Excessive Bleeding

History

History of present illness should determine the bleeding sites, the amount and duration of bleeding, and the relationship of bleeding to any possible precipitating events, including medication exposure.

Review of systems should specifically query about bleeding from sites other than those volunteered by the patient (eg, patients complaining of easy bruising should be questioned about frequent nosebleeds, gum bleeding while tooth brushing, melena, hemoptysis, blood in stool or urine). Patients should be asked about symptoms of possible causes, including abdominal pain and diarrhea (gastrointestinal illness); joint pain (systemic rheumatic disorders); and amenorrhea plus nausea (pregnancy).

Past medical history should seek known systemic conditions associated with defects in platelets or coagulation, particularly:

• Severe infection, cancer, cirrhosis, HIV infection, pregnancy, systemic lupus erythematosus, or uremia

• Prior excessive or unusual bleeding or transfusions

• Family history of excessive bleeding

Medication and drug history should be reviewed, particularly use of heparin, warfarin, P2Y12 inhibitors, direct oral inhibitors of thrombin or factor Xa (eg, apixaban, edoxaban, rivaroxaban), aspirin, and NSAIDs. Patients who are taking (eg, apixaban, edoxaban, rivaroxaban), aspirin, and NSAIDs. Patients who are takingwarfarin also should be questioned about intake of other medications, drugs, toxins, and foods (including rodent poison and herbal supplements) that impair the metabolism of warfarin or suppress platelet function or vitamin K–dependent coagulation factor synthesis and thus increase the risk of bleeding complications.

Physical examination

Vital signs and general appearance can indicate hypovolemia (tachycardia, hypotension, pallor, diaphoresis) or infection (fever, tachycardia, hypotension with sepsis).

The skin and mucous membranes (nose, mouth, vagina) are examined for petechiae, purpura, and telangiectasias.

Gastrointestinal bleeding can often be identified by digital rectal examination with fecal occult blood testing.

Signs of bleeding in deeper tissues may include tenderness during movement and local swelling, muscle hematomas, and, for intracranial bleeding, confusion, stiff neck, focal neurologic abnormalities, or a combination of these findings.

Characteristic findings of chronic excessive alcohol use or liver disease are telangiectases, ascites, splenomegaly (secondary to portal hypertension), and jaundice.

Red flags

The following findings are of particular concern:

• Signs of hypovolemia or hemorrhagic shock

• Pregnancy or recent delivery

• Signs of infection or sepsis

Interpretation of findings

Bleeding in a patient taking warfarin is especially likely if there has been a recent increase in dose or the addition of a medication or food that may interfere with warfarin inactivation.

Telangiectasias on the face, lips, oral or nasal mucosa, and tips of the fingers and toes in a patient with a positive family history of excessive bleeding is likely to indicate hereditary hemorrhagic telangiectasia.

Bleeding from superficial sites, including skin and mucous membranes, suggests a quantitative or qualitative defect in platelets or a defect in blood vessels (eg, amyloidosis, vitamin C deficiency).

Bleeding into deep tissues (eg, hemarthroses, muscle hematomas, retroperitoneal hemorrhage) suggests a defect in coagulation (coagulopathy).

A family history of excessive bleeding suggests an inherited coagulopathy (eg, hemophilia), a qualitative platelet disorder, a type of von Willebrand disease (VWD), or hereditary hemorrhagic telangiectasia. Absence of a known family history does not, however, unequivocally exclude an inherited disorder of hemostasis.

Bleeding in a patient who is pregnant or has recently delivered, who is in shock, or who has a serious infection suggests disseminated intravascular coagulation (DIC).

Bloody diarrhea and thrombocytopenia in a patient with fever and gastrointestinal symptoms suggest the hemolytic-uremic syndrome (HUS), which is often associated with infection by Escherichia coli O157:H7 (or other Shiga-like toxin-producing type of E. coli ).

In a child, a palpable, purpuric rash on the extensor surfaces of the extremities suggests immunoglobulin A–associated vasculitis, particularly if accompanied by fever, polyarthralgia, or gastrointestinal symptoms.

Patients with known alcohol use disorder or liver disease may have coagulopathy, splenomegaly, or thrombocytopenia.

