Coagulation

Coagulation laboratory tests

Abnormal PT and PTT - causes



Topic Completed: 1 December 2020

Minor changes: 21 May 2021

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PubMed Search: Abnormal PT and PTT - causes

Tori Seasor, M.D.
Karen A. Moser, M.D.
Page views in 2020: 4,333
Page views in 2021 to date: 8,180
Cite this page: Seasor T, Moser KA. Abnormal PT and PTT - causes. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/coagulationabnormalPTPTT.html. Accessed October 25th, 2021.
Definition / general
  • Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are common initial tests in the evaluation of patients with suspected bleeding disorders
  • PT evaluates extrinsic and common pathways
  • aPTT measures intrinsic and common pathways
Essential features
  • PT and aPTT methods measure time to fibrin clot formation
  • PT and aPTT results are reported in seconds
  • Common causes of prolonged PT or aPTT are factor deficiencies, inhibitors (specific or nonspecific), liver failure, disseminated intravascular coagulation (DIC), anticoagulants and preanalytic factors
  • Prolonged PT and aPTT can be further evaluated with mixing studies or other coagulation tests (such as factor activities and lupus anticoagulant testing) if indicated
Terminology
  • Prolonged PT or aPTT
  • Abnormal coagulation screening tests
  • Abnormal clotting time
Pathophysiology

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Schematic of coagulation cascade

Schematic of coagulation cascade

Clotting time prolonged Key differential diagnoses
Prothrombin time (PT)
  • Factor deficiency or inhibitor (VII, X, V, II)
  • Warfarin
  • Vitamin K deficiency
  • Liver disease
  • Direct Xa inhibitor
Activated partial
thromboplastin time (aPTT)
  • Factor deficiency or inhibitor (VIII, IX, XI, contact factors)
  • Rarely, von Willebrand disease (if VIII is low enough to prolong aPTT)
  • Heparin
  • Direct thrombin inhibitor
  • Lupus anticoagulant
PT and aPTT
  • Common pathway factor deficiency or inhibitor (X, V, II)
  • Warfarin (high doses) or superwarfarin
  • Vitamin K deficiency
  • Disseminated intravascular coagulation
  • Liver disease
  • Direct thrombin inhibitors
  • Direct Xa inhibitors
  • Lupus anticoagulant (rarely)
  • Heparin (very high doses)


