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Excessive Bleeding

by Joel L. Moake, MD

Unusual or excessive bleeding may be indicated by several different signs and symptoms. Patients may present with unexplained nosebleeds (epistaxis), excessive or prolonged menstrual blood flow (menorrhagia), or prolonged bleeding after minor cuts, tooth brushing or flossing, or trauma. Other patients may have unexplained skin lesions, including petechiae (small intradermal or mucosal hemorrhages), purpura (areas of mucosal or skin hemorrhage larger than petechiae), ecchymoses (bruises), or telangiectasias (dilated small vessels visible on skin or mucosa). Some critically ill patients may suddenly bleed from vascular punctures or skin lesions and have severe hemorrhage from these sites or from the GI or GU tract. In some patients, the first sign is a laboratory test abnormality suggesting the susceptibility to excessive bleeding that is found incidentally.

Etiology

Excessive bleeding can result from several mechanisms (see Some Causes of Excessive Bleeding), including the following:

  • Platelet disorders

  • Coagulation disorders

  • Defects in blood vessels

Platelet disorders may involve an abnormal number of platelets (typically too few platelets, although an extremely elevated platelet count may be associated either with thrombosis or with excessive bleeding), defective platelet function, or both. Coagulation disorders may be acquired or hereditary.

Overall, the most common causes of excessive bleeding include

  • Severe thrombocytopenia

  • Excessive anticoagulation with warfarin or heparin

  • Liver disease (inadequate production of coagulation factors)

Some Causes of Excessive Bleeding

Category

Examples

Platelet disorders

Decreased number of platelets (quantitative disorder)

Inadequate production (eg, in leukemias, aplastic anemia, and some myelodysplastic syndromes)

Splenic sequestration (eg, in cirrhosis with congestive splenomegaly)

Increased platelet destruction or consumption (eg, in idiopathic thrombocytopenic purpura, DIC, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, sepsis, and HIV infection)

Drug-induced destruction (eg, by heparin , quinidine, quinine, sulfonamides, sulfonylureas, rifampin, or gold salts)

Increased number of platelets (quantitative disorder)

Essential thrombocythemia (thrombosis may be more common than bleeding)

Inadequate platelet function (qualitative disorder)

Von Willebrand’s disease (inadequate VWF-mediated platelet adhesion)

Drug-induced dysfunction (eg, by aspirin or NSAIDs)

Systemic disorders (uremia; occasionally, myeloproliferative or myelodysplastic syndromes, multiple myeloma)

Coagulation disorders

Acquired

Vitamin K deficiency

Liver disease

Anticoagulation with warfarin or heparin

DIC

Hereditary

Hemophilia A (factor VIII deficiency)

Hemophilia B (factor IX deficiency)

Vascular disorders

Acquired

Vitamin C deficiency

Henoch-Schönlein purpura

Hereditary

Connective tissue disorders (eg, Ehlers-Danlos syndrome, osteogenesis imperfecta, Marfan syndrome)

Hereditary hemorrhagic telangiectasia

DIC = disseminated intravascular coagulation; VWF = von Willebrand’s factor.

Evaluation

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 factors.

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 (GI illness); joint pain (connective tissue disorders); and amenorrhea and morning sickness (pregnancy).

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

  • Severe infection, cancer, cirrhosis, HIV infection, pregnancy, SLE, or uremia

  • Prior excessive or unusual bleeding or transfusions

  • Family history of excessive bleeding

Drug history should be reviewed, particularly use of heparin , warfarin , aspirin, and NSAIDs. Patients also should be questioned about intake of drugs and foods (including herbal supplements) that decrease the metabolism of warfarin and thus increase its anticoagulant effect.


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. GI 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 alcohol abuse or liver disease are 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 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 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).

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’s disease (VWD), or hereditary hemorrhagic telangiectasia. Absence of a known family history does not, however, 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 child with fever and GI symptoms suggest the hemolytic-uremic syndrome (HUS), which is often associated with infection by Escherichia coli O157:H7.

In a child, a palpable, purpuric rash on the extensor surfaces of the extremities suggests Henoch-Schönlein purpura, particularly if accompanied by fever, polyarthralgia, or GI symptoms.

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

In patients with a history of IV drug abuse, HIV infection should be considered.


Testing

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

  • CBC with platelet count

  • Peripheral blood smear

  • PT and PTT

Screening tests evaluate the components of hemostasis, including the number of circulating platelets and the plasma coagulation pathways. 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.

Prothrombin time (PT) screens for abnormalities in the extrinsic and common pathways of coagulation (plasma factors VII, X, V, prothrombin, 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 sec. An INR > 1.5 or a PT 3 sec 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, 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; fibrinogen). The PTT tests for deficiencies of all clotting factors except factor VII (measured by the PT) and factor XIII. A typical normal range is 28 to 34 sec. A normal result indicates that at least 30% of all coagulation factors in the pathway are present in the 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 Hemophilia and see also Coagulation Disorders Caused by Circulating Anticoagulants) and antibodies against protein-phospholipid complexes (lupus anticoagulant—see also Thrombotic Disorders and see Coagulation Disorders Caused by Circulating Anticoagulants).

Prolongation of PT or PTT may reflect

  • Factor deficiency

  • Presence of an inhibitor of a component of the coagulation pathway

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 provides about 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 previously used bleeding time test is of doubtful reliability.

