Excessive Bleeding

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 drug exposure.

Review of systems should specifically query about bleeding from sites other than those volunteered (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 (connective tissue disorders); and amenorrhea plus morning sickness (pregnancy).

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

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 warfarin also should be questioned about intake of other drugs and foods (including herbal supplements) that impair the metabolism of warfarin and thus increase its anticoagulant effect.

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. 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 Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in North America), schistosomiasis (in endemic areas), or hepatic vascular abnormalities. Consequences... read more ), and jaundice.

The following findings are of particular concern:

Bleeding in a patient taking warfarin is especially likely if there has been a recent increase in dose or the addition of a drug 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 Hereditary Hemorrhagic Telangiectasia Hereditary hemorrhagic telangiectasia is a hereditary disorder of vascular malformation transmitted as an autosomal dominant trait affecting men and women. (See also Overview of Vascular Bleeding... read more .

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 Amyloidosis Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more ).

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 Hemophilia Hemophilias are common hereditary bleeding disorders caused by deficiencies of either clotting factor VIII or IX. The extent of factor deficiency determines the probability and severity of bleeding... read more ), a qualitative platelet disorder, a type of von Willebrand disease Von Willebrand Disease Von Willebrand disease (VWD) is a hereditary quantitative deficiency or functional abnormality of von Willebrand factor (VWF), which causes platelet dysfunction. Bleeding tendency is usually... read more (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 Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more (DIC).

Bloody diarrhea and thrombocytopenia in a patient with fever and gastrointestinal symptoms suggest the hemolytic-uremic syndrome Hemolytic-Uremic Syndrome (HUS) Hemolytic-uremic syndrome (HUS) is an acute, fulminant disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. HUS usually occurs in children... read more (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 Immunoglobulin A–Associated Vasculitis (IgAV) Immunoglobulin A–associated vasculitis (formerly called Henoch-Schönlein purpura) is vasculitis that affects primarily small vessels. It occurs most often in children. Common manifestations... read more , particularly if accompanied by fever, polyarthralgia, or gastrointestinal symptoms.

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

Patients with a history of IV drug abuse or unprotected sexual exposure may have HIV infection Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more .

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

Screening tests evaluate the components of hemostasis, including the number of circulating platelets and the plasma coagulation pathways (see figure Pathways in blood coagulation Pathways in Blood Coagulation ). The most common screening tests for bleeding disorders are the platelet count, PT, and PTT. If results are abnormal, a specific test 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 Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more ).

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 PTT; 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 INR is valuable in screening for abnormal coagulation in various acquired conditions (eg, vitamin K deficiency Vitamin K Deficiency Vitamin K deficiency results from extremely inadequate intake or fat malabsorption. Risk of bleeding is increased by use of coumarin anticoagulants. Deficiency is particularly common among breastfed... read more , liver disease, DIC). It is also used to monitor therapy with the oral vitamin K antagonist, warfarin.

Partial thromboplastin time (PTT) screens plasma for abnormalities in factors of the intrinsic and common pathways (prekallikrein; high molecular weight kininogen; factors XII, XI, IX, VIII, X, and V; prothrombin [II]; fibrinogen). The PTT 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 PTT, and the PTT is often used to monitor heparin therapy. Inhibitors that prolong the PTT include an autoantibody against factor VIII (see also Hemophilia Hemophilia Hemophilias are common hereditary bleeding disorders caused by deficiencies of either clotting factor VIII or IX. The extent of factor deficiency determines the probability and severity of bleeding... read more and Coagulation Disorders Caused by Circulating Anticoagulants Coagulation Disorders Caused by Circulating Anticoagulants Circulating anticoagulants are usually autoantibodies that neutralize specific clotting factors in vivo (eg, an autoantibody against factor VIII or factor V) or inhibit phospholipid-bound proteins... read more ) 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 Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more and other autoimmune disorders (see also Thrombotic Disorders Overview of Thrombotic Disorders In healthy people, homeostatic balance exists between procoagulant (clotting) forces and anticoagulant and fibrinolytic forces. Numerous genetic, acquired, and environmental factors can tip... read more ).

