent precipitant. It is important to distinguish between factor VIII inhibitors and other inhibitors in the aPTT assay such as lupus anticoagulants because factor VIII inhibitors may be associated with life-threatening bleeding whereas lupus anticoagulants may be associated with thrombosis. A distinguishing characteristic of factor VIII inhibitors is increased prolongation of the aPTT after one to two hours of incubation at 37°C relative to the degree of prolongation at five minutes of incubation. (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)", section on 'Evaluation'.)

Lupus anticoagulant-type inhibitors – Some antiphospholipid antibodies (aPLs) can act as in vitro anticoagulants and cause prolongation of the aPTT. The effect is due to interference with assembly of the prothrombinase complex on phospholipids in the in vitro assay; in vivo, these antibodies do not increase bleeding risk, and they may be prothrombotic. Lupus anticoagulants are defined by demonstrating prolongation of a phospholipid-dependent assay that does not correct with addition of normal plasma but does correct with addition of excess phospholipid. (See 'Lupus anticoagulant tests' below.)

In a series of 55 children with a prolonged aPTT on preoperative testing, 39 (71 percent) had a lupus anticoagulant [18]. Causes included a variety of diagnoses (mostly benign but some potentially requiring treatment). Although lupus anticoagulants cause aPTT prolongation, the most common phenotype is increased risk of thrombosis rather than bleeding. (See "Diagnosis of antiphospholipid syndrome".)

Lupus anticoagulants occasionally affect prothrombin and prolong the PT. (See 'Causes of prolonged PT' above.)

Medications – Some drugs (eg, oritavancin) may bind to phospholipid and cause prolongation of clotting tests in vitro, especially the aPTT. If a patient receiving a drug that prolongs the aPTT requires heparin therapy, monitoring and dosing should be based on an assay that is insensitive to this effect, such as an anti-factor Xa assay. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Prolonged baseline aPTT'.)

Polycythemia (hematocrit >55 percent) can artificially prolong the aPTT if the amount of citrated anticoagulant solution in the collection tube is not appropriately decreased. (See 'Sample collection and handling' above.)

Thrombin time (TT) — The thrombin time (TT) measures the final step of coagulation, the conversion of fibrinogen to fibrin (figure 1). The test is performed by incubating citrated plasma in the presence of dilute thrombin (bovine [cow] or human) and measuring the time to clot formation [19]. The normal range for the TT varies by laboratory and reagent instrument combination; in most cases it is approximately 14 to 19 seconds. The thrombin time is prolonged if fibrinogen levels are low or if an anticoagulant that inhibits thrombin is present in the sample.

Unlike the PT and aPTT, the thrombin time is not used as an initial screening test for hemostatic abnormalities. The TT may be used in the following clinical settings:

Evaluation of a patient with a prolonged PT and aPTT – (See 'Prolonged PT and/or aPTT without bleeding or thrombosis' below and "Approach to the adult with a suspected bleeding disorder", section on 'PT and aPTT both prolonged'.)

Evaluation of an inherited fibrinogen disorder – (See "Disorders of fibrinogen", section on 'Heritable (genetic) disorders'.)

Detection of heparin in a sample. If heparin is present, the TT will be significantly prolonged and the reptilase time will be normal. (See 'Reptilase time (RT)' below.)

The following additional conditions may cause a prolongation of the TT, although TT is not used routinely in their initial evaluation [20]:

Anticoagulants – Heparin, LMW heparin, and direct thrombin inhibitors (eg, bivalirudin or argatroban) will prolong the TT. In contrast, oral direct Xa inhibitors, danaparoid, fondaparinux, and warfarin do not prolong the thrombin time. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct thrombin inhibitors'.)

Acquired fibrinogen disorders – Generally, the TT becomes prolonged in hypofibrinogenemia if the plasma fibrinogen level is <100 mg/dL; TT can also be prolonged in dysfibrinogenemias. (See "Disorders of fibrinogen".)

DIC – In disseminated intravascular coagulation (DIC), coagulation factors become consumed and depleted, and fibrinolysis is increased. This may result in prolonged TT, both from depletion of fibrinogen and from effects of fibrin degradation products, both in inhibiting thrombin and in interfering with fibrin polymerization. Importantly, anticoagulant factors may also be depleted, and the TT does not reflect the overall hemostatic picture. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Clinical manifestations'.)

Liver disease – Liver disease may be associated with decreased production of fibrinogen and a prolonged TT. Importantly, liver disease is also associated with decreased production of anticoagulant factors. Thus, patients with liver disease may be at risk for both thrombotic and bleeding events, and the TT does not reflect the overall hemostatic picture [21]. (See "Hemostatic abnormalities in patients with liver disease", section on 'Physiologic effects of hepatic dysfunction'.)

Hypoalbuminemia – Patients with hypoalbuminemia may have prolonged TT [22].

Paraproteinemias – High concentrations of serum proteins, as occurs in multiple myeloma or amyloidosis, can prolong the TT via interference with fibrin polymerization [23].

