Chapter 233: Acquired Bleeding Disorders

Normal regulation of bleeding is a complex process involving platelets and the coagulation system (see chapter 232, "Tests of Hemostasis"). Platelet defects typically manifest with petechiae and mucosal bleeding, whereas coagulation defects usually present as spontaneous or excessive hemorrhage. Management of significant acquired bleeding disorders should be discussed with a hematologist because there are often subtleties in diagnosis and treatment.

Circulating platelets provide the initial defense against bleeding. Acquired platelet disorders may be quantitative (decreased number of circulating platelets) or qualitative (poorly functioning platelets). Both significant thrombocytopenia and qualitative platelet dysfunction are commonly manifested by the presence of nonpalpable petechiae, often most pronounced in the lower extremities and in areas where blood flow is restricted. Other typical findings may include purpura, mucosal bleeding (gingival, epistaxis), menorrhagia, hemoptysis, hematuria, and hematochezia, whereas deep tissue bleeding and hemarthrosis are less common.

Securing circulatory stability is the primary treatment priority in the bleeding patient. Once this is done, the history, physical examination, and directed laboratory testing are used to define the clinical syndrome. Recent illness, symptoms, and medications are potentially relevant in the patient who appears to have a platelet disorder. Physical examination should assess for additional bleeding sites and the type of bleeding. Assess for lymphadenopathy, splenomegaly, pallor, or jaundice that suggests diagnoses such as leukemia, lymphoma, systemic lupus erythematosus, infectious mononucleosis, or hemolytic anemia.

THROMBOCYTOPENIA

Quantitative defects that result in thrombocytopenia are caused by decreased production, increased destruction, splenic sequestration, platelet loss, or a combination (Table 233-1).¹ The etiologies of thrombocytopenia are diverse, and the pathologic mechanism is not always initially clear. Viral infections may impair thrombopoiesis due to direct infection of the megakaryocyte, toxic effects of viral proteins or cytokines, hemophagocytosis, or production of antibodies that bind to platelets and enhance immune destruction.² A drug history is important, because many medications have been implicated in causing thrombocytopenia or impairing platelet function (Table 233-2).^3,4

A CBC will establish the presence and degree of thrombocytopenia and determine whether other hematologic cell lines are affected. A peripheral smear should be examined to assess platelet morphology and evaluate other cell lines. Rarely, in vitro platelet agglutination occurs, which leads to spuriously low platelet counts reported by automated cell counters (pseudothrombocytopenia) when collected in ethylenediaminetetraacetic acid–coated blood tubes; this can be detected by the presence of platelet clumping on a peripheral smear. In this case, a correct platelet count may be obtained by using citrated or heparin-anticoagulated blood tubes.

Testing for human immunodeficiency virus and hepatitis C virus is recommended in cases of isolated thrombocytopenia, as low platelets may be the only readily apparent manifestation in early infections.⁵ If the etiology of low platelets remains unclear, further laboratory testing to evaluate for disorders such as hemolysis and disseminated intravascular coagulation (DIC) may be needed. Although usually not necessary in instances of isolated thrombocytopenia, bone marrow biopsy may be obtained when malignancy or other bone marrow pathologies are of concern.

When circulating platelet levels decrease to below 10,000 to 20,000/mm³ (10 to 20 × 10⁹/L), the risk of spontaneous bleeding becomes concerning, particularly for intracranial hemorrhage. Additional risk factors for bleeding include age, comorbid illness (i.e, renal disease, liver disease, connective tissue disease, peptic ulcer disease, hypertension), fall risk, and lifestyle activity. With the exception of a few specific disease processes, platelet transfusion in the nonbleeding patient should be considered when counts fall below 10,000/mm³ (10 ×10⁹/L), or higher if other comorbid illnesses are present.⁶ The cause of the platelet deficiency may also influence the risk of bleeding. At a given platelet level, patients with immune thrombocytopenia (ITP) typically bleed less than patients with aplastic anemia, as the younger platelets present in ITP are more effective in hemostasis.⁷

Immune Causes of Thrombocytopenia

ITP is an acquired immune-mediated disorder in which circulating platelets typically fall to very low levels.^3,8 ITP results from antiplatelet antibodies that attack platelet surface glycoproteins such as glycoprotein IIb/IIIa, leading to peripheral platelet destruction. There is evidence that the same antibodies lead to impaired platelet production by megakaryocytes.⁹ Despite very low platelet counts, the circulating platelets are not functionally impaired.

