Most bleeding seen in the emergency department is due to trauma, the result of local wounds, lacerations, or other structural lesions that occur in patients with normal hemostasis. Conversely, bleeding from multiple sites, bleeding from untraumatized sites, delayed bleeding several hours after trauma, and bleeding into deep tissues or joints suggest the possibility of a bleeding disorder. Historical data for the presence of a congenital bleeding disorder include the presence or absence of unusual or abnormal bleeding in the patient and other family members and the possible occurrence of excessive bleeding after dental extractions, surgical procedures, or trauma. Many patients with abnormal bleeding have an acquired disorder, commonly due to liver disease or drug use (particularly ethanol, aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs], warfarin, and antibiotics).

The site of bleeding may provide an indication of the hemostatic abnormality. Mucocutaneous bleeding, including petechiae, ecchymoses, epistaxis, or gastrointestinal, genitourinary, or heavy menstrual bleeding, is characteristic of qualitative or quantitative platelet disorders. Purpura is often associated with thrombocytopenia and commonly indicates a systemic illness. Bleeding into joints and potential spaces, such as between fascial planes and into the retroperitoneum, as well as delayed bleeding, is most commonly associated with coagulation factor deficiencies. Patients who demonstrate both mucocutaneous bleeding and bleeding in deep spaces may have disorders such as disseminated intravascular coagulation (DIC), in which both platelet abnormalities and coagulation factor abnormalities are present. Basic hemostatic tests and clinical evaluation are generally adequate for diagnosis (Table 41–1). Additional hemostatic studies are ordered as indicated (Table 41–2).

Disorders of Decreased Platelet Production

Neonatal infections, such as cytomegalovirus (CMV) or rubella, may cause isolated thrombocytopenia. Many medications impair platelet production and produce thrombocytopenia (Table 41–3). Chronic alcohol use is a common cause of thrombocytopenia and will generally resolve if the patient abstains from drinking for longer than 7 days. If multiple cell lines are affected, the differential diagnosis includes aplastic anemia, marrow infiltration from lymphoma or leukemia, or myelofibrosis. Usually, the history and physical examination determines the most likely source of thrombocytopenia; however, bone marrow biopsy is sometimes needed.

Immune Thrombocytopenia

Antibody-mediated platelet destruction can be related to medications, infections, or autoimmune diseases. Two of the more common antibody-mediated thrombocytopenic disorders are idiopathic thrombocytopenic purpura (ITP) and drug-induced immune thrombocytopenia.

Idiopathic Thrombocytopenic Purpura

General Considerations

Idiopathic thrombocytopenic purpura is an acquired autoimmune disease characterized by thrombocytopenia, the presence of purpura or petechiae, normal bone marrow, and no other identifiable cause for the thrombocytopenia. Platelet destruction is mediated by the production of autoantibodies that attach to circulating platelets, and the antibody-coated platelets are removed by the reticuloendothelial system. The bone marrow usually responds by increasing platelet production, but sometimes the same antibodies that bind to the platelets also bind to the megakaryocytes, limiting the bone marrow response. Despite the presence of antibodies, the circulating platelets function properly, and many people with ITP may not have significant bleeding despite low platelet counts.

ITP occurs in all age groups and may have an acute or chronic course. Acute ITP is more common among younger children, affects males and females equally, and typically resolves within 6 months. Chronic ITP lasts more than 3 months, is more common in adults, and rarely remits spontaneously. Additionally, patients with chronic ITP are more likely to exhibit an underlying disease or autoimmune disorder, such as HIV infection, systemic lupus, Graves’ disease, Hashimoto’s thyroiditis, or antiphospholipid antibody syndrome.

Clinical Findings

The most common symptom of ITP is petechiae; mild bleeding may also be seen at mucosal surfaces, including epistaxis, gingival bleeding, and menorrhagia in women of childbearing age. The physical examination is otherwise normal. The presence of lymphadenopathy, hepatosplenomegaly, anemia, or hyperbilirubinemia should suggest an alternative diagnosis, such as leukemia, lymphoma, systemic lupus erythematosus, infectious mononucleosis, or hemolytic anemia. The complete blood count (CBC) should be normal in all cell lines except for the platelets. In some patients with bleeding, a mild anemia may be present. The peripheral blood smear should show large, well-granulated platelets that are few in number. The diagnosis of ITP is based primarily on the history, physical examination, CBC, and peripheral smear.

