Hospital Medicine

Bleeding

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I. Problem/Condition.

Bleeding that develops spontaneously, without associated surgery or injury, should be considered pathological. In addition, in postoperative or traumatic settings, bleeding that is prolonged, unusually severe, or delayed in onset suggests a possible underlying hemostatic disorder.

A. What is the differential diagnosis for this problem?

Bleeding is most often the result of a localized pathological process. See separate topic discussions for approaches to the diagnosis and management of intracranial hemorrhage (subarachnoid and intracerebral hemorrhage, subdural hematoma, epidural hematoma), epistaxis, upper and lower gastrointestinal (GI) bleeding, hemoptysis, diffuse alveolar hemorrhage, hematuria, and gynecological sources of bleeding.

Bleeding associated with localized pathological processes may be exacerbated by disorders of the hemostatic process, or spontaneous bleeding can develop in their presence. These disorders may relate to thrombocytopenia or platelet dysfunction, clotting factor deficiency or consumption, or hypo- or dysfibrinogenemia. Abnormalities of blood vessel wall integrity can also cause or contribute to bleeding.

Platelet disorders

Thrombocytopenia will be addressed in more detail in another topic review. Very briefly, low platelets can be found in the setting of decreased production, increased destruction or sequestration from splenomegaly. Spontaneous bleeding is very rare outside of severe thrombocytopenia (less than 20,000 cells/microliter(uL); usually less than 10,000/uL), which is seen most commonly in immune or drug-induced thrombocytopenia, or in acute presentations of leukemia or following cytotoxic chemotherapy. Milder thrombocytopenia (less than 50-75,000 cells/uL) of any cause can contribute to excessive bleeding provoked by trauma or menses.

Platelet numbers may be normal but their function impaired. Most commonly, platelet dysfunction is an acquired problem, related to drugs, uremia or liver disease. Platelet inhibition is a therapeutic aim with the use of aspirin, clopidogrel (and other thienopyridines) and the glycoprotein IIb/IIa (GPIIb/IIIa) receptor antagonists, and indeed increased bleeding risk has been noted with all.

Non-aspirin non-steroidal anti-inflammatory drugs like ibuprofen and naproxen also reversibly inhibit cyclooxygenase 1 (COX-1) but appear to have little clinical platelet inhibitory effect; while they do increase risk for gastrointestinal (GI) bleeding this appears due to gastric and duodenal mucosal injury.

Von Willebrand disease (VWD), the most common inherited bleeding disorder, presents most often as a disorder of platelet adherence/plug formation, manifested by minor bleeding. There are many other heritable causes of platelet dysfunction, each rare. Of these rare disorders, Bernard-Soulier syndrome, gray platelet syndrome, Wiskott-Aldrich syndrome, and Glanzmann thrombasthenia have higher prevalence than others.

Coagulation factor disorders

Coagulation factor deficiencies, which can be complicated by bleeding issues, may be due to underproduction, consumption, or direct inhibition by autoantibodies or medications. The most common cause of underproduction is the therapeutic (or supratherapeutic) use of vitamin K antagonists like warfarin, which will reduce synthesis of vitamin-K-dependent coagulation proteins. Vitamin K may also become deficient from malnutrition or malabsorption, and factor production can also decline in the setting of liver disease.

Hemophilia A and B, the classic X-linked inherited bleeding disorders, result from genetic mutations leading to severe underproduction of factors VIII and IX, respectively. Patients can also bleed from acquired clotting factor deficiencies due to consumptive processes like disseminated intravascular coagulation (DIC) or due to autoantibody formation, most commonly directed at factors V or VIII.

The use of novel oral anticoagulants (NOACs) including direct thrombin inhibitors and factor Xa inhibitors will continue to increase the prevalence of acquired coagulation factor disorders involving the final few steps of the coagulation cascade.

Disorders of fibrinogen and fibrinolysis

Disorders of fibrinogen are rare but are another potential cause of hemorrhage. Hypo- or dysfibrinogenemias can be congenital or acquired. Liver disease and DIC are by far the most common causes of fibrinogen abnormalities. Abnormalities of the fibrinolytic system, also quite rare, may be associated with increased bleeding risk as well.