Bovine thrombin exposure – Patients who were previously exposed to bovine thrombin (eg, during a surgical procedure) may develop antibodies specific to the bovine protein. This will result in a prolonged TT in vitro when bovine thrombin is used in the assay. The TT will be normal if tested using human thrombin in the assay. Such patients are not thought to be at increased bleeding risk, except in the rare case where the antibodies cross-react with human thrombin. However, patients exposed to bovine thrombin have developed antibodies to bovine factor V in the bovine thrombin preparation that cross-react with human factor V and cause bleeding [24,25]. (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)", section on 'Factor II (prothrombin) and IIa (thrombin) inhibitors'.)

Reptilase time (RT) — The reptilase time (RT) is similar to the TT in measuring the conversion of fibrinogen to fibrin [26]. However, unlike the TT and the aPTT, the RT is insensitive to the effects of heparin because reptilase, an enzyme derived from the venom of Bothrops snakes, is not inhibited by antithrombin or the antithrombin-heparin complex.

The test is performed similarly to the TT (by incubating citrated plasma in the presence of the diluted enzyme), with the exception that reptilase is used instead of thrombin. Reptilase differs from thrombin by generating fibrinopeptide A, but not fibrinopeptide B, from fibrinogen and by resisting inhibition by heparin via antithrombin (AT).

The RT is useful for detecting abnormalities in fibrinogen (in which case the TT is also prolonged) and in detecting the presence of heparin; heparin will cause prolongation of the TT but not RT. Similar to heparin, direct thrombin inhibitors prolong the TT but not the RT. (See "Disorders of fibrinogen", section on 'Diagnostic testing' and 'Causes of prolonged aPTT' above.)

Inadvertent presence of a direct thrombin inhibitor is less likely to be clinically relevant, but RT could be used to test for this possibility.

Lupus anticoagulant tests

Indications and principles of LA testing — Lupus anticoagulant (LA) assays can detect antiphospholipid antibodies (aPL) that interfere with in vitro clotting tests that rely on phospholipids in the assay. They are done for two main reasons:

Evaluating for an aPL as the cause of unexplained prolongation of the aPTT (or less commonly, PT). (See 'Prolonged PT and/or aPTT without bleeding or thrombosis' below.)

Testing for aPL in the diagnosis of antiphospholipid syndrome (APS). (See "Diagnosis of antiphospholipid syndrome", section on 'Antiphospholipid antibody testing'.)

Standard aPTT reagents are often insensitive to LA, and it is important to use an assay that is properly calibrated and optimized to detect aPLs. Discussion with the coagulation laboratory can facilitate test ordering. The testing used is determined by the laboratory and may include an aPTT optimized for LA testing (aPTT-LA, with reduced phospholipid in the assay compared with a standard aPTT), silica clotting, time, dRVVT (see 'dRVVT' below), or other clot-based assay. Serologic testing may be appropriate in some cases. (See "Diagnosis of antiphospholipid syndrome", section on 'Specific antiphospholipid antibody tests'.)

An LA is confirmed when the clot-based test is prolonged with patient plasma and corrects with addition of phospholipids but not with control plasma.

Sources of interference with LA testing — Common interferences that may result in a false positive LA test include heparin, DOACs, and elevated C-reactive protein (CRP). Drug-induced interference from heparin and DOACs is the most common. It can be mitigated, as indicated, but this requires communication between the person ordering the test and the laboratory.

Heparin can be removed by adsorption or enzymatic degradation.

DOACs can be effectively removed from plasma using activated charcoal [27].

CRP is a phospholipid-binding protein that can mimic LA in test systems and should be considered in any patient with a systemic inflammatory state (eg, COVID-19). The risk of CRP interference depends on the specific aPTT reagent/instrument system in use.

If possible, the best practice is to stop anticoagulation therapy before testing for LA; however, anticoagulation in an individual at high risk for thrombosis should not be stopped merely to facilitate laboratory testing.

Conditions other than APS that can be associated with aPL are discussed separately. (See "Diagnosis of antiphospholipid syndrome", section on 'Other conditions associated with antiphospholipid antibodies'.)

dRVVT — The dilute Russell viper venom time (dRVVT, also called Russel viper venom time [RVVT]) is a clotting time test that takes advantage of the ability of the venom from the Russell's viper (Daboia russelii) to activate factor X directly (figure 1). (See "Overview of hemostasis", section on 'Multicomponent complexes'.)

The major use of the dRVVT is in testing for the LA phenomenon caused by aPL. The dRVVT is particularly sensitive to anti-beta-2-glycoprotein I antibodies, which are most closely correlated with thrombotic events and APS. LA due to an aPL can be confirmed by adding additional phospholipid to the assay [28]. (See 'Use of mixing studies' below.)

The dRVVT is also sensitive to the effects of the direct oral anticoagulants (DOACs) and has been proposed as an assay that could be adapted to DOAC monitoring, although this has not been validated for this purpose and is not in clinical use [29]. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

Assays for specific coagulation factors — Coagulation factor assays are mostly used to diagnose specific factor deficiencies.

Inherited factor deficiencies, including hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency), factor XI deficiency, and other rare factor deficiencies – (See "Clinical manifestations and diagnosis of hemophilia", section on 'Factor activity levels' and "Rare inherited coagulation disorders", section on 'Laboratory findings'.)

Acquired factor inhibitors, based on the finding of abnormal clotting times that fail to correct in a mixing study – (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)" and 'Use of mixing studies' below.)

In some cases, chromogenic assays may be used to monitor therapy for hemophilia or to monitor warfarin anticoagulation in a patient with a baseline prolonged PT/INR.