Treatment

Minimize bleeding risks in patients with ITP, for example, by avoiding the use of antiplatelet medications (eg, aspirin and NSAIDs), avoiding unnecessary invasive procedures, maintaining good blood pressure control, treating exacerbating comorbid conditions (eg, liver disease, renal disease), and addressing fall risks. Treatment of ITP depends on severity, comorbid conditions, and presence of bleeding.

Asymptomatic patients, who are otherwise healthy, with platelet counts greater than 50,000/μL require no treatment. Treatment is indicated for (1) nonbleeding patients with platelet counts less than 20,000/μL and (2) patients with bleeding or significant risk factors for bleeding and platelet counts less than 50,000/μL.

Initial therapy in adults is prednisone started at 60–100 mg/d (children, 1–2 mg/d) and tapered after the platelet count reaches normal (usually requires 4–8 weeks). For patients who do not respond to steroids, the main alternative therapy is splenectomy. For life-threatening bleeding, the current recommendation is high-dose steroid therapy (methylprednisolone 1–2 g/d intravenously for 2–3 days) with or without intravenous immunoglobulin. Additional research is being conducted using several days (4–8 days) of high dose dexamethasone (40 mg/d) in cycles separated by up to 28 days for up to 6 cycles with promising results. However, more study of this approach is needed before it can be recommended. Transfuse platelets as needed following the first dose of methylprednisolone or immunoglobulin; holding the platelet transfusion until the first dose of either is completed results in a better response. Conjugated estrogen, 25 mg intravenously one time, can be given for severe uterine bleeding.

Disposition

Hospitalization is required for ITP-related bleeding. It is generally not required for asymptomatic patients with platelet counts greater than 20,000/μL. At counts below 20,000/μL, hospitalization may not be required if patients are asymptomatic or have only mild purpura. Hospitalization is prudent when arranging patient follow-up is difficult, when compliance is in doubt, or when significant additional bleeding risk factors are present.

Drug-Induced Immune-Mediated Thrombocytopenia

Heparin is the drug most commonly associated with drug-induced immune-mediated thrombocytopenia. Platelet counts typically fall after the 5th day of therapy, even in heparin-naive patients, to usually to below 100,000/μL. Less than 10% of patients develop profound thrombocytopenia with counts less than 20,000/μL. Paradoxically, the complications from heparin-induced thrombocytopenia are usually thromboembolic (deep venous thrombosis, pulmonary embolism, stroke), the conditions heparin is used to treat. Immediate cessation of heparin therapy is indicated when the platelet count falls to below 100,000/μL or more than 50% from baseline. Substitute alternative agents (eg, danaparoid, hirudin, argatroban) for heparin. Although platelet transfusion in heparin-induced thrombocytopenia is typically considered contraindicated, recent data and clinical practice guidelines suggest that in patients with significant bleeding platelet transfusion may be both efficacious and safely performed. Avoid future exposure to either unfractionated heparin or the low-molecular-weight heparins.

The platelet glycoprotein IIb/IIIa receptor antagonists are associated with a 3–7% incidence of modest thrombocytopenia (platelet counts of 50,000–100,000/μL), typically occurring within the first 24 hours of treatment. Severe thrombocytopenia (below 20,000/μL) occurs in less than 1% of patients. Petechiae, wound hematomas, mucosal bleeding, and hematuria are the most common hemorrhage complications. Platelet counts return to normal within 2–3 days after drug discontinuation.

Other drugs rarely cause immune-mediated thrombocytopenia; the sulfonamide, penicillin, and cephalosporin antibiotics have been most commonly reported. In this circumstance, thrombocytopenia typically develops 7–10 days after start of the medications, platelet counts typically fall to below 20,000/μL, and the most common symptoms are petechiae and oral mucosal hemorrhagic blisters.

Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) involve platelet aggregation in the microvascular circulation via the mediation of von Willebrand factor (vWF). This leads to consumption thrombocytopenia and microangiopathic hemolytic anemia (MAHA) or schistocyte-forming hemolysis as red blood cells (RBCs) are fragmented during travel through these occluded arterioles and capillaries. TTP and HUS are clinical syndromes with characteristic features, but overlap between the syndromes makes differentiation sometimes difficult. TTP is traditionally more common in adults, whereas HUS is more common in children. TTP typically induces more prominent neurologic deficits with deposition of platelet aggregates in a broader, systemic distribution; HUS more specifically impairs the renal system. In general, adults presenting with clinical and laboratory evidence of MAHA accompanied by thrombocytopenia should receive treatment for TTP once other diagnoses have been excluded (eg, sepsis, metastatic cancer, systemic vasculitis, preeclampsia–eclampsia, Evans syndrome, heparin-induced thrombocytopenia with thrombosis, and malignant hypertension). Untreated TTP has an 80–90% mortality rate.