Immune thrombocytopenia may be classified as primary (formerly known as idiopathic thrombocytopenic purpura) or secondary when associated with other medical conditions (autoimmune disorders, infections) or drug exposures.⁸ This distinction is of clinical importance, as management of the underlying disorder or discontinuation of the drug in cases of secondary ITP may lead to normalization of the platelet count.

Primary ITP may occur at any age, with equal prevalence between genders, with the exception of those age 30 to 60 years, in which women predominate. Primary ITP is classified by duration of illness: newly diagnosed (diagnosis to 3 months), persistent (3 months to 12 months), and chronic (>12 months).⁸ The majority of adults with primary ITP progress to chronic illness.

The most common presenting sign of ITP is a petechial rash (Figure 233-1A). Mild epistaxis, gingival bleeding (Figure 233-1B), and menorrhagia in women of childbearing age may also be seen. Except for petechiae and bruising, the patient should have a normal physical examination.

The CBC should demonstrate normal cell lines except for the platelets. A mild anemia may be seen if bleeding is present. The peripheral smear should show large, well-granulated platelets, although they will be few in number. Bone marrow biopsy is not indicated unless clinical features are atypical. If the evaluation supports the diagnosis of primary ITP, then additional testing in the ED is not required.

Treatment for ITP is initiated based on the risk of bleeding (Table 233-3). Major bleeding complications in patients with platelets >50,000 /mm³ (>50 × 10⁹/L) are uncommon. As most fatal bleeding complications occur when platelet counts fall below 30,000/mm³ (30 × 10⁹/L), experts and guidelines recommend this level as the threshold for initiating treatment of ITP in adults.^5,6,9,10,11 Bleeding risk correlates with lower platelet counts and patient age greater than 60, a prior history of bleeding, certain chronic illnesses, and use of medications that alter hemostasis all heighten this risk. Therefore, certain patients may benefit from medical treatment despite a platelet count exceeding 30,000/mm³ (30 × 10⁹/L). For all patients with primary ITP, bleeding risk should be minimized, including avoiding use of antiplatelet medications when possible, maintenance of good blood pressure control, optimized treatment of exacerbating comorbid conditions (i.e., liver disease, renal disease), and addressing fall risks.

About two thirds of children with primary ITP will have spontaneous resolution within 6 months of diagnosis.¹¹ An antecedent viral infection is commonly reported. Additionally, the measles-mumps-rubella vaccination has been associated with the development of acute ITP, although this is rare and occurs in less than 1 per 25,000 doses given.¹² The risk of severe bleeding complications appears to be rare in children, regardless of their absolute platelet count.^5,8,13 Children without signs of active bleeding and good psychosocial support typically do not require hospitalization or medical treatment. Good anticipatory guidance should be provided to the family, and the child should abstain from contact sports or activities that might place them at risk for head injury.

First-line treatment for primary ITP generally includes corticosteroids, typically prednisone 1 milligram/kg per day for 4 weeks (shorter courses may be considered for children).^5,9,10,11,13 Initial response may not be seen for 4 to 14 days, and peak effect can be expected between 7 and 28 days. IV immunoglobulin may also be considered, either alone or in combination with corticosteroids, at a dose 1 g/kg/per day for 3 days. Initial response to IV immunoglobulin is more rapid than corticosteroids, occurring between 1 and 3 days, with peak effect seen between 2 and 7 days. Side effects of IV immunoglobulin may include aseptic meningitis, transient neutropenia, acute kidney injury, and transfusion reactions/hypotension.

Anti-Rho(D) immunoglobulin at 50 to 75 micrograms/kg for a single dose may also be considered as a first-line treatment strategy in patients who are Rh(D) positive and have not undergone splenectomy.¹⁴ Initial response rate and peak effect are similar to that seen with IV immunoglobulin. Mild hemolysis can be expected, and rare serious or even fatal cases of intravascular hemolysis, DIC, and renal failure have been reported with anti-Rho(D) use, prompting the U.S. Food and Drug Administration to administer a warning pertaining to its use in 2010. Second-line treatment modalities include splenectomy and use of newer agents, such as the monoclonal antibody rituximab, which blunts the autoimmune destruction of platelets, and thrombopoietin receptor agonists, which stimulate platelet production (i.e., romiplostin, eltrombopag).

