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Tufts OpenCourseware
Author: Kanchan Ganda, M.D.
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1. The Clotting Pathway

1.1. Elements of Hemostasis:

  1. Platelets (normal: 150- 400,000/μl)
  2. Von Willebrand’s Factor (VWF)
  3. Clotting Factors
  4. Blood Vessels

1° (Primary) Hemostasis is the first line of defense forming the primary clot. Platelets, Von Willebrand’s Factor (VWF) and blood vessel response, contributes to 1° hemostatis. Primary hemostasis is reinforced by the formation of a Fibrin clot via clotting factor interractions.

2° (Secondary) Hemostasis is the second line of defense.

1.2. Clotting Cascade: Mechanism of Clot Formation

vessel wall injury vessel wall contraction platelet adhesion platelet aggregation fibrin formation plugging of injured vessel wall

The clotting pathway:

The clotting pathway

1.3. Von Willebrand’s Factor (VWF)

  • VWF promotes the sticking together of platelets and thus, platelet adherence.
  • This factor plays a dual role in the arrest of bleeding.
  • It helps platelets to plug the injured blood vessel walls, and it is also a carrier for factor VIIIc, which is vital in the CLOTTING CASCADE discussed below.
  • In the absence of VWF, blood coagulation and platelet plug could be abnormal, thus affecting both primary and secondary hemostatis.

1.4. Bleeding time

  • Time required for the patient to stop bleeding after an injury.
  • BT (bleeding time) measures the functioning capacity of the platelets.
  • Normal bleeding time range is: 2-10 minutes.
  • A normal BT indicates absence of Von Willebrand’s disease and normal platelet function.

It tells us nothing specific about the actual platelet number.

1.5. PT/INR and PTT/APTT

  • These blood tests check clotting factor function.
  • Partial thromboplastin time or activated partial thromboplastin time (PTT/APTT) measures the activity of the intrinsic and common pathways.
  • The normal range of PTT is 25–38 seconds.
  • This test checks factors XII to I (fibrin). Prothrombin time/ International Normalized Ratio, (PT/INR) measures the extrinsic and the common path-ways.
  • The normal range of PT is 10–12 seconds. PT/INR check factors VII to I (fibrin).
  • The PT test has been replaced by the more sophisticated test, the INR.
  • The normal INR is 0.9-1.2.
  • The INR was developed to standardize the different preparations of thromboplastin, universally.

1.5.1. INR

INR= Patient PT *ISI
Control PT
Normal INR: 0.9 - 1.2
*International Sensitivity Index of Thromboplastin
  • INR: 2.0 - 3.0 : It is the Theraputic Range maintained with warfarin sodium
  • INR under 2.0 is associated with minimal bleeding
  • INR of 3 - 4.5: Is associated with excessive bleeding
  • INR is checked every 4-6 weeks

Note: All of the clotting factors except VIII are produced in the liver.

  • Factor VIII is manufactured in the endothelial cells of the blood vessels.
  • We see a prolonged PT/INR and PTT/APTT in patients with cirrhosis of the liver (liver failure) when the clotting factor pool has dropped below 50% of normal.
  • Factors II, VII, IX, and X are vitamin K dependent clotting factors.
  • Without adequate vitamin K, we see prolonged PT/INR and PTT/APTT values.
  • Vitamin K is a fat soluble vitamin and needs the presence of bile to be absorbed from the GI tract.
  • Low bile production, inadequate vitamin K intake, and chronic small intestinal disease can all result in chronic vitamin K deficiency and prolonged PT/INR and PTT/APTT values.
  • Factor VII has the shortest half-life compared to the other factors.

1.6. Blood thinners

Blood thinners frequently used in patients with an increased tendency toward intravascular clotting or thrombus formation, e.g., deep vein thrombosis, stroke, atrial fibrillation, etc.

  • In life threatening situations, Heparin sodium is administered intravenously (IV). It is quick acting, has a half-life of one hour, and the drug is completely eliminated in six hours. It is the drug of choice during an emergency (heart attack (MI), CVA (stroke)). Heparin sodium is given IV q6h (every six hours) until the patient is stable. The Warfarin is started next, by mouth. Heparin sodium affects the intrinsic pathway, thus prolonging the PTT/APTT. We check the PTT/APTT to determine how the patient is doing on Heparin sodium. We administer heparin and maintain PTT at 1.5-2.0 times the normal PTT/APTT values ( thus increased to 38-76 seconds). This range of prolongation is referred to as the therapeutic index for Heparin sodium. A PTT/APTT above 76 seconds will result in excessive bleeding.
  • Warfarin is a vitamin K antagonist and is administered orally. It blocks the function of the vitamin K dependent clotting factors (II, VII, IX, X). Thus large doses of Warfarin affects both the intrinsic and the extrinsic pathways. It takes 9-16 hours for Warfarin effects to show up in the blood after oral intake (PO) and 36 to 48 hours for complete effectiveness, i.e for therapeutic index levels for the drug to occur. Factor VII has the shortest half-life of all factors.
  • Only PT/INR is measured to establish therapeutic levels of Warfarin activity, instead of both PT/INR and PTT. Excess intake of Warfarin (beyond therapeutic levels) will result in low levels of factors II, IX and X. The patient will then have a prolonged PTT in addition to a prolonged PT/INR. Too much Warfarin will cause spontaneous bleeding in the patient. So at therapeutic levels, only PT/INR is affected. We administer and maintain Warfarin at 1.3- 1.5 times the normal PT values of 10-12 seconds (13-18 seconds). This is the therapeutic index. Warfarin is given only after an emergency situation has been stabilized by Heparin sodium. Once Warfarin is established, the patient then maintains blood thinning by daily oral intake of Warfarin.

    All patients on Warfarin get their PT/INR levels done every 6 weeks to confirm that they are in the "therapeutic range." Most patients are maintained at an INR of 2.0-3.0.

    Patients with a higher INR of 3.5-4.5 have a greater tendency towards bleeding. (The higher INR is maintained to prevent thrombosis.)