  • PT evaluates clotting within the extrinsic and common coagulation pathways
  • Causes of isolated prolonged PT (Clin Lab Med 2009;29:253, Lab Med 2017;48:295)
    • Deficiency of or inhibitor to factor VII
    • Mild decrease in common pathway factor(s)
    • Medications: warfarin and other vitamin K antagonists, direct Xa inhibitors
    • Liver disease (early / mild)
    • DIC (early)
    • Vitamin K deficiency
  • aPTT evaluates clotting within the intrinsic and common coagulation pathways
  • Causes of isolated prolonged aPTT (Lab Med 2017;48:295, Semin Thromb Hemost 2014;40:195, Am J Hematol 2013;88:82):
    • Deficiency of or inhibitor to factors VIII, IX, or XI
    • Deficiency of contact factors (factor XII, prekallikrein, high molecular weight kininogen)
      • Contact factor deficiency is not associated with clinical bleeding
    • Isolated aPTT prolongation rarely occurs with multiple factor deficiencies such as DIC or liver failure
    • Lupus anticoagulant (nonspecific inhibitor)
    • Medications: unfractionated heparin (note: aPTT is commonly used to monitor unfractionated heparin therapy), direct thrombin inhibitors
  • Causes of prolonged PT and aPTT
    • Deficiency of or inhibitor to common pathway factors
    • Dilutional coagulopathy
    • DIC
    • Nonspecific inhibitor: lupus anticoagulant with hypoprothrombinemia
    • Afibrinogenemia, hypofibrinogenemia or dysfibrinogenemia
    • Severe liver disease
    • Vitamin K deficiency (severe)
    • Medications: supratherapeutic warfarin, superwarfarins, supratherapeutic unfractionated heparin, direct Xa inhibitors (high levels), direct thrombin inhibitors (high levels)
  • Prolonged PT or aPTT can prompt further evaluation with a mixing study or factor assays if factor deficiency or inhibitor suspected (Lab Med 2017;48:295, Mayo Clin Proc 2007;82:864)
    • A mixing study is nonspecific but patterns may support either a factor deficiency or a factor inhibitor
Clinical features
  • Conditions associated with prolonged PT or aPTT: (Lab Med 2017;48:295, Mayo Clin Proc 2007;82:864, Clin Lab Med 2009;29:253, Am J Hematol 2013;88:82)
    • Factor deficiency:
      • Decreased factor activity with one or more factor assays
      • Includes hemophilia (deficiency of factor VIII, IX or XI)
      • Bleeding
    • Specific factor inhibitor:
      • Decreased factor activity and positive Bethesda (inhibitor) assay for a specific factor
      • Bleeding
    • Nonspecific inhibitor (e.g. lupus anticoagulant):
      • Positive lupus anticoagulant testing (e.g. dRVVT, hexagonal phospholipid neutralization assay, platelet neutralization procedure)
      • No specific factor inhibitor detected with Bethesda assay
      • May have thrombosis or be asymptomatic
    • Vitamin K deficiency:
      • Decreased activity of factors II, VII, IX, X
      • May have bleeding or be asymptomatic
    • Anticoagulant medications:
      • Heparin - prolonged aPTT and prolonged TT that correct with heparin neutralization, normal reptilase time
      • Warfarin - decreased activity of factors II, VII, IX, X
      • Direct thrombin inhibitors - prolonged aPTT and prolonged TT that do not correct with heparin neutralization, normal reptilase time
      • Direct Xa inhibitors - abnormal anti-Xa activity assay
    • Disseminated intravascular coagulation (DIC):
      • Decreased activity of multiple factors, including fibrinogen; markedly elevated D-dimer
      • May have bleeding and / or thrombosis
    • Liver failure:
      • Decreased activity of all coagulation factors except for factor VIII which is not produced by hepatocytes
      • Factor V activity is decreased in liver failure but not with vitamin K antagonists or vitamin K deficiency
      • May have bleeding or be asymptomatic
    • Dysfibrinogenemia, hypofibrinogenemia, afibrinogenemia:
      • Dysfibrinogenemia - fibrinogen activity decreased to a greater degree than fibrinogen antigen
      • Hypofibrinogenemia / afibrinogenemia - fibrinogen activity and antigen decreased to a similar degree
      • Bleeding
Symptoms
  • Abnormal PT / aPTT can be asymptomatic or associated with bleeding or clotting, depending on the underlying cause
Laboratory
  • PT / aPTT testing are clotting times (Lab Med 2017;48:295)
    • Current coagulation analyzers use 1 of 2 strategies for clot detection
      • Electromechanical
      • Optical
  • Sample for testing: platelet poor plasma in 3.2% sodium citrate
  • PT: thromboplastin (tissue factor combined with phospholipid) and calcium chloride are added to the sample to initiate clotting
  • aPTT: a contact factor activator (e.g. kaolin, silica) combined with phospholipid and calcium chloride are added to the sample to initiate clotting
  • Reagents used for PT and aPTT testing vary between labs and show different factor sensitivities as well as different sensitivity to lupus anticoagulants and anticoagulant medications
    • Each laboratory must understand the performance characteristics of the reagent it uses
  • PT and aPTT results are reported in seconds
Differential diagnosis
  • Preanalytic variables that may falsely prolong PT and aPTT (Lab Med 2017;48:295, Mayo Clin Proc 2007;82:864)
  • Sample drawn in EDTA instead of citrate
    • EDTA strongly chelates calcium, falsely prolonging PT and aPTT, among other abnormalities (Lab Med 2012;43:1)
  • Delay in specimen processing
    • Loss of labile factors (V, VIII) may falsely prolong PT and aPTT
  • Underfilling blood collection tube
    • Causes relative citrate excess and false prolongation of PT and aPTT
  • High hematocrit
    • Increased RBC and decreased plasma in tube causes relative citrate excess and false prolongation of PT and aPTT
Board review style question #1
Which of the following is the most likely possible cause of combined PT and aPTT prolongation?

  1. Factor VII deficiency
  2. Low hematocrit
  3. Lupus anticoagulant
  4. Underfilled collection tube
Board review style answer #1
D. Underfilled collection tube. Underfilling the blood collection tube will result in a prolongation of aPTT and PT due to the increased concentration of citrate. High hematocrit (not low hematocrit) can also result in a relative excess of citrate due to increased red blood cells and a relatively smaller volume of plasma in the tube. Lupus anticoagulant affects aPTT to a greater degree than PT due to the high concentration of phospholipids in PT reagents. Factor VII deficiency would be expected to prolong the PT but not the aPTT.

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Reference: Abnormal PT and PTT - causes
Board review style question #2
A 68 year old man has an aPTT of > 150 s (reference interval 24 - 35 s) and PT of 12 s (reference interval 12 - 15.5 s). A 1:1 aPTT mixing study result is 33 s. He has no personal or family history of a bleeding disorder. What is the most likely cause of his aPTT prolongation?

  1. Factor IX deficiency
  2. Factor XIII deficiency
  3. Prekallikrein deficiency
  4. Von Willebrand factor deficiency
Board review style answer #2
C. Prekallikrein deficiency. Prekallikrein deficiency causes prolonged aPTT that corrects in a 1:1 mixing study and is not associated with clinical bleeding. The other contact factors (factor XII and high molecular weight kininogen) give a similar picture. Factor IX deficiency can also cause a prolonged aPTT that corrects in a mixing study but it is associated with a bleeding diathesis (hemophilia B). Factor XIII deficiency does not prolong the PT or aPTT (recall that factor XIII crosslinks fibrin but the PT and aPTT reaction endpoint is the formation of fibrin and these tests do not measure the effect of factor XIII). Some types of von Willebrand disease may be associated with prolonged aPTT (e.g. type 2N, type 3) due to significantly decreased factor VIII activity but the degree of aPTT prolongation is typically less than was seen in the case in this question.

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Reference: Abnormal PT and PTT - causes
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