Abnormal vascular integrity

Lastly, vascular integrity may be compromised in a number of settings, resulting in bleeding even in the presence of normal coagulation and platelet-mediated primary hemostasis. Vascular abnormalities may be the primary manifestation of disease, as in hereditary hemorrhagic telangiectasia (also known as Osler-Weber-Rendu syndrome), or one of the multiple manifestations of a connective tissue disease, such as Ehlers-Danlos disease, which is heritable, or acquired states like scurvy and steroid-induced purpura.

Vasculitides and amyloidosis, primary or secondary, may also lead to a vascular-mediated bleeding diathesis.

B. Describe a diagnostic approach/method to the patient with this problem

History and exam are the most important elements of the diagnostic evaluation. Often, the diagnosis will be readily evident, and laboratory testing can be targeted to confirm initial suspicions. A step-wise approach to laboratory testing will yield a diagnosis in most other cases.

1. Historical information important in the diagnosis of this problem.

  • Where is the bleeding focused (superficial cutaneous/mucosal pattern, including GI/genitourinary (GU) bleeding; versus deep tissue/hemarthrotic pattern)?

    Platelet disorders tend to present with cutaneous and mucosal bleeding, while bleeding in the setting of coagulation defects most often takes the form of larger ecchymoses that spread to deeper tissues. Hemarthrosis suggests hemophilia or another severe inherited coagulation defect.

  • Was the current bleeding event spontaneous or provoked? What were the specific circumstances?

    Spontaneous bleeding suggests a more severe underlying defect. Multisystem illness, in particular critical illness, should prompt consideration of DIC or thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS).

  • Was bleeding immediate or delayed?

    While either platelet or coagulation disorders can lead to immediate bleeding, delayed hemorrhage after a trauma or procedure (i.e. resumption of bleeding several hours after initial cessation) suggests a coagulation defect.

  • Have there been prior bleeding problems, including substantial bleeding after minor injuries or easy bruising? When were they first noted? Were there any bleeding complications surrounding past surgeries, childbirths, tooth extractions, or other major traumas?

    If a patient has had such procedures or traumas, without excessive bleeding, s/he is very unlikely to have an inherited bleeding disorder. If bleeding issues were noted since childhood, this increases the likelihood of a heritable condition.

  • What background medical issues does the patient have? Give special attention to the presence of liver disease, advanced renal disease, pregnancy, and malnutrition/malabsorption. Any history of iron deficiency anemia?

    Liver disease is associated with multiple hemostasis abnormalities, including both reduced clotting factor production and increased consumption, both thrombocytopenia and platelet dysfunction, and increased fibrinolysis.

    Be aware, however, that most bleeding in the setting of liver disease is due to localized pathological processes (e.g. varices, ulcers). Because the liver also synthesizes natural anticoagulants like protein C, protein S and antithrombin, liver patients are also at increased risk for thrombosis (e.g. deep vein thrombosis, portal vein thrombosis).

    Uremia will cause platelet dysfunction. In pregnant women who hemorrhage, consider HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), fatty liver of pregnancy with accompanying liver failure, or TTP/HUS. Malnutrition or malabsorption can lead to vitamin K deficiency and associated coagulopathy. Iron deficiency anemia suggests prior occult bleeding and perhaps a longer-standing process.

  • What medications is the patient prescribed? Are any new/recently changed? Any over the counter medications or herbal treatments?

    Rarely, drugs can induce idiosyncratic reactions including severe thrombocytopenia, aplastic anemia, and vascular purpura. Much more commonly, antiplatelet and anticoagulant medications used purposefully to reduce the risk of venous or arterial thromboembolism contribute to bleeding events. The risk of bleeding rises considerably in the setting of dual and, in particular, triple antithrombotic therapy used for treatment of cardiovascular disease (major bleeding rate ~5-10% per year with triple therapy).

    Importantly, many drugs also interact with warfarin, by a variety of mechanisms, and can potentiate its effect. Pay particular heed to antibiotics (fluoroquinolones, macrolides, metronidazole, tetracyclines, trimethoprim-sulfamethoxazole, cephalosporins), azole antifungal agents, antiarrhythmics (amiodarone, propafenone), cholesterol-lowering agents, glucocorticoids, omeprazole, cimetidine, and selective serotonin reuptake inhibitors (SSRIs).