Clot-based assays — Factor activity can be measured by using the aPTT (for intrinsic pathway factors) or PT (for factor VII and common pathway factors). These assays use a clotting endpoint and are calibrated for individual factors using factor-deficient plasmas and reported as percent activity. These assays, referred to as "one-stage" clot-based assays, are the most commonly used method to determine factor activity levels.

Chromogenic assays — Chromogenic assays use cleavage of a chromogenic (colored) substrate and a calibration curve to assess factor activity.

Factor VIII chromogenic assay — A chromogenic assay for factor VIII activity can be useful in assessing factor VIII levels in patients with aPTT interferences such as lupus anticoagulants. Additionally, in some patients with hemophilia A, a chromogenic factor VIII assay correlates better with bleeding phenotype than a one-stage clot-based assay.

Chromogenic assays that use bovine reagents are required when assessing underlying factor VIII activity in patients who are receiving emicizumab (see "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab for hemophilia A'). For this reason, specialized coagulation laboratories and hemophilia treatment centers often have both one-stage and chromogenic factor VIII activity assays available for use [30]. Some of the recombinant or modified long half-life factor VIII and factor IX products in many cases are better monitored with chromogenic assays [31]. (See "Hemophilia A and B: Routine management including prophylaxis" and "Treatment of bleeding and perioperative management in hemophilia A and B".)

Factor X chromogenic assay — A chromogenic assay for factor X activity is useful for monitoring warfarin therapy in selected patients who have interferences with PT/INR measurement, such as a prolonged PT/INR due to a lupus anticoagulant. The chromogenic factor X assay can also be used in patients receiving argatroban or other direct thrombin inhibitors who are being transitioned to warfarin. The INR range of 2 to 3 corresponds to a chromogenic factor X assay of approximately 20 to 30 percent.

Of note, the chromogenic factor X assay is different from the anti-factor Xa activity assay used to monitor heparins, fondaparinux, and direct factor Xa inhibitors. (See 'Monitoring heparins' below.)

Antigenic assays — Antigenic assays such as ELISAs (enzyme-linked immunosorbent assays) can also be used to measure clotting factors. This is typically done when there is a need to distinguish quantitative from qualitative factor deficiencies (decreases in both antigen and functional activity versus decreased functional activity with preserved antigen levels). These assays are typically only available at specialized referral centers.

Fibrinogen — Fibrinogen is the precursor to fibrin, the principle component of a fibrin clot. Abnormally low levels of fibrinogen (typically, <50 to 100 mg/dL) can result in impaired clot formation and increased bleeding risk. Evaluation of fibrinogen disorders (reduced fibrinogen levels and abnormally functioning fibrinogen [dysfibrinogenemia]) is presented separately. (See "Disorders of fibrinogen", section on 'Diagnostic testing' and "Disorders of fibrinogen", section on 'Biology'.)

Clinical uses of plasma fibrinogen levels include evaluation for the following:

Disseminated intravascular coagulation (DIC) – (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Diagnostic evaluation'.)

Liver disease – (See "Tests of the liver's biosynthetic capacity (eg, albumin, coagulation factors, prothrombin time)" and "Hemostatic abnormalities in patients with liver disease".)

Inherited or acquired disorders of fibrinogen – (See "Disorders of fibrinogen", section on 'Acquired abnormalities' and "Disorders of fibrinogen", section on 'Heritable (genetic) disorders'.)

Clot solubility — Tests that measure the solubility of clots in the presence of a strong denaturing agent can detect abnormalities of factor XIII (factor 13), which crosslinks the fibrin clot after it has formed. Examples include solubility in 5M urea, 1 percent chloroacetic acid, or 2 percent acetic acid. Lysis in any of these solutions within 24 hours suggests factor XIII deficiency. These tests will detect severe factor XIII deficiency. More specific functional and immunologic assays for factor XIII deficiency are available from reference laboratories; these can be used to confirm severe factor XIII deficiency or to detect milder factor XIII deficiency. (See "Rare inherited coagulation disorders", section on 'Factor XIII deficiency (F13D)'.)

Fibrin D-dimer — Fibrin D-dimer is one of the major fibrin degradation products released upon cleavage of crosslinked fibrin by plasmin. The dimer consists of two D domains from adjacent fibrin monomers that have been crosslinked by activated factor XIII.

Normal plasma levels of D-dimer by ELISA testing are <500 ng/mL for fibrin equivalent units (FEU) or <250 ng/mL for D-dimer units (DDU). Elevated concentrations of plasma D-dimer indicate recent or ongoing intravascular coagulation and fibrinolysis [32]. Plasmin cleaves crosslinked fibrin at multiple sites, generating other fibrin degradation products (FDPs), but D-dimer is the best-studied and validated for clinical assessment.

Clinical uses of the D-dimer include evaluation for the following (table 2):

Deep vein thrombosis – (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity", section on 'D-dimer'.)

Pulmonary embolism – (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'D-dimer'.)

DIC – (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Diagnostic evaluation'.)

Primary hyperfibrinolysis – (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'Disorders with excess bleeding'.)

Prognostic assessment in coronavirus disease 2019 (COVID-19) – (See "COVID-19: Hypercoagulability", section on 'Coagulation abnormalities'.)