In the event of life-threatening hemorrhage where hemostasis must be achieved rapidly, IV corticosteroids (such as dexamethasone) and IV immunoglobulin should be administered concomitantly.¹³ Platelet transfusions should be initiated, and doses two to three times the typical dose might be required due to persistent autoimmune destruction.⁶ Platelet transfusions may need to be repeated frequently until bleeding subsides or targeted treatment modalities take effect. Emergent splenectomy may be considered if all other treatment options are exhausted.

Drug-Induced Immune Thrombocytopenia

Over 200 drugs have been implicated in causing immune-mediated suppression of platelet production or increased platelet destruction (Table 233-2).^3,4 The clinical presentation is similar to ITP, and the thrombocytopenia may severe. Drug-induced thrombocytopenia typically occurs 5 to 14 days following initiation of a drug, but may occur sooner if there has been recent prior exposure. A careful history should not only include prescribed medications, but also herbal remedies and food and beverage use (i.e., quinine in tonic water, alcohol use, tahini). Chronic alcohol use is a common cause of thrombocytopenia. Platelet counts typically normalize with cessation of the causative agent. Heparin-induced thrombocytopenia causes a significant drop in platelets, but patients are paradoxically hypercoagulable due to platelet activation (see chapter 239, "Thrombotics and Antithrombotics").

Nonimmune Causes of Thrombocytopenia

Thrombocytopenia may occur from various non–immune-mediated causes (Table 233-1). In thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, thrombotic microangiopathy occurs when vessel injury results in deposition of platelet-fibrin thrombi (see chapters 143 "Oncologic and Hematologic Emergencies in Children" and 237, "Acquired Hemolytic Anemia"). DIC is also a well-described cause of platelet destruction. In patients with marked hemorrhage, large-volume fluid resuscitation may lead to a dilutional thrombocytopenia. Additionally, certain bacterial, rickettsial, and viral infections can cause direct toxic destruction of platelets. Thrombocytopenia specific to pregnancy may be a result of the hemolysis–elevated liver enzymes–low platelets (HELLP) syndrome, pre-eclampsia, or gestational thrombocytopenia (see chapter 100, "Maternal Emergencies after 20 Weeks of Pregnancy and in the Postpartum Period"). Finally, an enlarged spleen can sequester a significant portion of the platelet pool.

Thrombocytopenia is present in up to 70% of patients with chronic liver disease.¹⁵ The etiology appears multifactorial. Patients often have underlying medical conditions related to their liver disease such as alcohol use, viral hepatitis, or nutritional deficiencies that impair platelet production. Thrombopoietin, which is produced by hepatocytes, may be decreased. Portal hypertension may lead to splenic sequestration. Endotoxemia from infection may promote platelet aggregation. Some patients also demonstrate platelet autoantibodies. The degree of quantitative thrombocytopenia may be mitigated by an increased level of circulating von Willebrand factor that is typically seen, which promotes platelet adhesion. For this reason, routine platelet transfusion is not recommended in the absence of clinically significant bleeding. However, a platelet count of >50,000/mm³ (>50 × 10⁹/L) should be achieved prior to invasive procedures (i.e., lumbar puncture, surgery, liver biopsy).¹⁶

FUNCTIONAL PLATELET DISORDERS

Several disease processes can cause acquired qualitative or functional abnormalities of platelets (Table 233-4).¹⁷ In the myeloproliferative diseases, platelets are often dysfunctional, even if the platelet count is normal or elevated. Patients can have prolonged bleeding times and clinically significant bleeding. To control acute bleeding, transfusion should be considered to raise the level of normal platelets to 50,000/mm³ (50 × 10⁹/L). In macroglobulinemia and related disorders, the elevated level of viscous proteins interferes with platelet function. Patients with clinically significant bleeding may require plasmapheresis to reduce the protein level and correct hemostatic function.

Many drugs can influence platelet function (Table 233-2 and Table 233-5). Of these, the most commonly used are aspirin, which produces an irreversible impairment in platelet aggregation, and the nonsteroidal anti-inflammatory drugs, clopidogrel and ticlopidine, which produce temporary impairment in platelet adhesion and aggregation (see chapter 239).

