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Author: Hedy Smith

1. History

Key elements include:

  • severity of bleeding
  • duration of bleeding, lifelong versus new
  • family history
  • drug history
  • what type of bleeding mucocutaneous vs muscle and joint bleeds
  • surgeries and experience with past dental work
  • menstrual and obstetric history
  • delayed vs immediate
  • need for transfusion or iron supplementation related to bleeding

2. Assays

Bleeding time: evaluates primary hemostasis

  • Prolonged in platelet disorders (quantitative and qualitative), von Willebrand's disease, connective tissue disorders
  • Controversial! Not very specific. Does not correlate with bleeding before procedures.

Prothrombin time PT (INR): measures the time taken for VIIa to complex with tissue factor (TF) to form a clot, i.e., the extrinsic pathway of coagulation

  • Prolongation indicative of VII deficiency or VIIa inhibitor
  • Congenital VII deficiency is rare and most cases are acquired in the context of liver disease or Vit K deficiency seen in newborn and with Vit K antagonists such as Warfarin

Activated Partial thromboplastin time (aPTT): measures the time taken for clotting in the intrinsic pathway

  • Prolongation is indicative of:
    • factor deficiency (XI, IX, VIII)
    • Marked prolongation of XII deficiency but not associated with bleeding
    • Antiphospholipid antibody
    • Factor (VIII, IX, XI) inhibitor
    • Drug (heparin)

Prolongation of PT and aPTT

  • Deficiency or or inhibitor of factors X, V, II (prothrombin), i.e., the common pathway factors
  • Fibrinogen deficiency (<80 mg/dl)
  • High doses of anticoagulants
  • Elevated in DIC

Thrombin time

  • Measures conversion of fibrinogen to fibrin by thrombin (IIa)
  • elevated in DIC, dysfibrinogenemias or hypofibrinogenemias, heparin

Factor XII deficiency

  • Bleeding without prolongation of PT or PTT
  • High incidence of intracranial hemorrhage, umbilical stump hemorrhage and women with spontaneous abortions
  • Does not prolong the aPTT so have screen for deficiency with clot solubility assay or assay for factor level

Factor Assay

  • Quantitates the amount of factor in a given individual

Mixing studies

  • Indicated for prolongation in PT or aPTT
  • Allows one to determine whether elevation in these tests is causes by factor deficiency or inhibitor
  • Patient's abnormal plasma is mixed in 1:1 ratio with normal plasma and abnormal test (PT or PTT) is repeated. Possible results include:
    • Normalization of aPTT or PT at time zero that remains normal at 2 hours is diagnostic of a factor deficiency or inhibitor of von Willebrand's factor (VWF)
    • Normalization at time zero with prolongation on incubation implies the presence of an inhibitor (an acquired antibody)
    • No or partial correction at time zero, with aPTT prolonging with incubation suggestive of antiphospholipid antibody

von Willebrand's screening

  • Factor VIII assay
  • VWF antigen (VWF:Ag) most commonly by ELISA
  • Ristocetin cofactor activity (VWF:RCo)
  • VWF multimer analysis

Inhibitor Assay / Bethesda Assay

  • Serial dilutions of the patient's plasma mixed in 50:50 ratio with normal plasma, followed by assay for the factor that is being inhibited
  • Expressed as a Bethesda titre with one Bethesda unit (BU) being the amount of the inhibitor (i.e., the dilution of the patient's plasma) that neutralizes 50% of the factor in the normal plasma

Other points

  • Vit K dependent coagulation factors: II, VII, IX, X, protein C and Protein S
  • Be aware that infants are deficient in Vit K dependent factors