Point-of-care testing — Point-of-care testing refers to testing that can be performed using a device located at or near the location of the patient (eg, patient’s home, operating room) rather than in a central laboratory. A number of tests can be performed at the point of care, including clotting times (PT, INR, aPTT, ACT, TT) and D-dimer [33]. (See 'Clotting times' above and 'Fibrin D-dimer' above.)

Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are global tests of hemostasis performed on whole blood that reflect platelet function and coagulation. These tests can be used at the point of care to obtain a rapid assessment of the kinetics of clot formation, strength, and dissolution, as well as to manage bleeding and assess the response to interventions as they are made. TEG, ROTEM, and related testing are frequently used in the settings of trauma and surgery to guide transfusion therapy.

Information regarding the mechanics of this testing, indications, and sample tracings are presented separately. (See "Platelet function testing", section on 'Viscoelastic testing (TEG and ROTEM)' and "Etiology and diagnosis of coagulopathy in trauma patients", section on 'Viscoelastic hemostatic assays'.)

The rationale for testing at the point of care is that the more rapid generation of results will improve patient care. This testing is subject to the same strict quality control procedures that exist in central laboratories.

Clinical uses of point of care testing include the following:

Home monitoring of warfarin therapy – (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Self-monitoring and self-management'.)

Assessment of global hemostasis in patients with liver disease – (See "Hemostatic abnormalities in patients with liver disease", section on 'Laboratory abnormalities'.)

Diagnosis/management of coagulopathy associated with trauma – (See "Etiology and diagnosis of coagulopathy in trauma patients", section on 'Viscoelastic hemostatic assays' and "Etiology and diagnosis of coagulopathy in trauma patients" and "Ongoing assessment, monitoring, and resuscitation of the severely injured patient", section on 'Transfusion' and "Ongoing assessment, monitoring, and resuscitation of the severely injured patient", section on 'VHA-based dosing'.)

Evaluation/management of bleeding in the operating room – (See "Perioperative blood management: Strategies to minimize transfusions".)

Challenges and limitations of these devices include cost, the need for specialized training, and strict adherence to quality standards outside of the clinical laboratory setting.

ANTICOAGULANT MONITORING

Monitoring vitamin K antagonists — As noted above and discussed in more detail separately, the PT/INR is used to monitor therapy with warfarin or other vitamin K antagonists (VKA). (See 'Prothrombin time (PT) and INR' above and "Warfarin and other VKAs: Dosing and adverse effects" and "Antithrombotic therapy for mechanical heart valves", section on 'Approach to antithrombotic therapy'.)

If the patient has a prolonged baseline INR and requires warfarin therapy, the factor X chromogenic assay can be used. (See 'Factor X chromogenic assay' above.)

Monitoring heparins — Therapeutic-dose unfractionated heparin requires monitoring. Low molecular weight (LMW) heparins generally are administered without monitoring, regardless of the dose.

Prophylactic-dose heparin (unfractionated or LMW) does not require monitoring, although laboratory testing may be appropriate in selected patients to determine if there is drug effect (eg, in a patient with bleeding) or, in a patient receiving prophylactic dosing, to determine if the dose is too high (therapeutic level).

Unfractionated heparin – Patients receiving unfractionated heparin at full therapeutic doses can be monitored using the aPTT or using an anti-factor Xa activity (sometimes called "anti-Xa") assay. Anti-Xa is a functional assay performed by adding patient plasma to reagent factor Xa and measuring the activity of factor Xa using an artificial factor Xa substrate that releases a colored compound when cleaved (ie, chromogenic assay) [34]. (See 'Activated partial thromboplastin time (aPTT)' above and 'Factor X chromogenic assay' above and "Heparin and LMW heparin: Dosing and adverse effects", section on 'Unfractionated heparin'.)

When used to monitor heparin given by continuous infusion, the aPTT or anti-factor Xa activity can be measured at any time, as a random level.

Anti-factor Xa activity is especially useful in individuals with a prolonged aPTT at baseline, such as those with antiphospholipid syndrome (APS), liver disease, or an acquired factor inhibitor. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Prolonged baseline aPTT'.)

When using anti-factor Xa activity, the assay must be calibrated for the specific anticoagulant. Unfractionated heparin is reported as international units/mL, while an anti-factor Xa assay calibrated for LMW heparins would be calibrated in anti-Xa units/mL, and factor Xa inhibitors are reported as drug concentrations using drug-specific calibration curves. When using the aPTT, the assay should be calibrated properly, as discussed separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Laboratory monitoring and dose titration (unfractionated heparin)'.)

The anti-factor Xa activity assay is different from the chromogenic factor X assay used to monitor warfarin in selected patients. (See 'Monitoring vitamin K antagonists' above.)

High-dose unfractionated heparin – Patients receiving high-dose unfractionated heparin for cardiopulmonary bypass or other procedures such as extracorporeal membrane oxygenation (ECMO) or hemodialysis can be monitored using the activated clotting time (ACT) [35,36]. In these settings, the aPTT may not be useful because the doses of heparin administered often result in a plasma heparin concentration >1 unit/mL, which prolongs the aPTT beyond the linear monitoring range. In contrast, the ACT shows a dose-response to heparin concentrations in the range of 1 to 5 units/mL [37]. (See "Early noncardiac complications of coronary artery bypass graft surgery", section on 'Prevention' and "Anticoagulation for the hemodialysis procedure" and "Extracorporeal life support in adults in the intensive care unit: Overview".)