Thrombocytosis, a platelet count exceeding 500,000/mm³ (500 × 10⁹/L), can be seen in many disorders including inflammatory reactions, malignancy, polycythemia, and postsplenectomy. Platelet function can be normal or abnormal depending on the underlying condition. Therefore, thrombocytosis can be associated with bleeding (mucosal, ecchymotic, GI) or thromboembolic (deep venous thrombosis, portal or mesenteric thrombosis, splenic vein thrombosis) manifestations. However, these events are unusual, even with platelet counts in excess of 1,000,000/mm³ (1000 × 10⁹/L).

Acquired coagulation disorders can result from underlying medical disease and autoimmune factor inhibitors.

LIVER DISEASE

Acute and chronic liver disease is commonly associated with laboratory tests of impaired coagulation. Hepatocytes synthesize all of the coagulation factors and related regulatory proteins, with the exception of factor VIII and von Willebrand factor. Diseases affecting the hepatic parenchyma may result in a decreased synthesis of these factors, including the vitamin K–dependent carboxylation of factors II (prothrombin), VII, IX, and X. Because vitamin K is a fat-soluble vitamin, malabsorption can occur with processes that interfere with the absorption of fat-soluble vitamins, including impaired bile acid metabolism (i.e., primary biliary cirrhosis), intrahepatic or extrahepatic cholestasis, and treatment with bile acid binders. Thus, prolonged prothrombin time is common in patients with decompensated hepatic function. Despite marked prolongations of prothrombin time and activated partial thromboplastin time (PTT) seen in advanced liver disease and cirrhosis, these tests poorly predict onset and severity of bleeding, including bleeding from esophageal varices or invasive procedures or surgery.^16,18,19,20 Although there may be marked reduction in procoagulant proteins in liver disease, there is typically a parallel decrease in the endogenous anticoagulant proteins such as protein C and antithrombin. Therefore, primary hemostasis may be relatively maintained. In fact, patients with liver disease may be susceptible to both increased bleeding and thrombosis. Patients with liver disease and cirrhosis are twice as likely to develop unprovoked deep venous thrombosis and have a relatively high incidence of portal venous thrombosis.²¹

In the actively bleeding patient with liver disease, attention to volume and circulatory status is paramount. Transfusion of packed red blood cells should be used to maintain an adequate hemoglobin and hemodynamic stability. Fresh frozen plasma transfusions or platelets should be transfused if significant hemorrhage (e.g., from esophageal varices) is associated with a coagulopathy or thrombocytopenia with a platelet count below 60,000/mm³ (60 × 10⁹/L).¹⁶ Plasma transfusions should be used cautiously because they may incite thrombosis and expand intravascular volume, exacerbating portal hypertension and increasing the severity of variceal bleeding. There is no evidence that recombinant activated factor VII or four-factor prothrombin complex concentrate (Kcentra^®) provides benefit.²² The benefit of vitamin K in these patients has also been called into question, and its routine use is not substantiated.^22,23

Primary prevention of bleeding in patients with liver disease should focus on medical optimization of their risk factors, rather than treatment of abnormal tests of coagulation or thrombocytopenia.^16,18 These include management and prevention of portal hypertension, treatment of esophageal varices, management of primary causes for liver disease (i.e., alcohol use, hepatitis C), optimization of renal function, and management and prevention of sepsis/infection.

RENAL DISEASE

Patients with renal disease frequently manifest disorders of hemostasis. Early renal impairment has been associated with a tendency for thrombosis relating to increased production of procoagulant factors as well as decreased formation of tissue plasminogen activator.²⁴ In advanced renal disease, bleeding complications are of particular concern due to qualitative platelet dysfunction from decreased ability to adhere to damaged endothelium and aggregate. Patients with chronic kidney disease are at increased risk for minor bleeding (mucosal and cutaneous) and major bleeding (intracerebral and GI hemorrhage). Serum prothrombin time, activated PTT, and platelet counts are often normal, although bleeding time will usually be prolonged. Abnormalities in platelet function can be due to direct effects of uremic toxins and impaired drug elimination. Anemia itself has been associated with platelet dysfunction. Thrombocytopenia can occur from dialysis, and the heparin used may also potentiate bleeding.