    While drug interactions are less frequent with NOACs, concomitant use of P-glycoprotein and CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, dronaderone, human immunodeficiency virus protease inhibitors) can increase bleeding risk.

  • Is there a family history of a bleeding tendency?

    This of course increases the odds of an inherited hemorrhagic disorder, though even hemophiliacs will often have no family history of the disorder.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

  • Vital signs, including orthostatic measurements, to estimate acuity and significance of blood/volume loss.

  • Skin/muscular exam.

    • Are there petechiae? Their presence suggests a platelet disorder or vasculitis. They will typically be found in dependent areas (most dense at ankles/feet), with sparing of the soles of the feet. Thrombocytopenic petechiae will not be palpable, whereas vasculitic petechiae will be. Distinguish telangiectasias (more common on face, lips, tongue, buccal mucosa, fingertips, and dorsal hand) and angiomata (blanching, present on the face and trunk).

    • Are there ecchymoses? There will typically be multiple, blue-purple areas, without spread to deeper soft tissues in the case of a platelet disorder, but with potentially deeper hematoma in coagulopathies.

  • Mucosal exam:

    Evaluate nasal and oral cavities for gingival bleeding, petechiae and purpura. This suggests a platelet disorder. Mucosal hemorrhagic bullae ("wet purpura") may herald life-threatening bleeding.

  • Joint exam:

    Is there evidence of joint effusion/inflammation or destructive arthritis? Again, hemarthrosis suggests a severe heritable coagulation defect like hemophilia.

3. Laboratory tests that are likely to be useful in diagnosing the cause of this problem.

  • Prothrombin time and internationalized normalized ratio (PT/INR):

    This test will be abnormal in a disorder involving the extrinsic or common coagulation pathways.

  • Activated partial thromboplastin time (aPTT):

    aPTT will be prolonged in a disorder involving the intrinsic or common coagulation pathways. It is less sensitive than PT to common pathway abnormalities.

  • Platelet count:

    A value below 50,000 cells/uL is highly suggestive of thrombocytopenia as a cause of or contributor to bleeding. The peripheral smear should be reviewed to ensure there is no evidence of pseudothrombocytopenia.

  • Peripheral smear:

    The smear should be examined to exclude pseudothrombocytopenia, but also to look for platelet morphology or clumping pattern abnormalities that might suggest the presence of a congenital platelet function disorder.

  • Bleeding time (BT):

    An examination of the natural process of hemostasis, BT is generally considered as a diagnostic test for platelet disorders. While it will often be prolonged in the setting of thrombocytopenia or platelet dysfunction, including in VWD, it is operator dependent, and therefore poorly reproducible, and fairly insensitive. It is also non-specific, as it may be abnormal in patients with disorders of vascular integrity or of fibrinogen. For these reasons, BT is used infrequently.

  • Platelet function analyzer testing (PFA-100):

    This measures the closure time, or decrease in flow rate, as a hemostatic plug is formed in a membrane within a capillary tube. An abnormal closure time suggests platelet dysfunction, potentially including VWD. It is thought to be a more sensitive test for VWD than BT. The result will also be affected by anemia and thrombocytopenia but will remain normal in the setting of coagulopathies or vascular dysfunction.

  • Platelet aggregometry:

    There are several different tests available that measure platelet aggregation upon addition of agonists to a sample. These can help detect platelet defects and are used in some centers to monitor platelet inhibition by drugs like aspirin, clopidogrel and GPIIb/IIIa receptor antagonists.

  • Fibrinogen:

    This can be measured functionally or immunologically; measurements will be low in the setting of fibrinogen deficiency or consumption but can be discordant by the two methods in some of the inherited fibrinogen disorders. Fibrinogen level will be normal in dysfibrinogenemias.

  • Thrombin time (TT) and reptilase time (RT):

    These measure the rate of fibrin clot formation following exposure of plasma to thrombin or reptilase. They will be prolonged in the setting of fibrinogen disorders, including hypo- or dysfibrinogenemia. TT, but not RT, will be abnormal in the presence of heparin. TT will be abnormal in the presence of dabigatran.