Pallor, jaundice or scleral icterus, fatigue, and dyspnea on exertion are common because of the hemolytic anemia. With significant thrombocytopenia, purpura or mucosal bleeding may be evident. Focal neurologic deficits (often vacillating), aphasia, seizure, coma, visual disturbance, chest pain, cardiac conduction disorders, abdominal pain, oliguria, and hypertension indicate end-organ involvement.

Thrombotic Thrombocytopenic Purpura

Clinical Findings

Symptoms and Signs

TTP classically comprises the following pentad of symptoms and signs: (1) thrombocytopenia, (2) MAHA, (3) fever, (4) renal impairment, and (5) neurologic impairment. It is uncommon for all five features to occur in any one patient, but if they are, severe end-organ ischemia or damage has likely taken place. In comatose patients with extensive brain abnormalities on MRI, resolution of imaging abnormalities and near-full neurologic recovery is possible. As a result, aggressive interventions should still be pursued. Thrombocytopenia and MAHA are the most common features, and fever is the least frequent finding.

A common feature of acquired TTP is the development of autoantibodies to a vWF-cleaving metalloprotease termed ADAMTS-13. Pregnancy is the most common precipitating event for TTP. Preeclampsia has some features similar to TTP, but TTP usually presents earlier during pregnancy, around 23–24 weeks. Delivery does not affect the course of TTP. Other triggers of TTP include infection (particularly HIV), vaccination, and autoimmune disorders such as systemic lupus erythematosus. Several drugs have been associated with TTP, including quinidine, cyclosporine, tacrolimus, and the antiplatelet agents ticlopidine and clopidogrel. A particularly refractory form of TTP has been seen in post-bone marrow transplant patients after treatment with the cancer chemotherapeutic agents mitomycin and gemcitabine.

Laboratory Findings

TTP is still a clinical diagnosis, but characteristic laboratory findings include severe anemia, thrombocytopenia, schistocytes or helmet cells on peripheral smear, decreased haptoglobin, elevated reticulocyte count, and elevated unconjugated (indirect) bilirubin from intravascular hemolysis. Additional study suggests that an under recognized cause of morbidity and mortality among patients with TTP is acute myocardial infarction. An LDH elevated above 1000 U/L and an initial troponin I greater than 0.2 ng/mL (troponin T is also used) are excellent predictors of poor outcome. The direct Coombs’ test (DAT) is characteristically negative, because the hemolysis seen in TTP does not involve anti-RBC autoantibodies. Because TTP thrombi do not involve fibrin, TTP is distinguished from DIC based on normal coagulation studies.

Treatment

Acquired TTP is treated with daily plasma exchange consisting of (1) plasmapheresis to remove large vWF multimers and autoantibodies and (2) plasma infusion to give the patient back one calculated daily volume of fresh frozen plasma (FFP) or cryoprecipitate-poor plasma (cryosupernatant). The advent of plasma exchange has decreased TTP mortality rates from 90% to 10–20%, and remains the mainstay of treatment. When TTP is suspected, plasma exchange should be initiated without delay for a final definitive diagnosis. If plasmapheresis cannot be performed immediately, initial FFP infusion should be started but infusion should never replace exchange. Plasma exchange is performed daily until several days after remission is achieved. Remission usually occurs within 1 week but may require up to 4 weeks. Remission is defined by normalization of the platelet count and lactate dehydrogenase (LDH) combined with clinical resolution of tissue ischemia and thrombosis. Corticosteroids (usually prednisone, 1–2 mg/kg/d) may be helpful in the presence of a high-autoantibody titer and if plasma exchange does not provide the desired response.

