What causes prolonged protime (prothrombin time)?

Prolonged Prothrombin Time: Causes and Clinical Approach

Primary Mechanisms and Pathophysiology

Prolonged PT results from deficiencies or dysfunction in the extrinsic and common coagulation pathways, specifically involving factors VII, X, V, II (prothrombin), and fibrinogen. 1

• Isolated factor VII deficiency causes PT prolongation without aPTT abnormality, as factor VII is unique to the extrinsic pathway 1
• Combined PT and aPTT prolongation indicates common pathway defects (factors X, V, II, fibrinogen) or multiple factor deficiencies 1

Medication-Related Causes

Warfarin and Vitamin K Antagonists

• Warfarin is the most common cause of prolonged PT, inhibiting vitamin K-dependent clotting factors (II, VII, IX, X) by blocking vitamin K epoxide reductase 1, 2
• Drug interactions that inhibit S-warfarin metabolism significantly prolong PT: phenylbutazone, sulfinpyrazone, metronidazole, trimethoprim-sulfamethoxazole, and amiodarone 1
• Elderly patients show exaggerated warfarin response due to reduced drug clearance with age 1
• Hereditary warfarin resistance is rare but requires 5- to 20-fold higher doses than average 1
• A mutation in the factor IX propeptide (present in 1.5% of the population) causes marked factor IX decrease during warfarin therapy with bleeding risk not reflected in PT 1

Antibiotic-Induced Vitamin K Deficiency

• Antibiotics commonly cause PT prolongation through vitamin K deficiency, particularly in patients receiving intravenous fluids without vitamin K supplementation 1
• Vitamin K deficiency was the most common cause of isolated prolonged PT in outpatient studies 3

Heparin Effects

• Heparin prolongs the one-stage PT and must be considered when interpreting PT results 2
• Unfractionated heparin, low-molecular-weight heparin, and direct oral anticoagulants (DOACs) can all affect PT values 4

Hepatic Dysfunction

• Hepatic dysfunction prolongs PT through impaired synthesis of coagulation factors, typically requiring loss of >70% of synthetic function to manifest as coagulopathy 5
• Liver disease causes decreased synthesis of liver-derived procoagulant factors (V, VII, X), causing PT prolongation 5
• Liver disease was the most common cause of combined PT and aPTT prolongation in outpatient studies 3
• Standard coagulation tests (PT/INR) primarily reflect deficiencies in liver-produced factors but don't account for the balanced reduction in both pro- and anticoagulant factors 5
• INR should only be used for warfarin monitoring, not for evaluating liver disease, as it lacks validity for hepatic dysfunction, DIC, or acute bleeding 1
• In liver failure, INR fails to yield a PT expression independent of the thromboplastin used; only activity percentage expression provides standardization 6

Hereditary and Metabolic Conditions

Glycogen Storage Diseases

• Hereditary fructose intolerance causes hepatomegaly with prolonged PT, hypoalbuminemia, elevation of bilirubin, and proximal tubular dysfunction 7
• Hypoglycemia is provoked by fructose intake, with improvement of symptoms following fructose restriction 7

Factor X Deficiency

• Factor X deficiency presents with prolongation of both PT and aPTT that can be corrected in a 50:50 mix with normal plasma 7
• Diagnosis is confirmed by quantifying plasma factor X activity through serial dilutions with factor X-deficient plasma 7
• Severe factor X deficiency (FX:C levels <10 IU/dL) presents with mucocutaneous bleeds (72%), hemarthroses (69%), GI bleeding (38%), and heavy menstrual bleeding (50%) 7

Acquired Coagulopathies

Acquired Hemophilia and Inhibitors

• Acquired hemophilia presents with prolonged aPTT with normal PT; typical finding is prolonged activated PTT with normal PT 7
• Determination of Bethesda unit level of inhibitor is essential for diagnosis 7
• Lupus anticoagulant was the most common cause of isolated prolonged aPTT in outpatient studies 3