The ACT measures the time it takes whole blood (rather than plasma) to clot when exposed to substances that activate the contact factors. Like the aPTT, this test assesses the intrinsic and common pathways of coagulation. The ACT test is performed by adding celite or kaolin to freshly drawn whole blood and measuring the time to clot formation.

LMW heparins – LMW heparins generally are administered without monitoring. If a need for monitoring is determined, the anti-factor Xa activity is tested four hours after the dose is administered. The assay should be calibrated for the specific LMW heparin drug.

As discussed above, anti-factor Xa activity assays are calibrated to the specific anticoagulant and are not interchangeable.

Results of anti-factor Xa assays may differ between centers due to variability in the type of assays used. Because of these differences, target anti-factor Xa levels may vary for different laboratories. As examples:

Some centers use separate titration curves for unfractionated and low molecular weight (LMW) heparins, while other centers use a single hybrid curve. Depending on which is used, there may be slight differences in anti-factor Xa activity units reported from different centers.

The majority of centers (80 to 90 percent) use assays without added antithrombin (AT). Rarely, a center may use an assay that adds exogenous AT to potentiate the effect of heparin. This can affect results of anti-Xa testing in patients with underlying AT deficiency.

Monitoring argatroban and hirudin — The aPTT is used to monitor therapy the direct thrombin inhibitor argatroban. (See 'Activated partial thromboplastin time (aPTT)' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Argatroban'.)

The ecarin clotting time (ECT) may also be used [38]. Ecarin is a metalloproteinase derived from the venom of the saw-scaled viper Echis carinatus. It activates prothrombin to meizothrombin, an intermediate step in the conversion of prothrombin to thrombin. Meizothrombin has markedly reduced fibrinogen clotting activity compared with thrombin, and it is not susceptible to inhibition by antithrombin (AT) or the heparin-AT complex (due to steric hindrance), but it can readily complex with direct thrombin inhibitors. Accordingly, the ECT is prolonged with increasing amounts of these agents [39-41]. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct thrombin inhibitors'.)

Monitoring direct oral anticoagulants — Direct oral anticoagulants are administered without monitoring.

In rare cases, such as when it is desirable to determine whether anticoagulant activity is present (for a patient with bleeding or emergency surgery), testing can be used:

The presence of dabigatran can be assayed using a thrombin time (TT) or ECT. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Dabigatran' and "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Coagulation testing'.)

The presence of an oral direct factor Xa inhibitor (apixaban, edoxaban, rivaroxaban) can be assayed using an anti-factor Xa assay calibrated for the specific drug. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct factor Xa inhibitors'.)

EVALUATION OF ABNORMAL RESULTS — The pace and extent of the evaluation of abnormal coagulation testing depends on the patient’s clinical status and whether the abnormalities have a suspected underlying cause or are unexpected.

Patient with bleeding — The evaluation of abnormal clotting times in a patient with active bleeding, a history suggestive of abnormal/excessive bleeding, or a family history of a bleeding disorder is presented in detail separately. (See "Approach to the child with bleeding symptoms" and "Approach to the adult with a suspected bleeding disorder".)

In addition, a patient may have abnormal bleeding despite a normal aPTT and PT. In this setting, potential causes may include thrombocytopenia, platelet dysfunction, mild deficiency of von Willebrand factor, vascular disorders, and, rarely, factor XIII deficiency or a disorder of the fibrinolytic system. The evaluation of such patients is discussed separately.

Patient with thrombosis — The evaluation of abnormal clotting times in a patient with thrombosis should assess the possibility of conditions associated with ongoing coagulation. These include the following:

DIC – (See "Disseminated intravascular coagulation in infants and children" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Disseminated intravascular coagulation (DIC) during pregnancy: Clinical findings, etiology, and diagnosis".)

Antiphospholipid syndrome (APS) with the lupus anticoagulant phenomenon – (See "Clinical manifestations of antiphospholipid syndrome" and "Diagnosis of antiphospholipid syndrome".)

Heparin-induced thrombocytopenia (HIT), in which clotting times may be abnormal due to the use of an anticoagulant, and thrombosis may be present due to the HIT antibody – (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Pathophysiology'.)

In contrast to these syndromes, small-vessel thrombotic microangiopathies (TMAs) such as thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), or drug-induced TMA (DITMA) are not associated with abnormal clotting times, with the exception of patients with tissue ischemia due to TMA that leads to DIC. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Drug-induced thrombotic microangiopathy (DITMA)".)

Prolonged PT and/or aPTT without bleeding or thrombosis — Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are often obtained in patients with no clinical suspicion of bleeding. Prolonged/increased values for these tests in a patient not receiving an anticoagulant warrant evaluation because they suggest a possible increased risk of bleeding (or, rarely, thrombosis), even if they are noted as an incidental finding.

Repeating the abnormal test(s) to verify its accuracy is usually the appropriate first step. The pace of the evaluation depends on the patient's clinical status. In many cases, a stepwise approach to investigating the cause can be taken. However, other situations may require a more rapid investigation in which several tests are obtained simultaneously (eg, severely abnormal test, urgently needed surgical procedure).

