Coagulation

• 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

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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

• 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

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

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

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

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