Supportive measures may be needed to address systemic complications associated with TTP, including RBC transfusion for anemia, anticonvulsants for seizures, antihypertensives for hypertension, and hemodialysis for severe renal insufficiency. The general recommendation regarding platelet transfusion is to avoid it unless life-threatening bleeding or intracranial hemorrhage is present since thrombosis may worsen acutely, leading to rapid renal failure and potentially death. While this remains a standard recommendation, recent evidence suggests the warning may be overstated. Aspirin can worsen hemorrhagic complications in the setting of severe thrombocytopenia and also should be avoided. Heparin is not beneficial in TTP. Relapse rates after appropriate treatment may be as high as 30%, and maintenance therapies have not been shown to prevent relapse.

Hemolytic Uremic Syndrome

Clinical Findings

HUS is a disease primarily of early childhood, with a peak incidence between ages 6 months and 4 years. The adult form of HUS may be very difficult to distinguish from TTP. The overall mortality rate is 5–15% with the prognosis being worse in older children and adults. HUS is characterized by acute renal failure, MAHA, and thrombocytopenia. HUS often follows a viral or bacterial illness.

Although several infectious agents have been implicated, Escherichia coli serotype O157:H7 is a well-recognized factor. Between 20% and 40% of patients with E. coli O157:H7 infection have bloody diarrhea, and 15% of children and 5% of adults go on to develop HUS. Onset of HUS is typically 2–14 days after diarrhea develops. Other organisms implicated in HUS include Shigella, Yersinia, Campylobacter, Salmonella, Streptococcus pneumoniae, varicella, echovirus, and coxsackievirus A and B.

In HUS the microthrombi are confined mostly to the kidneys, whereas in TTP they occur throughout the microcirculation. Laboratory studies reflect the presence of MAHA, and thrombocytopenia may be present but generally not to the degree seen in TTP. The serum creatinine may be markedly elevated, and urine contains protein and RBCs (although the urine can be normal). Increasingly TTP and HUS are considered to be similar diseases within a spectrum, with some experts simply using the term TTP-HUS syndrome. The sometimes blurred lines between the many varied disease presentations are beyond the scope of this text and likely impossible to fully define within the patient stay in the emergency department. In general, the presence of a preceding diarrheal illness and the predominant laboratory finding of renal failure with minimal to no neurologic changes makes the HUS diagnosis and treatment algorithm more appropriate.

Treatment

Patients with mild HUS with less than 24 hours of urinary symptoms require only fluid and electrolyte correction and supportive care. Steroid therapy may be beneficial. In the setting of more severe disease, plasma exchange or infusion have been performed with equivocal results. Patients whose disease resembles TTP may respond to plasma exchange, but the overall low mortality of HUS makes routine use of plasma exchange questionable.

Hemodialysis may be required in the setting of acute renal failure, especially in adults because acute renal failure tends to be more severe. A shorter duration of dialysis therapy is associated with increased likelihood of recovery from HUS. Do not treat infection with E. coli O157:H7 with antimotility drugs because these agents appear to increase the risk of developing HUS. Antibiotic treatment of E. coli O157:H7 dysentery is controversial, but meta-analysis has found no evidence that antibiotic treatment increases or decreases the risk of developing HUS.

Qualitative Platelet Abnormalities

Several disease processes can cause acquired qualitative or functional platelet abnormalities (Table 41–4). In the myeloproliferative diseases, despite frequently elevated platelet counts, the platelets are often dysfunctional and patients can develop mucosal hemorrhages or clinically significant bleeding. To control acute bleeding, consider transfusion to raise the level of normal platelets to 50,000/μL. In macroglobulinemia and related disorders, the elevated serum proteins interfere with platelet function, and patients with clinically significant bleeding may require plasmapheresis to reduce the protein level and correct hemostatic function.

Many commonly used drugs can influence platelet function (see Table 41–3). Of these, the most commonly used are aspirin, the NSAIDs, and clopidogrel. Aspirin inhibits platelet function by acetylating and irreversibly inactivating platelet cyclooxygenase, which inhibits platelet aggregation. This antithrombotic effect can be seen in doses as small as 30 mg, occurs within 1 hour after ingestion, and continues for the lifespan of the platelets. Because the NSAIDs reversibly inhibit platelet cyclooxygenase, the impairment of platelet aggregation lasts only as long as the active drug is present in the circulation, usually less than 24 hours. An exception is the drug piroxicam, which has a 2-day half-life.

Ticlopidine and clopidogrel are related substances that inhibit platelet function by impairing fibrinogen binding to glycoprotein IIb/IIIa receptors and by inhibiting platelet binding. Platelet inhibition occurs within 24–48 hours after ingestion and continues for approximately 4–10 days after discontinuation of therapy.