Hypermetabolic States

• Hypermetabolic states (fever, hyperthyroidism) increase PT by accelerating catabolism of vitamin K-dependent coagulation factors 1

Hypothermia and Trauma

• Hypothermia impairs platelet function between 33-37°C and the activity of clotting factors and fibrinogen synthesis below 33°C 7
• Partial thromboplastin time levels increased from 36.0 seconds at 37°C to 57.2 seconds at 28°C 7
• Temperatures below 33°C inhibit thrombin, glycoprotein Ib-IX complex, platelet aggregation, and thromboxane B2 production 7

Laboratory Artifacts and Technical Considerations

Specimen Collection Issues

• Underfilling blood collection tubes causes excess citrate and spuriously prolonged PT results 1, 8
• Specimen tubes should be filled to at least 90% of capacity to avoid falsely elevated PT or APTT results 8
• Using 3.2% citrate collection tubes rather than 3.8% reduces the problem of excess citrate 1
• Accurate PT values in the therapeutic range were obtained only with filling to 80% or more of capacity (using moderately sensitive thromboplastin, ISI = 2.06) or 90% or more of capacity (using highly sensitive thromboplastin, ISI = 1.01) 8

Test Interpretation Pitfalls

• Coagulation tests are very sensitive to specimen handling and should be performed in laboratories experienced with these assays; inappropriate handling commonly leads to false-positive results 7
• aPTT can be falsely prolonged in the presence of a lupus anticoagulant, or can be prolonged without indicating a true bleeding disorder, such as in factor XII deficiency or other contact factor deficiencies 7
• Patients who experience traumatic brain injury often have transient coagulopathy that does not reflect an underlying congenital disorder 7
• Prolongation of PT and/or aPTT because of parenchymal damage has been noted in abusive head trauma and should not automatically be interpreted as evidence of a primary bleeding disorder 7

INR Limitations

• PT may be only modestly prolonged in severe illness; in COVID-19 non-survivors, median PT was 15.5 seconds versus 13.6 seconds in survivors 1
• ISI values for a specific thromboplastin can vary among different models of coagulometers from a manufacturer using the same method for clot identification 9

Diagnostic Approach

Initial Evaluation

• Review all medications systematically, including unfractionated heparin, low-molecular-weight heparin, DOACs, and warfarin 4
• Repeat PT, aPTT, fibrinogen, and platelet count as early combined measurement is essential for characterizing coagulopathy 4
• Add viscoelastic testing (TEG/ROTEM) if available to characterize coagulopathy in real-time, as conventional PT/aPTT only monitor the initiation phase (first 4% of thrombin production) 4

Mixing Studies

• Mixing studies differentiate between factor deficiency and inhibitors by mixing patient plasma 50:50 with normal plasma 7
• The estimated factor correction (EFC) method was superior to other correction methods, correctly identifying 38 of 39 known inhibitors, single and multiple factor deficiencies 10
• For a given factor level, multiple factor deficiencies prolonged the PT/aPTT more than single factor deficiency, necessitating different thresholds for defining correction 10

Pattern Recognition

• Isolated PT prolongation: Consider factor VII deficiency, early warfarin effect, vitamin K deficiency, or early liver disease 1, 3
• Isolated aPTT prolongation: Consider lupus anticoagulant, heparin, factor VIII/IX/XI deficiency, or von Willebrand disease 3
• Combined PT and aPTT prolongation: Consider liver disease, vitamin K deficiency, warfarin, DIC, or common pathway factor deficiencies 1, 3

Clinical Significance and Management Considerations

• In outpatient studies, 29% had normal PT/aPTT on repeat testing, 64% had acquired conditions, 22% had congenital conditions, 9% had unclear etiology, and 5% were laboratory artifacts 3
• Maintain PT/aPTT <1.5 times normal control during interventions for life-threatening hemorrhage or emergency neurosurgery including ICP probe insertion 4
• Do not empirically transfuse fresh frozen plasma or other blood products in asymptomatic patients without bleeding or planned procedures 4