Abnormal bleeding can result from disorders of the coagulation system, of platelets, or of blood vessels. Disorders of coagulation can be acquired or hereditary.
The major causes of acquired coagulation disorders are
Liver disease
Severe liver disease (eg, cirrhosis, fulminant hepatitis, acute fatty liver of pregnancy) may disturb hemostasis by impairing clotting factor synthesis. Because all coagulation factors are made in the liver (by hepatocytes and hepatic sinusoidal endothelial cells), both the prothrombin time (PT) and partial thromboplastin time (PTT) are prolonged in severe liver disorders. (PT results are typically reported as INR [international normalized ratio].) Occasionally, decompensated liver disease also causes excessive fibrinolysis and bleeding due to decreased hepatic synthesis of alpha 2-antiplasmin.
The most common hereditary disorder of hemostasis is
The most common hereditary coagulation disorders are
The hemophilias
Testing for Coagulation Disorders
Patients in whom a coagulation disorder is suspected require laboratory evaluation beginning with
Prothrombin time (PT) and partial thromboplastin time (PTT)
Complete blood count (CBC) with platelet count
Peripheral blood smear
Results of these tests narrow the diagnostic possibilities and guide further testing.
Normal results
Normal results on initial tests exclude many bleeding disorders. The main exceptions are
Von Willebrand disease is a common entity in which the associated deficiency of factor VIII is frequently insufficient to prolong the PTT. Patients who have normal initial test results, along with symptoms or signs of bleeding and a positive family history, should be tested for von Willebrand disease by measuring plasma von Willebrand factor (VWF) antigen, ristocetin cofactor activity (an indirect test of VWF function), VWF multimer pattern, and factor VIII levels.
Hereditary hemorrhagic telangiectasia (also called Osler-Weber-Rendu syndrome) is a hereditary disorder of vascular malformation. Patients with this disorder have small red-to-violet lesions on the face, lips, oral and nasal mucosa, and tips of the fingers and toes. They may experience recurrent bleeding from the nasal mucosa and gastrointestinal tract and may have other potentially serious consequences of arteriovenous malformations.
Thrombocytopenia
If thrombocytopenia is present, the peripheral blood smear often suggests the cause.
If the smear is normal, patients should be tested for HIV infection and hepatitis C. If these tests are negative and the patient is not pregnant and has not taken a medication known to cause platelet destruction, then immune thrombocytopenia (ITP) is likely.
If the smear also shows signs of hemolysis (fragmented red blood cells), thrombotic thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS) should be suspected. "Classic" HUS occurs in patients with Shiga-like toxin-induced hemorrhagic colitis that occurs during infections with several Escherichia coli serotypes. An "atypical" form of HUS occurs uncommonly in individuals with congenital abnormalities of the alternative complement pathway. The Coombs test is negative in TTP and HUS.
If the CBC and peripheral blood smear demonstrate other cytopenias or immature white blood cells, a hematologic abnormality affecting multiple cell types should be suspected. Bone marrow aspiration and biopsy are then necessary for diagnosis.
Prolonged PTT with normal platelets and PT
A prolonged PTT with a normal platelet count and PT suggests hemophilia A or B, and factor VIII and IX assays are indicated. Inhibitors that specifically prolong the PTT include an autoantibody against factor VIII and antibodies against protein-phospholipid complexes (lupus anticoagulant). Clinicians suspect one of these inhibitors when a prolonged PTT does not correct after 1:1 mixing with normal plasma. In patients with normal factor VIII and factor IX levels, factor XI deficiency (hemophilia C, or Rosenthal disease) should also be considered. Factor XI deficiency is particularly common in patients with Ashkenazi Jewish ancestry.
Prolonged PT with normal platelets and PTT
vitamin K deficiency, or in patients with incipient liver disease.
Prolonged PT and PTT with thrombocytopenia
A prolonged PT and PTT with thrombocytopenia suggests DIC, especially in patients with obstetric complications, sepsis, cancer, or shock.
Confirmation is by finding elevated levels of D-dimer (or fibrin degradation products) and decreasing plasma fibrinogen levels on serial testing.
A prolonged PT, prolonged PTT, and thrombocytopenia can also result from liver disease because hepatocytes synthesize most coagulation factors (except factor VIII) as well as thrombopoietin, the primary platelet growth factor. In patients with liver disease and portal hypertension, thrombocytopenia also results from splenic sequestration. Many patients with liver disease and thrombocytopenia also have leukopenia and anemia. Testing for hepatitis C is recommended.
Prolonged PT or PTT with normal platelet count
A prolonged PT or PTT with a normal platelet count can occur with liver disease or vitamin K deficiencythrombinScreening Laboratory Test Results and Treatment of Inherited Blood Coagulation Defects).
Liver disease is suspected based on history or physical examination findings (eg, jaundice, hepatomegaly, splenomegaly, telangiectasia) and is confirmed by finding elevations of serum aminotransferases and bilirubin.