Desmopressin is the most common agent used to correct bleeding in patients with uremic platelet dysfunction, producing an increase in serum von Willebrand factor and enhancing the platelet's ability to aggregate.²⁵ The dose is 0.3 milligram/kg SC or IV, with a rapid onset and duration of action lasting at least 4 hours. Side effects are generally mild and include headache, flushing, minor hypotension, tachycardia, nausea, abdominal cramps, and local site reaction. Other strategies that improve platelet function include the use of cryoprecipitate, conjugated estrogens, erythropoietin to improve anemia, and hemodialysis to remove toxins.²⁴ Platelet transfusions alone are generally ineffective because the infused platelets quickly acquire the platelet defect. Cryoprecipitate and platelet transfusions should be reserved for life-threatening bleeding and should be used in combination with packed red blood cells, desmopressin, and conjugated estrogens.

DISSEMINATED INTRAVASCULAR COAGULATION

DIC is an acquired syndrome characterized by inappropriate and widespread activation of the coagulation system resulting in intravascular thrombin generation, small vessel thrombosis, and consumption of clotting factors and platelets.²⁶ Concomitant activation of the fibrinolytic system also occurs, resulting in the breakdown of fibrin clots and subsequent bleeding. DIC is associated with a wide variety of precipitating disorders (Table 233-6).

Pathogenesis

Although the diseases triggering DIC are diverse, the common pathway of these illnesses is that they lead to an inappropriate loss of localization or compensated control in the intravascular activation of coagulation (Figure 233-2). Immune, inflammatory, and coagulant pathways are involved. Damaged endothelial cell walls trigger activation of the intrinsic clotting cascade, leading to thrombin generation and subsequent intravascular fibrin clot deposition. Increased thrombin generation leads to consumption of anticoagulant regulatory proteins (i.e., protein C, protein S, and antithrombin), further potentiating thrombosis and ischemic tissue damage. Production of thrombin and fibrin indirectly activates tissue plasminogen activator and the counterregulatory fibrinolytic system. When hyperfibrinolysis occurs, the hemostatic clots dissolve and bleeding ensues.

Clinical Features

Clinical features of DIC vary with the underlying precipitating illness.²⁷ Hypercoagulation may predominate in certain conditions such as sepsis, where signs of ischemic end-organ failure are common, and physical findings in these patients may include cutaneous gangrene or thrombotic purpura. In other instances such as DIC associated with leukemia, hyperfibrinolysis may predominate and clinical features may include petechiae, ecchymoses, oozing from catheter or venipuncture sites, or hematuria. Certain DIC-related disorders such as trauma and obstetric complications tend to have both strong hypercoagulation and hyperfibrinolysis elements and lead to major bleeding complications (i.e., wounds, intracranial, GI). Yet other conditions may be associated with mild and compensated DIC in which outward signs of thrombosis and bleeding are subclinical.

Laboratory Findings

The typical laboratory results in acute DIC (Table 233-7) include thrombocytopenia, prolonged prothrombin time, low fibrinogen level, and elevation of fibrin-related markers (i.e., d-dimer, fibrin degradation products, soluble fibrin). The most commonly observed abnormality is thrombocytopenia; a progressive drop in the platelet count is sensitive, although not specific, for DIC. Depletion of coagulation factors is reflected by a prolonged prothrombin time. Fibrinogen is an acute-phase reactant and may be normal or elevated in early DIC. Scoring systems have been developed and validated to aid in the diagnosis (Table 233-8).^28,29

Differential Diagnosis

Primary fibrinolysis is a rare syndrome whereby plasmin and fibrinolysis occur without the production of thrombin. Severe liver disease will also manifest with coagulation abnormalities and low platelets. These two entities can be differentiated from DIC based on clinical history and laboratory tests. The hematologic abnormalities in liver disease should be relatively stable in contrast to the worsening abnormalities associated with acute DIC. Additionally, the d-dimer assay will usually be normal or minimally elevated in both primary fibrinolysis and liver disease, but is often significantly elevated in DIC.

Treatment

Paramount to the management of DIC is the elimination of the underlying disorder whenever possible. Treatment strategies in DIC include blood product support and strategies to modulate thrombin formation (Table 233-9).^26,27,29 Generally speaking, blood products should only be administered when there is evidence of bleeding.

