What is the cause of abnormal bleeding with a normal prothrombin time (PT)?

From the Guidelines

Abnormal bleeding with a normal prothrombin time (PT) in patients with cirrhosis should not be managed with correction of PT, as it does not predict bleeding and patients are likely in a 'rebalanced' haemostatic state 1.

Causes of Abnormal Bleeding

The most likely causes of abnormal bleeding with a normal PT include:

• Platelet disorders (thrombocytopenia or platelet dysfunction)
• Von Willebrand disease
• Factor XIII deficiency
• Vascular abnormalities These conditions can lead to bleeding complications, even with a normal PT, as they affect different aspects of the hemostatic system.

Evaluation and Management

Initial evaluation should include:

• Complete blood count to assess platelet count
• Bleeding time
• Von Willebrand factor assay
• Factor XIII activity While waiting for results, tranexamic acid (1g orally three times daily or 10mg/kg IV) can help control bleeding by inhibiting fibrinolysis. For severe bleeding, consider desmopressin (DDAVP) 0.3μg/kg IV to stimulate release of von Willebrand factor and factor VIII. Platelet transfusions may be necessary if thrombocytopenia is present (platelets <50,000/μL) or if platelet dysfunction is suspected. Specific factor replacement would be needed if a deficiency is identified.

Hemostatic Changes in Cirrhosis

Patients with cirrhosis have multiple alterations in their hemostatic system, including defective hepatic synthetic capacity, decreased platelet numbers, and elevated plasma levels of hemostatic proteins 1. These changes can lead to a complex imbalance between prohemostatic and antihemostatic pathways, making it difficult to determine the risk of bleeding or thrombosis using traditional laboratory measures of coagulation.

Global Hemostasis Tests

Global tests of hemostasis, such as plasma-based thrombin generation tests and whole-blood viscoelastic tests, may be useful in evaluating the hemostatic system in patients with cirrhosis. However, these tests have limitations and should be interpreted cautiously, as their predictive value for spontaneous or procedural bleeding is unproven 1.

From the FDA Drug Label

1. 4 Laboratory Tests Laboratory coagulation parameters (PT/INR, aPTT, FVII:C) have shown no direct correlation to achieving hemostasis. Assays of prothrombin time (PT/INR), activated partial thromboplastin time (aPTT), and plasma FVII clotting activity (FVII:C), may give different results with different reagents Treatment with NOVOSEVEN has been shown to produce the following characteristics: PT: As shown below, in patients with hemophilia A/B with inhibitors, the PT shortened to about a 7-second plateau at a FVII:C level of approximately 5 units per mL. For FVII:C levels > 5 units per mL, there is no further change in PT The clinical relevance of prothrombin time shortening following NOVOSEVEN RT administration is unknown.

The use of recombinant factor VIIa (IV) may not directly correlate with normal prothrombin time (PT) in preventing abnormal bleeding.

• Key points:
  • Laboratory coagulation parameters, including PT, have shown no direct correlation to achieving hemostasis.
  • The clinical relevance of prothrombin time shortening following NOVOSEVEN RT administration is unknown.
  • Treatment with NOVOSEVEN RT may shorten PT, but this does not directly predict bleeding outcomes. 2

From the Research

Abnormal Bleeding with Normal Prothrombin Time

• Abnormal bleeding with a normal prothrombin time (PT) can be caused by various factors, including platelet disorders or other coagulation factor deficiencies 3.
• A study published in the Mayo Clinic proceedings in 2007 discussed the interpretation and pursuit of abnormal PT, activated partial thromboplastin time (APTT), and bleeding time in adults, which may be helpful in evaluating abnormal bleeding with a normal PT 4.
• The laboratory diagnosis of bleeding disorders, including basic screening tests such as bleeding time, platelet count, APTT, PT, and thrombin time, was discussed in a 1984 study published in Postgraduate medicine 3.
• Another study published in Emergency medicine clinics of North America in 1986 reviewed coagulation studies, including PT, APTT, and bleeding time, which may be relevant to evaluating abnormal bleeding with a normal PT 5.

Diagnostic Approach

• A thorough history, including a family history, and a physical examination may provide clues to diagnosis, as discussed in a 2008 study published in American family physician 6.
• Initial laboratory evaluations should include a complete blood count with platelet count, peripheral blood smear, PT, and APTT, as recommended in the 2008 study 6.
• More specialized tests, such as the Platelet Function Analyzer-100, mixing studies, and inhibitor assays, may also be helpful in diagnosing platelet function disorders, quantitative platelet disorders, factor deficiencies, and factor inhibitors 6.

Coagulation Studies

• A study published in Anesthesiology in 1994 compared whole blood and laboratory assays with coagulation factor analysis in patients presenting for cardiac surgery, which may be relevant to understanding the relationship between PT, APTT, and coagulation factor levels 7.
• The study found that whole blood PT and platelet count values correlated well with those obtained from the laboratory, but there was a discrepancy between measurement systems in APTT values 7.