  • Other tests include individual factor assays, mixing studies to evaluate for clotting factor inhibitors, von Willebrand Factor (VWF) antigen assay, ristocetin cofactor activity, fibrin split products, and euglobulin clot lysis time.

PT/INR, aPTT and platelet count are the highest yield tests, and evaluation should start with these. Patients whose diagnosis is not evident from history and exam can be stratified into diagnostic categories based first on coagulation times.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

As outlined above, history and exam combined with targeted laboratory evaluation can usually confirm a diagnosis in the setting of bleeding. Below we present the coagulation profile patterns commonly encountered and describe a process to move from identifying these patterns to confirming the correct diagnosis. The diagnoses fall into four major categories: platelet disorders, coagulation disorders, fibrinogen/fibrinolytic disorders, and abnormalities of vascular integrity.

Normal prothrombin time, internationalized normalized ratio and activated partial thromboplastin time

This pattern suggests a disorder of platelets, including VWD, or of fibrinolysis or vascular integrity. Factor XIII deficiency, a rare entity, can also present with normal aPTT and PT/INR.

  • Low platelets will confirm thrombocytopenia, the most common etiology, after the clinical pattern of bleeding is identified (superficial cutaneous and mucosal petechiae and ecchymoses). A platelet count more than 50,000/uL is unlikely to lead to bleeding, and other causes should be sought.

  • If the platelet count is normal, PFA-100 testing can be used to assess for platelet dysfunction or VWD. History (antiplatelet medication use, symptoms of uremia) will often suggest a source of platelet dysfunction. BT is not sensitive for VWD, so a normal value does not exclude it. Consider VWF antigen immunoassay, ristocetin cofactor activity and factor VIII level testing to evaluate further for VWD. Abnormal platelet morphology suggests the presence of several of the inherited disorders of platelet function.

  • If NOAC use is suspected, normal aPTT makes significant levels of dabigatran unlikely, and normal PT/INR essentially excludes measurable levels of rivaroxaban or edoxaban. However, TT (for dabigatran) and anti-Xa activity (for the direct Xa inhibitors) are more sensitive tests in this setting. Of note, PT/INR and aPTT may remain normal despite therapeutic or supratherapeutic apixaban levels, so anti-Xa activity, calibrated to apixaban, must be tested if its use is suspected.

  • Bleeding time may be prolonged in the setting of abnormalities of vascular integrity, but these diagnoses are made primarily by the pattern of mucocutaneous bleeding combined with other disease specific manifestations. These conditions include connective tissue disorders, vasculitides, amyloidosis, and scurvy.

Normal prothrombin time and internationalized normalized ratio and prolonged activated partial thromboplastin time

This pattern suggests a disorder of the intrinsic pathway, most often hemophilia, VWD or exposure to heparin, dabigatran, or edoxaban. Acquired inhibitors to factors VIII, IX, XI, or XII can also present this way, as can a lupus inhibitor, but the latter does not present with bleeding.

  • A 50:50 mixing study can distinguish factor deficiency from inhibition.

  • Early onset of bleeding problems or a family history of bleeding can provide a clue to congenital coagulation factor deficiencies like the hemophilias, and individual factor assays can confirm the diagnosis of inherited or acquired specific factor deficiencies.

  • VWD is often accompanied by factor VIII deficiency, so additional VWD testing (as described above) may be indicated in patients with isolated aPTT prolongation.

  • A prolonged TT supports measurable dabigatran levels, and increased anti-Xa activity suggests significant rivaroxaban, apixaban, or edoxaban levels.

Prolonged prothrombin time and internationalized normalized ratio and normal activated partial thromboplastin time

This pattern suggests a disorder of the extrinsic pathway, most often from liver disease, vitamin K deficiency, warfarin or rivaroxaban exposure, or factor VII deficiency. Factor VII inhibitors are quite rare.

  • Correction of PT/INR on repeat testing following vitamin K administration can diagnose vitamin K deficiency.

  • Factor VII deficiency can be confirmed with a factor VII assay.

  • A 50:50 mixing study can help to assess for an inhibitor.