Prolongation of PT or PTT may reflect

The PT and PTT do not become prolonged until one or more of the clotting factors tested are about 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 almost completely the prolongation 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 Von Willebrand Disease Von Willebrand disease (VWD) is a hereditary quantitative deficiency or functional abnormality of von Willebrand factor (VWF), which causes platelet dysfunction. Bleeding tendency is usually... read more and hereditary hemorrhagic telangiectasia Hereditary Hemorrhagic Telangiectasia Hereditary hemorrhagic telangiectasia is a hereditary disorder of vascular malformation transmitted as an autosomal dominant trait affecting men and women. (See also Overview of Vascular Bleeding... read more . VWD is a common entity in which the associated modest 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 VWD by measuring plasma von Willebrand factor (VWF) antigen, ristocetin cofactor activity (an indirect test for large VWF multimers), VWF multimer pattern, and factor VIII levels.

If thrombocytopenia is present, the peripheral blood smear often suggests the cause (see table Peripheral Blood Findings in Thrombocytopenic Disorders Peripheral Blood Findings in Thrombocytopenic Disorders ). If the smear shows no evidence of other abnormalities, patients should be tested for HIV infection Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more . If the result of the HIV test is negative and the patient is not pregnant and has not taken a drug known to cause platelet destruction, then immune thrombocytopenia Immune Thrombocytopenia (ITP) Immune thrombocytopenia (ITP) is a bleeding disorder usually without anemia or leukopenia. Typically, it is chronic in adults, but it is usually acute and self-limited in children. Spleen size... read more is likely. If there are signs of hemolysis (fragmented red blood cells on smear, decreasing hemoglobin level), DIC Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more , thrombotic thrombocytopenic purpura Thrombotic Thrombocytopenic Purpura (TTP) Thrombotic thrombocytopenic purpura (TTP) is an acute, fulminant disorder characterized by thrombocytopenia and microangiopathic hemolytic anemia. Other manifestations may include alterations... read more (TTP) or hemolytic uremic syndrome Hemolytic-Uremic Syndrome (HUS) Hemolytic-uremic syndrome (HUS) is an acute, fulminant disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. HUS usually occurs in children... read more (HUS) should be suspected, although sometimes other hemolytic disorders can cause these findings. HUS occurs in patients with hemorrhagic colitis. The Coombs test Indirect Antiglobulin (Indirect 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 PTT with normal platelets and PT suggests hemophilia A or B Hemophilia Hemophilias are common hereditary bleeding disorders caused by deficiencies of either clotting factor VIII or IX. The extent of factor deficiency determines the probability and severity of bleeding... read more . 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.

Prolonged PT with normal platelets and PTT 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 incipient liver disease. Major sites of coagulation protein production include endothelial cells, including those lining liver sinusoids. Liver sinusoidal endothelial cells are often damaged in various liver disorders.

Prolonged PT and PTT with thrombocytopenia suggest DIC Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more , especially in association with obstetric complications, sepsis Sepsis and Septic Shock Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection. In septic shock, there is critical reduction in tissue perfusion; acute failure... read more , cancer, or shock Shock Shock is a state of organ hypoperfusion with resultant cellular dysfunction and death. Mechanisms may involve decreased circulating volume, decreased cardiac output, and vasodilation, sometimes... read more . Confirmation is by finding elevated levels of D-dimers (or fibrin degradation products) and decreasing plasma fibrinogen levels on serial testing.

Prolonged PT or PTT with a normal platelet count occurs with liver disease or vitamin K deficiency Vitamin K Deficiency Vitamin K deficiency results from extremely inadequate intake or fat malabsorption. Risk of bleeding is increased by use of coumarin anticoagulants. Deficiency is particularly common among breastfed... read more or during anticoagulation with warfarin, unfractionated heparin, or the direct oral anticoagulants that inhibit thrombin 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, head CT should be done 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.