Laboratory Tests of Hemostasis by Phase

Test

Purpose

Formation of initial platelet plugs

Platelet count

Quantifies platelet number

Platelet aggregation

Evaluates adequacy of platelet responsiveness to physiologic stimuli that activate platelets (eg, collagen, ADP, arachidonic acid)

Detects abnormal patterns in hereditary or acquired platelet functional disorders

VWF antigen

Measures total concentration of plasma VWF protein

VWF multimer composition

Evaluates distribution of VWF multimers in plasma (eg, large multimers are missing in type 2 variants of VWD)

Ristocetin agglutination

Screens for large multimers of VWF in plasma (often done as part of routine laboratory evaluation for VWD—see Von Willebrand Disease : Diagnosis)

Ristocetin cofactor activity

Quantifies large multimers of VWF in plasma (see Von Willebrand Disease : Diagnosis)

Formation of fibrin

PT

Screens for the factors in extrinsic and common pathways (factors VII, X, and V; prothrombin; and fibrinogen)

PTT

Screens for the factors in intrinsic and common pathways (prekallikrein; high molecular weight kininogen; factors XII, XI, IX, VIII, X, and V; prothrombin; and fibrinogen)

Specific functional assays for coagulation factors

Determines activity of the specific coagulant factor tested as a percentage of normal

Thrombin time

Evaluates the last step of coagulation (thrombin cleavage of fibrinogen to fibrin)

Is prolonged by heparin activation of antithrombin and in conditions resulting in qualitative fibrinogen abnormalities or hypofibrinogenemia

Reptilase time

If it is normal and thrombin time is prolonged, provides presumptive evidence that a plasma sample contains heparin (eg, residual heparin after extracorporeal bypass or in a sample drawn from an IV line kept open with heparin flushes) because reptilase time is not affected by heparin activation of antithrombin

Fibrinogen level

Quantifies plasma fibrinogen, which is increased in acute phase reactions and decreased in severe liver disease and severe DIC

Fibrinolysis

Clot stability during 24-h incubation in saline and in 5M urea

Causes lysis of clots in saline if fibrinolytic activity is excessive or in 5M urea if factor XIII is deficient

Should be done in patients with defective wound healing or frequent miscarriages

Plasminogen activity

Quantifies plasma plasminogen, which is decreased in patients with congenital early-onset venous thromboembolism (rare)

α 2 -Antiplasmin

Quantifies plasma level of this fibrinolysis inhibitor, which is reduced in patients with excessive bleeding due to increased fibrinolysis (rare)

Serum fibrinogen andfibrin degradation products

Screens for DIC

Increased levels when plasmin has acted on fibrinogen or fibrin in vivo (eg, in DIC)

Superseded by plasma d -dimer assay

Plasma d -dimer

Is measured with a monoclonal antibody latex agglutination test or with an ELISA

If high, indicates that thrombin has been generated in vivo with resultant deposition of fibrin, activation of the cross-linking enzyme factor XIII, and secondary fibrinolysis

Has the practical advantage that it can be done on citrate-treated plasma and thus, unlike the test for serum fibrin degradation products, does not require blood clotting in a special tube to prepare serum free of residual fibrinogen

Is useful in the diagnosis of in vivo thrombosis (eg, deep venous thrombosis, pulmonary embolism), especially the sensitive ELISA version

ADP = adenosine diphosphate; DIC = disseminated intravascular coagulation; ELISA = enzyme-linked immunosorbent assay; VWD = von Willebrand’s disease; VWF = von Willebrand’s factor.

Normal results on initial tests exclude many bleeding disorders. The main exceptions are VWD and hereditary hemorrhagic telangiectasia. VWD 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 VWD by measuring plasma von Willebrand’s 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 Peripheral Blood Findings in Thrombocytopenic Disorders). If the smear is normal, patients should be tested for HIV. 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 idiopathic thrombocytopenic purpura is likely. If there are signs of hemolysis (fragmented RBCs on smear, decreasing Hb level), thrombotic thrombocytopenic purpura (TTP) or HUS is suspected, although sometimes other hemolytic disorders can cause these findings. HUS occurs in children with hemorrhagic colitis. The Coombs’ test is negative in TTP and HUS. If the CBC and peripheral blood smear demonstrate other cytopenias or abnormal WBCs, a hematologic abnormality affecting multiple cell types is suspected, and a bone marrow aspiration or biopsy is necessary for diagnosis.

Prolonged PTT with normal platelets and PT suggests hemophilia A or B. 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 (eg, in patients given warfarin anticoagulation or in patients with incipient liver disease).

Prolonged PT and PTT 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. Prolonged PT or PTT with normal platelet count occurs with liver disease or vitamin K deficiency or during anticoagulation with warfarin or unfractionated heparin. Liver disease is suspected based on history and is confirmed by finding elevation 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.


Treatment

Treatment is directed at the underlying disorder and at any hypovolemia. For immediate treatment of bleeding due to a coagulopathy that has not yet been diagnosed, fresh frozen plasma, which contains all coagulation factors, should be infused pending definitive evaluation.

Key Points

  • DIC should be suspected in patients with sepsis, shock, or complications of pregnancy or delivery.

  • Drug causes are common, particularly mild platelet dysfunction caused by aspirin or NSAIDs.

  • Easy bruising with no other clinical manifestations and normal laboratory test results is probably benign.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • RIFADIN, RIMACTANE
  • No US brand name
  • PANHEPRIN
  • COUMADIN
  • QUALAQUIN
  • ADENOCARD

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