  • Elevated anti-Xa activity levels can help confirm ongoing significant rivaroxaban drug levels.

Prolonged prothrombin time, internationalized normalized ratio and activated partial thromboplastin time

This pattern suggests a common pathway disorder, including deficiency or inhibitors of prothrombin, fibrinogen or factors V or X; advanced liver disease; DIC; supratherapeutic warfarin or heparin dosing; NOAC or combined anticoagulant use; or combined factor deficiencies/inhibitors.

  • Fibrinogen concentration and TT or RT can be checked to assess for fibrinogen/fibrinolytic disorders. Fibrinogen levels will be low in hypofibrinogenic and hyperfibrinolytic states, but not in dysfibrinogenemias. TT will be prolonged in fibrinogen disorders.

  • A normal or elevated factor VIII assay suggests liver disease, since it is not vitamin K dependent or produced in the liver. A low level is more suggestive of DIC.

  • Low platelets and low or low-normal fibrinogen plus elevated fibrin degradation products will often be found in DIC.

  • Specific factor assays are available to evaluate for deficient prothrombin or factor V or X.

  • 50:50 mixing studies can help to assess for the presence of inhibitor(s).

  • In the setting of NOAC use, prolonged TT supports measurable dabigatran levels, and increased anti-Xa activity suggests significant rivaroxaban, apixaban, or edoxaban levels.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Bleeding time in assessing for platelet dysfunction has largely been replaced by PFA-100 testing.

A. Management of bleeding.

For specific treatment recommendations of individual bleeding disorders, see separate topic reviews.

General approach to the treatment of significant active bleeding

  • Attempt local control of bleeding site(s).

  • Observe hemodynamic status and airway safety closely.

  • Check basic hemostasis lab tests: hematocrit, platelet count, PT/INR, aPTT, and fibrinogen. Expand testing based on recommendations above.

  • Transfuse blood products as appropriate. Some suggested guidelines for use:

    • Packed red blood cells (PRBCs): 340 milliliters (mL), hematocrit (hct) 60-70%

      • Generally indicated in the setting of ongoing severe bleeding, regardless of the hematocrit (hct), or hct <21%.

      • A higher PRBC transfusion threshold (hct 24-30%) may be indicated in the context of active/recent myocardial ischemia.

      • Each unit of PRBCs raises hct by ~3%.

    • Platelets (plts):

      • If plts <50,000 cells/uL, give one unit of single donor platelet pheresis product (preferred) or 5-6 units of pooled platelet concentrates; either will increase platelets by approximately 30,000 cells/uL in a patient who is not platelet-refractory.

      • Platelets may not be fully functional until 4 hours after transfusion.

      • Consider checking a 15 minute post-transfusion platelet count; an increment of less than 10,000 platelets/uL suggests alloimmunization. If a patient has HLA antibodies, HLA-matched platetlets can be transfused, or in rare cases continuous platelet transfusions can be given.

      • If the platelet count responds initially but declines at 24 hours, this suggests consumption from sepsis, disseminated intravascular coagulation (DIC), or drug effect.

      • Platelet transfusion in TTP may worsen the disease.

    • Fresh frozen plasma (FFP): derived from one unit of whole blood; ~225 mL

      • Contains all coagulation factors

      • Consider giving 2-4 units of FFP if INR is > 2.0 and/or aPPT is >1.3 times the control value.

      • Most useful in the setting of documented coagulation defects (factor V or XI deficiency, DIC), warfarin use, or massive transfusion.

      • In the setting of liver disease and variceal bleeding, FFP is generally ineffective and may be harmful (increases portal pressures, which can increase rebleeding; precipitates anasarca; and exposes patients to transfusion-related acute lung injury or cardiogenic pulmonary edema)

    • Cryoprecipitate: derived from 1 unit of FFP thawed at 4°Celsius

      • Contains ~150 mL fibrinogen, 80 units of factor VIII, and von Willebrand factor

      • Consider giving 10 units of cryoprecipitate if fibrinogen is <125 mg/dL, or as a source of fibrinogen in the setting of DIC or massive transfusion

      • May be used in von Willebrand disease or haemophilia but is not a first choice product for either