Patients with a history of use of IV illicit drugs or unprotected sexual exposure may have an HIV infection.

Testing

Most patients require laboratory evaluation (see table Laboratory Tests of Hemostasis by Phase). The initial tests are:

• Complete blood count (CBC) with platelet count

• Peripheral blood smear

• Prothrombin time (PT) and activated partial thromboplastin time (aPTT)

Screening tests evaluate the components of hemostasis, including the number of circulating platelets and the plasma coagulation pathways (see figure Pathways in Blood Coagulation). The most common screening tests for bleeding disorders are the platelet count, PT, and aPTT. If results are abnormal, more specific coagulation tests can usually pinpoint the defect. Determination of the level of fibrin degradation products measures in vivo activation of fibrinolysis (usually secondary to excessive coagulation in DIC).

Prothrombin time (PT) screens for abnormalities in the extrinsic and common pathways of coagulation (plasma factors VII, X, V, prothrombin [II], and fibrinogen). The PT is reported as the international normalized ratio (INR), which reflects the ratio of the patient’s PT to the laboratory’s control value; the INR controls for differences in reagents among different laboratories. Because commercial reagents and instrumentation vary widely, each laboratory determines its own normal range for PT and aPTT; a typical normal range for the PT is between 10 and 13 seconds. An INR > 1.5 or a PT ≥ 3 seconds longer than a laboratory’s normal control value is usually abnormal and requires further evaluation. The PT is valuable in screening for abnormal coagulation in various acquired conditions (eg, vitamin K deficiency, liver disease, DIC). The INR is used to monitor therapy with the oral vitamin K antagonist, warfarin.

Activated partial thromboplastin time (aPTT) screens plasma for abnormalities in factors of the intrinsic and common pathways (prekallikrein; high molecular weight kininogen; factors XII, XI, X, IX, VIII, and V; prothrombin [II]; fibrinogen). The aPTT tests for deficiencies of all clotting factors except factor VII (measured by the PT) and factor XIII (measured by a factor XIII assay). A typical normal range is 28 to 34 seconds. A normal result indicates that at least 30% of all coagulation factors in the pathway are present in the tested plasma. Heparin prolongs the aPTT, and the aPTT is often used to monitor heparin therapy. Inhibitors that prolong the aPTT include an autoantibody against factor VIII (see also Hemophilia and Coagulation Disorders Caused by Circulating Anticoagulants) and the lupus anticoagulant. The latter is an antibody against protein-phospholipid complexes that is found in the plasma of patients with systemic lupus erythematosus and other autoimmune disorders and is a marker for a thrombotic state (see also Thrombotic Disorders).

Prolongation of PT or aPTT may reflect:

• Clotting factor deficiency

• Presence of an inhibitor of a component of the coagulation pathway (including the presence in the circulation of a direct oral anticoagulant inhibiting thrombin or factor Xa)

The PT and aPTT do not become prolonged until one or more of the clotting factors tested are approximately 70% deficient. For determining whether prolongation reflects a deficiency of one or more clotting factor or the presence of an inhibitor, the test is repeated after mixing the patient’s plasma with normal plasma in a 1:1 ratio. Because this mixture contains at least 50% of normal levels of all coagulation factors, failure of the mixture to correct the prolongation almost completely suggests the presence of an inhibitor in patient plasma.

The bleeding time test is not sufficiently reproducible to be reliable for clinical decision-making.

Normal results on initial tests exclude many bleeding disorders. The main exceptions are VWD, platelet disorders, and hereditary hemorrhagic telangiectasia. VWD is a common entity in which the associated modest deficiency of factor VIII is frequently insufficient to prolong the aPTT. Patients who have normal initial test results, along with symptoms or signs of bleeding and a positive family history, should be tested for VWD by measuring plasma von Willebrand factor (VWF) antigen; VWF function as measured by the GP1BM assay; VWF collagen binding activity; or the less sensitive ristocetin cofactor assay. Platelet function disorders can be investigated using platelet aggregometry, which tests platelet responses to different platelet stimulatory chemicals (agonists). Platelet aggregometry is only available in specialized coagulation laboratories.