Our general approach to evaluating abnormal coagulation times in a patient without bleeding or thrombosis is to first perform a mixing study to determine if the cause of the clotting time prolongation is due to a factor deficiency or factor inhibitor (algorithm 1). (See 'Use of mixing studies' below.)

Evaluation of the PT and aPTT results can be used to localize the clotting defect to the intrinsic, extrinsic, or common pathway:

If the aPTT is prolonged and the PT (INR) is normal, the problem is localized to the intrinsic pathway of coagulation, which includes factors XI, IX, VIII, and XII. The most common inherited bleeding disorders presenting with this picture are von Willebrand disease (VWD), in which factor VIII levels may be reduced due to decreased stability of factor VIII; or isolated deficiencies of factors VIII (hemophilia A), factor IX (hemophilia B), or factor XI. Common acquired causes of this pattern are heparin therapy and the lupus anticoagulant phenomenon, caused by the presence of antiphospholipid (aPL) antibodies. VWD and deficiencies or acquired inhibitors of factors VIII, IX, or XI can cause clinical bleeding, and aPL antibodies can cause thrombosis.

Isolated prolongation of the aPTT is also seen with deficiencies of factors XII, prekallikrein (PK), or high molecular weight kininogen (HMWK); in contrast to the deficiencies of factors VIII, IX, and XI, deficiencies of factors XII, PK, and HMWK are not associated with clinical bleeding.

If the patient has a known family history of VWD or a specific factor deficiency, it is appropriate to test for the disorder, as discussed in separate topic reviews. (See "Clinical presentation and diagnosis of von Willebrand disease" and "Clinical manifestations and diagnosis of hemophilia" and "Factor XI (eleven) deficiency" and "Rare inherited coagulation disorders".)

If there is a possibility of heparin exposure that requires further evaluation, the thrombin time (TT) and reptilase time (RT) are performed; a finding of prolonged TT and normal RT is confirmatory of heparin effect.

If the aPTT is normal and the PT (INR) is prolonged, the problem lies in the extrinsic pathway, which includes factor VII, a vitamin K-dependent factor. The most common acquired causes are the use of warfarin, chronic liver disease, and vitamin K deficiency. Rarer causes include an acquired inhibitor of factor VII or a congenital factor VII deficiency. Warfarin use, chronic liver disease, and vitamin K deficiency are usually obvious from the medication list, patient history, and liver function testing. However, if these are not revealing, a mixing study and measurement of factor VII activity is appropriate. (See 'Use of mixing studies' below and "Rare inherited coagulation disorders", section on 'Diagnostic evaluation' and "Acquired hemophilia A (and other acquired coagulation factor inhibitors)", section on 'Factor VII inhibitors'.)

If both the aPTT and PT (INR) are prolonged, the problem is likely to be in the final common pathway, which includes factor X, V, prothrombin (factor II), and fibrinogen (factor I). Common acquired conditions giving a prolonged PT and aPTT are liver disease, DIC, and over-anticoagulation with warfarin or other vitamin K antagonist (or rarely, severe vitamin K deficiency or superwarfarin poisoning). Less commonly, disorders of fibrinogen can be responsible. These conditions are usually obvious from the patient history, physical examination, and laboratory testing including liver function tests and fibrinogen level. Their evaluation is presented separately. (See "Hemostatic abnormalities in patients with liver disease", section on 'Liver disease versus DIC' and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Superwarfarin poisoning' and "Anticoagulant rodenticide poisoning: Clinical manifestations and diagnostic evaluation".)

For those in whom the cause is not obvious from the patient evaluation, the TT can be used to distinguish abnormalities of the common pathway from disorders affecting fibrinogen. (See 'Thrombin time (TT)' above.)

If the TT is abnormal, then a fibrinogen disorder is suspected. Liver disease and DIC can cause hypofibrinogenemia if severe. Further evaluation of fibrinogen disorders is presented separately. (See "Disorders of fibrinogen", section on 'Diagnostic testing'.)

If the TT is normal, then the problem is due to abnormalities in prothrombin, and/or factors V or X. This may be seen in the setting of decreased production of one or more of these factors (eg, in DIC or severe vitamin K deficiency). Less commonly, an inherited factor deficiency or acquired factor inhibitor may be responsible. Mixing studies can be used to distinguish among these possibilities.

Use of mixing studies

Mixing studies overview — Mixing studies are appropriate in a patient with an unexplained prolongation of a clotting test. Mixing studies are useful because they distinguish between an abnormally prolonged clotting time due to a factor deficiency versus a factor inhibitor. Inhibitors typically are autoantibodies that interfere with coagulation factor function in the patient (eg, acquired factor VIII inhibitor) or in the laboratory test (eg, lupus anticoagulant). Other interfering substances that can also act as inhibitors include heparins, fondaparinux, direct oral anticoagulants (DOACs), and elevated C-reactive protein [42,43].

Mixing studies can be performed for any of the standard coagulation tests, including the prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT).

Discussion with the consulting hematologist and/or laboratory personnel may be helpful to ensure that appropriate testing is done in a timely fashion.

Mixing studies are performed by measuring the clotting time of the patient’s plasma diluted serially with normal plasma. The clotting time of a 1:1 mixture of patient plasma and normal plasma can be measured immediately upon incubation, and after incubation at body temperature (typically, two hours). The degree of "correction" of the coagulation time at both time points (immediately and after incubation) is reported.