Hemophilia

General Considerations

Hemophilia is a disorder of coagulation caused primarily by a deficiency or defect in one of two circulating plasma proteins. Hemophilia A, or classic hemophilia, is caused by a deficiency of factor VIII and is the most common cause of hemophilia in the United States, affecting 1 in 10,000 males. Hemophilia B, or Christmas disease, is caused by a deficiency of factor IX. This form of hemophilia is less common, affecting approximately 1 in 30,000 males.

Hemophilia A and B are clinically indistinguishable from each other, and specific factor testing is required for diagnosis. Both hemophilia A and B are X-linked recessive disorders; therefore, hemophilia is a disease of men, and women are asymptomatic carriers.

Clinical Findings

Symptoms and Signs

Bleeding manifestations in patients with all forms of hemophilia (Table 41–5) are directly attributable to the decreased plasma levels of either factor VIII or IX. Individuals with factor levels below 1% of normal are classified as having severe disease, and these people will experience severe spontaneous bleeding episodes and difficult-to-control bleeding related to traumatic events. Patients with factor levels of 1–5% of normal are classified as having moderate disease; although they may bleed spontaneously, more commonly their bleeding is related to a traumatic event. Patients with factor levels of 5–50% of normal are classified as having mild disease and usually bleed only after trauma.

As a result of exposure to blood products, many hemophiliacs have chronic viral hepatitis or are infected with HIV. Fortunately, as a result of newer viral inactivation procedures and recombinant technology, few seroconversions have resulted from the use of currently available factor replacement products.

An interesting clinical feature is the apparent protective effect of hemophilia and for carriers of hemophilia for coronary heart disease (CHD) for which studies have shown up to an 80% reduction in coronary disease related mortality.

Laboratory Findings

Routine coagulation studies (prothrombin time [PT] or activated partial thromboplastin time [aPTT]) require only 30% of normal factor VIII or IX level to be normal; therefore, patients with mild disease may have normal values. Coagulation studies are unlikely to yield new information in the known hemophiliac and are not routinely indicated when the patient presents with mild to moderate bleeding episodes.

Treatment

A general principle in managing major or life-threatening bleeding in a hemophilic patient is early and complete factor replacement, before or at the same time as other resuscitative and diagnostic maneuvers. Spontaneous or traumatic bleeding into the neck, tongue, retropharynx, or pharynx has a high potential for airway compromise. Any patient with hemophilia who complains of a new headache, localizing neurologic symptoms, or a blunt head injury requires immediate factor replacement therapy followed by urgent CT scanning of the head. Hemophilic patients with complaints of back, thigh, groin, or abdominal pain may have bleeding into the retroperitoneum. At times the initial manifestations of bleeding can be subtle. Simple injuries such as ankle and wrist sprains may at first appear benign but can be complicated by bleeding. Compartment syndromes result from muscle bleeds within the fascial compartments of the extremities, both spontaneously and after minimal trauma to an extremity.

One of the most common manifestations of hemophilia is hemarthrosis. Clinical evidence of an acute problem with the joint may or may not present, but these patients can reliably report when bleeding is occurring. Prompt treatment of hemarthroses can prevent or reduce the long-term sequelae of hemophilic arthropathy. Recent research has investigated using regular factor infusions versus episodic infusions at the time of injury for comparison of joint damage seen on MRI years following initiation and has shown that episodic infusions are inferior. The cost and communicable disease risk of infusions, however, is probably to blame for this practice not being the standard in most institutions. Many patients and their families have a sophisticated understanding of the disease. These patients will know to seek treatment at the first sign of a problem, and as stated earlier, little outward evidence of pathology may be present initially. Despite minimal findings, take seriously the concerns of these patients. Additionally, many known hemophiliacs will have in their medical records a detailed treatment plan for how to manage acute bleeding episodes. Consult these records when they are available.

Do not place central lines, including femoral lines and external jugular lines, in patients with hemophilia without giving factor replacement therapy. Similar rules apply to arterial blood gases or lumbar puncture. Patients with hemophilia should never receive intramuscular injections unless factor replacement is given and maintained for several days. Do not give compounds that contain aspirin for pain relief.