Platelet transfusions are recommended in actively bleeding patients who have platelet counts below 50,000/mm³ (50 × 10⁹/L) and may be considered in those considered to be at high risk for bleeding (such as DIC resulting from chemotherapy) when platelet counts fall below 10,000 to 20,000/mm³ (10 to 20 × 10⁹/L). Plasma should be administered in bleeding patients when prothrombin time/activated PTT exceeds 1.5 times normal or when fibrinogen levels fall below 150 milligrams/dL (1.5 grams/L). The initial recommended dose is 15 mL/kg, although there is some evidence that 30 mL/kg may be superior when volume overload is not of concern. Fibrinogen concentrate should be considered when hypofibrinogenemia persists despite use of plasma. Patients with a prolonged prothrombin time should receive parenteral vitamin K.

There is no proven benefit in DIC with other coagulation factor products, such as three- or four-factor prothrombin complex concentrate or recombinant factor VIIa. Although there is no evidence demonstrating improved outcomes, low-molecular-weight heparin may be considered in patients with DIC where thrombotic complications predominate the clinical picture or in patients with evidence of early compensated DIC.²⁹ Patients with DIC are at very high risk for developing venous thromboembolism, and routine prophylaxis with low-molecular-weight heparin, in the absence of major bleeding, is recommended. Antifibrinolytic medications (i.e., tranexamic acid) should generally be avoided in patients with DIC. One notable exception is in trauma-related DIC, where their use reduces mortality.³⁰

CIRCULATING INHIBITORS OF COAGULATION

Acquired inhibitors of blood coagulation, also known as circulating anticoagulants, are antibodies directed against one or more of the coagulation factors. Although inhibitors may develop spontaneously in previously healthy patients with normal hemostasis, most inhibitors develop in patients with hereditary bleeding disorders who receive transfusion of plasma products. Inhibitors have been described for most of the coagulation factors; the two most common inhibitors are factor VIII inhibitors and antiphospholipid antibodies. Factor VIII inhibitors are "specific" inhibitors, directed only against factor VIII, as opposed to antiphospholipid antibodies, including lupus anticoagulant and anticardiolipin antibodies, which are "nonspecific" inhibitors directed against several of the coagulation factors. Lupus anticoagulant and anticardiolipin antibodies often result in thrombosis (see chapter 234, "Clotting Disorders").

Factor VIII Inhibitors

Factor VIII inhibitors most commonly develop in patients with hemophilia A (see chapter 235, "Hemophilias and von Willebrand's Disease"), but can also develop spontaneously in patients with previously normal hemostasis, a condition termed acquired hemophilia.^31,32 The incidence of spontaneously arising inhibitors is rare—estimated at 1.4 cases per 1 million persons per year. Although uncommon, it is important to recognize this clinical entity because the mortality rate approaches 22%. The majority of acquired hemophilia cases, approximately 85%, occur in the elderly. In about half of cases, inhibitors develop in association with preexisting disorders, such as autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis) and lymphoproliferative disorders (multiple myeloma, Waldenström's macroglobulinemia, benign monoclonal gammopathy of uncertain significance), and in patients with allergic drug reactions (penicillins, sulfonamides, phenytoin).

Patients without a prior bleeding history who develop factor VIII inhibitors can present with massive spontaneous ecchymoses, hematomas, and hematuria. Laboratory studies classically show a normal prothrombin time, normal thrombin clotting time, and a greatly prolonged activated PTT that does not correct with mixing. A factor VIII–specific assay will show very low or absent factor VIII activity. Other factor-specific assays should be normal or only slightly decreased. Quantitative measurement of the inhibitor by the Bethesda inhibitor assay is important for the emergency management of bleeding episodes. Long-term management of acquired factor VIII inhibitors is with steroids, IV immunoglobulin, cytotoxic agents, or rituximab to suppress antibody production. A hematologist should direct the management of an acute, clinically significant bleeding episode.

There is no proven therapy to control bleeding episodes in patients with acquired factor VIII inhibitors.³³ Treatment options include administration of factor VIII, three- or four-factor prothrombin complex, recombinant factor VIIa, desmopressin acetate, and plasmapheresis. Additionally, the use of aspirin, nonsteroidal anti-inflammatory drugs, and intramuscular injections should be avoided and conservative therapies should be considered, including compression and immobilization of the bleeding site.^31,32