Clotting time corrects — The following are the most common causes of abnormal clotting times that correct in a mixing study:

Pure factor deficiency – Any pure factor deficiency will correct in a mixing study. This is because a 1:1 mix with normal plasma will provide at least 50 percent activity of any factor required for the test, which is more than sufficient to normalize the clotting time. If the 1:1 dilution corrects the abnormal test, the deficient factor(s) can be determined by individual clotting factor assays. The coagulation factor(s) evaluated depends on which clotting test is prolonged (table 1). (See 'Assays for specific coagulation factors' above.)

Multiple factor deficiency – Certain conditions can cause deficiency of multiple coagulation factors. Examples include severe liver disease, vitamin K deficiency, and rare inherited coagulation disorders that affect more than one factor. Typically, these will be obvious from the patient history (or the family history in the latter case). (See "Hemostatic abnormalities in patients with liver disease" and "Overview of vitamin K", section on 'Vitamin K deficiency' and "Rare inherited coagulation disorders".)

Clotting time does not correct — Most factor inhibitors will not correct in a mixing study. This is because most antibodies will not be sufficiently diluted by an equal volume of normal plasma to result in correction of the clotting time. Importantly, however, some antibodies do not act immediately on their target coagulation factor. This delayed activity is characteristic of factor VIII inhibitors [44]. In such cases, the mixing study will appear to correct at the early time point, but will not correct after one or two hours of incubation. The laboratory should report results from the immediate mix as well as after incubation. (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)", section on 'Inhibitor screen and titer'.)

If the 1:1 dilution does not correct, the subsequent evaluation depends on the suspected cause of the inhibitor and the patient’s clinical status. Early involvement of the consulting hematologist and/or appropriate laboratory personnel is advised as some of these conditions can cause potentially life-threatening bleeding (eg, acquired factor inhibitors), thrombosis (eg, antiphospholipid antibodies), or both (eg, disseminated intravascular coagulation [DIC]).

Common causes of coagulation inhibitors and their evaluations include the following:

DOACs – In our institution, the presence of direct oral anticoagulants (DOACs) in the sample, most often direct factor Xa inhibitors, are the most common cause of a prolonged aPTT referred for testing. Thus, review of the patient medication list on the hospital information system (HIS) or confirming the presence of anti-Xa activity in the sample can be useful in resolving aPTT prolongations in these patients. (See 'Sources of interference with LA testing' above.)

Heparin – Heparin in the blood sample prolongs the aPTT and TT but not the reptilase time (RT). Thus, the RT can be used to confirm a suspected diagnosis of heparin effect. (See 'Reptilase time (RT)' above.)

For lupus anticoagulant testing when heparin cannot be discontinued, heparinase can be used. (See 'Sources of interference with LA testing' above.)

Lupus anticoagulant – Antiphospholipid (aPL) antibodies with a lupus anticoagulant effect most commonly prolong the aPTT. A lupus anticoagulant that affects the aPTT will not correct in a mixing study with normal plasma, but it will correct with excess phospholipid. If an aPL is suspected, the dilute Russell's viper venom time (dRVVT) or low phospholipid content aPTT reagent (eg, aPTT-LA) can be used to evaluate this possibility. (See 'Lupus anticoagulant tests' above and 'dRVVT' above.)

DIC – Fibrin degradation products may cause prolongation of the PT and aPTT, as may occur in patients with DIC or thromboembolism. (See "Disseminated intravascular coagulation in infants and children" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

Factor inhibitors in individuals with hemophilia – Inhibitory alloantibodies directed against factor VIII or IX in patients with severe hemophilia that develop in response to factor infusion may cause increased bleeding and a prolonged aPTT that does not improve with factor infusion. (See "Inhibitors in hemophilia: Mechanisms, prevalence, diagnosis, and eradication".)

Acquired coagulation factor inhibitor – Autoantibodies directed against factors VIII, IX, V, or X may prolong the PT and/or aPTT, depending on which factor is targeted. Importantly, some acquired factor inhibitors can be associated with potentially life-threatening bleeding. (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)".)

If an inhibitor is present, mixing studies can also be used to determine the titer of the inhibitor when appropriate. Serial dilutions of patient plasma are mixed with normal plasma until the proportion of patient plasma is reduced to the point that the mixing study does correct. The titer often is reported in Bethesda units (BU); the titer is equal to the reciprocal of the dilution of patient plasma that results in 50 percent factor activity. The titer correlates with the strength of the inhibitor (ie, the stronger the inhibitor, the higher the titer). Assessment of the titer is appropriate for patients who may receive factor replacement or may require other therapies for bleeding.

Shortened PT and/or aPTT — Under most circumstances, shortening of the PT and/or aPTT reflects poor sample collection or preparation techniques. (See 'Ensuring accuracy' above.)

However, clotting factors may be increased or activated in vivo, as in malignancy, DIC, or following short-term exercise, resulting in shortening of clotting times, especially the aPTT [45].

A shortened clotting time that does not appear to reflect technical error has been associated with an increased risk of thrombosis, recurrent thrombosis, recurrent miscarriage, or bleeding, and may increase the risk of thrombosis associated with other common thrombotic risk factors (eg, factor V Leiden, obesity, increased levels of D-dimer) [46-53]. There is no specific intervention recommended based on the laboratory abnormality alone; management of the underlying condition may decrease the thrombotic risk.