  • If the patient is receiving antithrombotic medications, stop the drug(s) and, in the setting of major hemorrhage and recent drug administration, consider attempting to reverse as indicated for each of the following agents:

    • Antiplatelet agents

      • Aspirin

        • Desmopressin, 0.3 microgram/kilogram (mcg/kg) IV x 1

        • Platelet transfusion, 1 pheresis unit

      • Platelet P2Y12 receptor blockers (clopidogrel, prasugrel, ticagrelor)

        • Desmopressin, 0.3 mcg/kg IV x 1

        • Platelet transfusion, 2 pheresis units

      • Gp IIb/IIIa inhibitors (abciximab, tirofiban, eptifibatide)

        • Platelet transfusion, 2 pheresis units

        • Desmopressin, 0.3 mcg/kg IV x 1 – not helpful for abciximab

        • Cryoprecipitate, 10 units – not helpful for abciximab

    • Anticoagulant agents

      • Warfarin

        • Vitamin K, 5-10 mg intravenous (IV) or oral

        • FFP, 10-15 mL/kg

        • Prothrombin complex concentrates (PCC), 1500-2000 units - consider in life-threatening bleeding (e.g., intracranial haemorrhage)

        • Recombinant factor VIIa (rVIIa) - consider in life-threatening bleeding (e.g., intracranial haemorrhage)

      • Heparin/low molecular weight heparin (LMWH)

        • Protamine (discuss dosing with a pharmacist)

      • Fondaparinux

        • PCC or rVIIa

    • Novel oral anticoagulants - discuss with Hematology and/or Blood Bank

      • Dabigatran

        • Removal of excess drug through hemodialysis and/or oral activated charcoal (if last dose taken within 2 hours)

        • Antifibrinolytic therapy (e.g., tranexamic acid)

        • Specific antidote: idarucizumab

        • Activated PCC (e.g., FEIBA) - consider in life-threatening bleeding if idarucizumab is not available

        • In development: universal small molecule antidote (PER977)

      • Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban)

        • Removal of excess drug using oral activated charcoal (if last dose taken within 2-8 hours)

        • Antifibrinolytic therapy (e.g., tranexamic acid)

        • PCC - consider in life-threatening bleeding

        • In development: specific antidote (andexanet alpha), universal small molecule antidote (PER977)

Recommendations for prophylactic correction of platelet/coagulation abnormalities in the non-bleeding patient

  • Low risk, prevention of spontaneous bleeding

    • Platelets:

      • Transfuse if platelets <10,000 cells/uL in hospitalized patients with therapy-induced hypoproliferative thrombocytopenia

    • Coagulation abnormalities:

      • Consider vitamin K 1-5 mg oral for INR >4.5

  • Minor procedures

    • Platelets:

      • Unclear benefit, limited evidence

      • Many will transfuse if platelets <20,000 cells/uL for elective central venous catheter placement or <50,000 cells/uL for diagnostic lumbar puncture

    • Coagulation abnormalities:

      • Unclear benefit, limited evidence

      • Many minor procedures (e.g., dental procedures, cutaneous procedures, cardiac device implantation in some centers) are now being performed safely through therapeutic anticoagulation

      • Some practitioners continue to prefer FFP transfusion to bring INR <1.5 and aPTT <1.5 x control (though this often is not possible, in particular in the setting of liver disease)

  • Intermediate-risk procedures

    • Platelets: transfuse if platelets <50,000 cells/uL

    • Coagulation abnormalities:

      • Unclear benefit, limited evidence

      • Many minor procedures (e.g., dental procedures, are now being performed safely through therapeutic anticoagulation)

      • Some practitioners continue to prefer FFP transfusion to bring INR <1.5 and aPTT <1.5 x control (though this often is not possible, in particular in the setting of liver disease)

  • High-risk procedures (e.g., neurosurgery, spinal anesthesia)

    • Platelets: transfuse if platelets <50-100,000 cells/uL

    • Coagulation abnormalities:

      • Unclear benefit, limited evidence

      • PCC or FFP are often used to attempt to correct INR to <1.5 and aPTT to <1.3 x control (though this may not be possible, in particular in the setting of liver disease)

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

N/A

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