Bernard-Soulier syndrome is an inherited platelet function disorder characterized by deficiency or dysfunction of the glycoprotein Ib/IX/V complex (the von Willebrand receptor) on platelets. Patients with Bernard-Soulier syndrome have large platelets and moderate thrombocytopenia. They typically have moderate to severe bleeding manifestations (menorrhagia, gastrointestinal bleeding).

Glanzmann thrombasthenia is an inherited disorder of glycoprotein IIb/IIIa (the fibrinogen receptor on platelets) which results in moderate to severe bleeding. Platelet count and size are normal. Platelet storage pool disorders are characterized by deficiencies of platelet alpha or delta granules which contain adhesive proteins (eg, fibrinogen, von Willebrand factor) or platelet activators (eg, ATP, ADP, serotonin). These patients typically have a mild to moderate bleeding tendency.Glanzmann thrombasthenia is an inherited disorder of glycoprotein IIb/IIIa (the fibrinogen receptor on platelets) which results in moderate to severe bleeding. Platelet count and size are normal. Platelet storage pool disorders are characterized by deficiencies of platelet alpha or delta granules which contain adhesive proteins (eg, fibrinogen, von Willebrand factor) or platelet activators (eg, ATP, ADP, serotonin). These patients typically have a mild to moderate bleeding tendency.

If thrombocytopenia is present, the peripheral blood smear often suggests the cause (see table Peripheral Blood Findings in Thrombocytopenic Disorders). If the smear shows no evidence of other abnormalities, patients should be tested for HIV infection. If the result of the HIV test is negative and the patient is not pregnant and has not taken a medication known to cause platelet destruction, then immune thrombocytopenia is likely. If there are signs of hemolysis (fragmented red blood cells on smear, decreasing hemoglobin level), DIC, thrombotic thrombocytopenic purpura (TTP), or hemolytic uremic syndrome (HUS) should be suspected, although other hemolytic disorders can sometimes cause these findings. HUS occurs in patients with hemorrhagic colitis. The Coombs test is negative in TTP and HUS. If the CBC and peripheral blood smear demonstrate other cytopenias or abnormal white blood cells, a hematologic abnormality affecting multiple cell types should be suspected, and a bone marrow aspiration and biopsy are necessary for diagnosis.

Prolonged aPTT with normal platelets and PT suggests hemophilia A or B. Factor VIII, IX, and XI assays are indicated. Inhibitors that specifically prolong the aPTT include an autoantibody against factor VIII and antibodies against protein-phospholipid complexes (lupus anticoagulant). Clinicians suspect one of these inhibitors when a prolonged aPTT does not correct after 1:1 mixing with normal plasma.

Prolonged PT with normal platelets and aPTT suggests factor VII deficiency. Congenital factor VII deficiency is rare; however, the short half-life of factor VII in plasma causes factor VII to decrease to low levels more rapidly than other vitamin K–dependent coagulation factors in patients beginning warfarin anticoagulation or in patients with early vitamin K deficiency or incipient liver disease.

Prolonged PT and aPTT with thrombocytopenia suggest DIC, especially in association with obstetric complications, sepsis, cancer, or shock. Confirmation is by finding elevated levels of D-dimers (or fibrin degradation products) and decreasing plasma fibrinogen levels on serial testing. Cirrhosis can result in a prolonged PT and aPTT and thrombocytopenia because hepatocytes produce all the coagulation factors (except factor VIII) and thrombopoietin, the primary platelet growth factor.

Prolonged PT or aPTT with a normal platelet count occurs with liver disease or vitamin K deficiency or during anticoagulation with warfarin, unfractionated heparin, or the direct oral anticoagulants that inhibit or during anticoagulation with warfarin, unfractionated heparin, or the direct oral anticoagulants that inhibitthrombin or factor Xa. Liver disease is suspected based on history and is confirmed by finding elevations of serum aminotransferases and bilirubin; hepatitis testing is recommended.

Imaging tests are often required to detect occult bleeding in patients with bleeding disorders. For example, CT of the head should be performed in patients with severe headaches, head injuries, or impairment of consciousness. Abdominal CT is needed in patients with abdominal pain or other findings compatible with intraperitoneal or retroperitoneal hemorrhage.