Patient on anticoagulant — Some anticoagulants produce predictable changes in coagulation tests that may be used in routine monitoring and dose adjustment. In addition, many of these agents also have the potential to affect other coagulation tests not used in routine monitoring, depending on drug levels and other clinical factors (eg, plasma levels of coagulation factors). Information about these other effects may be useful in preventing unnecessary evaluation of an abnormal test result and/or in verifying that an anticoagulant is no longer producing a measurable change in vitro parameters (eg, in patients with bleeding or about to undergo surgery).

Effect of anticoagulants on clotting tests includes the following (table 3):

Vitamin K antagonists (eg, warfarin) – Prolong the PT/INR (used for monitoring); may weakly prolong the aPTT

Unfractionated heparin – Prolongs the aPTT (used for monitoring), increases anti-factor Xa activity

Low molecular weight (LMW) heparins (eg, enoxaparin, dalteparin) – May prolong the aPTT, increase anti-factor Xa activity

Fondaparinux – May prolong aPTT, increases anti-factor Xa activity

Direct thrombin inhibitors (eg, hirudin, argatroban, dabigatran) – Prolong the PT/INR and aPTT (aPTT is used for monitoring parenteral agents)

Direct factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban) – Prolong the PT/INR and aPTT, increase anti-factor Xa activity

In patients being transitioned from one anticoagulant to another, multiple coagulation tests may be prolonged during the period of overlap. Specialized tests are available for monitoring such patients [54]. Institution specific guidelines should be followed when available. (See "Management of heparin-induced thrombocytopenia", section on 'Transition to warfarin or other outpatient anticoagulant'.)

Fibrinolytic agents such as recombinant tissue-type plasminogen activator (tPA) cause a systemic lytic state with low fibrinogen and increased fibrin degradation products, which will result in prolongation of the PT and aPTT. The anti-factor Xa activity should not be prolonged by fibrinolytic agents.

If thrombophilia testing is indicated, some testing (such as DNA-based testing) can be performed while the individual is receiving an anticoagulant; some other testing may be inaccurate (table 4). Indications for testing are discussed separately. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors", section on 'Evaluation for hypercoagulable disorders'.)

As noted above, an investigational modified PT assay that could be used to assess multiple anticoagulants is being evaluated. (See 'Prothrombin time (PT) and INR' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Prothrombin time and INR (PT/INR) (The Basics)")

SUMMARY AND RECOMMENDATIONS

Sample collection – Accurate coagulation testing requires that the blood sample be collected and handled appropriately, and that potential sources of test interference are addressed. (See 'Ensuring accuracy' above.)

Commonly used tests and what they measure

PT/INR – The prothrombin time (PT) measures the time it takes plasma to clot when exposed to tissue factor, which assesses the extrinsic and common pathways of coagulation (figure 1). Common causes of a prolonged PT include anticoagulants, vitamin K deficiency, liver disease, and disseminated intravascular coagulation (DIC). Some coagulation factor deficiencies may also prolong the PT (table 1). The international normalized ratio (INR) was developed to allow patients receiving warfarin at steady state to compare values obtained at different times and from different laboratories; it is also commonly used as a surrogate for the PT in bleeding patients and to assess end-stage liver disease as part of the model for end-stage liver diseases (MELD) score. (See 'Prothrombin time (PT) and INR' above.)

aPTT – The activated partial thromboplastin time (aPTT) measures the time it takes plasma to clot when exposed to substances that activate the contact factors coagulation, which assesses the intrinsic and common pathways of coagulation. Causes of a prolonged aPTT include anticoagulants; liver disease; DIC; von Willebrand disease (VWD); inherited deficiency of factor VIII (hemophilia A), factor IX (hemophilia B), factor XI, or other coagulation factors; acquired factor inhibitors; and antiphospholipid (aPL) antibodies. (See 'Activated partial thromboplastin time (aPTT)' above.)

TT, RT, lupus anticoagulant, and dRVVT – The thrombin time (TT), reptilase time (RT), and lupus anticoagulant assays, including dilute Russell's viper venom time (dRVVT), can be especially helpful in evaluating prolonged clotting times, identifying an antiphospholipid antibody (aPL) and diagnosing antiphospholipid syndrome (APS), or detecting heparin in the sample. (See 'Thrombin time (TT)' above and 'Reptilase time (RT)' above and 'Lupus anticoagulant tests' above and 'dRVVT' above.)

Anticoagulant monitoring – A number of tests are available to monitor anticoagulant therapy. (See 'Anticoagulant monitoring' above.)

Evaluating abnormal findings

Asymptomatic individual – Our general approach to evaluating a patient with prolongation of the PT and/or aPTT is presented in the algorithm (algorithm 1) and outlined above. Mixing studies are appropriate in a patient with an unexplained prolongation of a clotting test; they distinguish between an abnormally prolonged clotting time due to a factor deficiency versus a factor inhibitor (typically, an autoantibody). (See 'Prolonged PT and/or aPTT without bleeding or thrombosis' above.)

Individual with bleeding or thrombosis – The evaluation of abnormal clotting times in a patient with bleeding or thrombosis is presented in detail separately. (See "Approach to the adult with a suspected bleeding disorder" and "Diagnosis of antiphospholipid syndrome" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)

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Topic 1368 Version 73.0

References

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