Two different factor replacement types are available: recombinant or plasma derived (Table 41–6). The highest level of purity comes from the recombinant factors, but these products cost 2–3 times more than plasma-derived products, and they are not available everywhere. Another concern with the plasma-derived factors is that some of the preparations may contain other coagulation factors, some partially activated. Prolonged use of the less pure concentrates may increase the risk of DIC or, in some cases, cause paradoxical clotting. Safety, cost, and availability must be considered when choosing the product to use in replacement therapy, but because the recombinant forms are perceived to be safer, approximately 60% of patients with severe hemophilia in the United States receive these preparations.

The dosing regimen used in the hemophilic patient is based on the clotting factor’s volume of distribution, the factor’s half-life, and the hemostatic level of factor required to control the bleeding (Table 41–7). Clotting factor is dosed in units (U) of activity; 1 unit of factor represents the amount of factor present in 1 mL of normal plasma. For hemophilia A, 1 unit of factor VIII per kilogram of body weight raises the plasma level by approximately 0.02 U/mL (2%) with a half-life of approximately 8–12 hours. For hemophilia B, 1 unit of factor IX per kilogram of body weight will raise the plasma level by approximately 0.01 U/mL (1%) with a half-life of approximately 16 hours.

Bleeding from the mouth is common in hemophiliacs, particularly children. If an oral bleed is present, identify the area, clean it of inadequate clot, and place a dry topical thrombin on the bleeding site. In addition to factor replacement, antifibrinolytic agents such as ϵ-aminocaproic acid (EACA) and tranexamic acid are useful to prevent bleeding when the clot falls off. For superficial mucosal injuries, it may be possible to manage the bleeding with antifibrinolytic therapy alone. The dose of EACA is 75–100 mg/kg for children (6 g for adults) every 6 hours, given orally or intravenously. Topical hemostatic agents used to help control oral or nasal bleeding include microfibrillar collagen hemostats, thrombin, and absorbable gelatin sponges.

Patients with mild hemophilia A (factor levels of 5% or greater) who have mild bleeding may not always require factor replacement. Rather, these patients may be given desmopressin, which causes endothelial storage sites to release vWF that is capable of carrying additional amounts of factor VIII in the plasma. This medication is well tolerated, and patients can administer it at home by subcutaneous injection or intranasal spray. The dose of intravenous desmopressin is 0.3 μg/kg (maximum dose, 20 μg) over 30 minutes. The concentrated intranasal form of desmopressin is an antidiuretic agent, and fluid restriction may be needed during use. For children older than 5 years, a single spray in a single nostril (150 μg total dose) is adequate. For adolescents and adults, a single spray in each nostril is used (300 μg total dose). This dose of intranasal desmopressin increases the factor VIII level by 2–3 times. This treatment can be repeated in 8–12 hours, but the patient’s stores of factor VIII will be depleted, and subsequent effect will be less.

In response to the clotting factors used to treat bleeding episodes, some people will develop inhibitors, or antibodies against the replacement factor. Inhibitors tend to occur most commonly in patients with severe hemophilia because of frequent factor replacement. These inhibitors not only interfere with the effectiveness of factor replacement therapy but also cause anaphylaxis to factor administration in patients with hemophilia B. Inhibitors occur in 10–25% of those with hemophilia A and in 1–3% of those with hemophilia B. The use of factor replacement in hemophilic patients with inhibitors is guided by the concentration of inhibitor (measured in Bethesda Inhibitor Assay [BIA] units) and by the type of response the patient has to factor concentrates. Bleeding episodes are more difficult to treat in these patients, but options do exist. Given the complexity of these patients, consultation or transfer to a center with hematology is recommended.

Disposition

Many patients with hemophilic bleeding episodes can receive factor replacement in the emergency department or clinic and then be discharged home with follow-up in 12–24 hours. Hemophilic patients with bleeding episodes that require hospital admission include (1) those with bleeding involving the central nervous system, neck, pharynx, retropharynx, or retroperitoneum, (2) those with potential compartment syndrome, (3) those for whom treatment requires more than three doses (relative indication), (4) those unable to use, or lacking access to, factor replacement, or (5) those in whom pain cannot be controlled with oral analgesics.

von Willebrand Disease

General Considerations

von Willebrand disease is the most common congenital bleeding disorder; it is present in 1–2% of the population. This disease is a group of disorders caused by abnormalities of vWF. The disease is heterogeneously inherited and expressed, and although multiple subtypes exist, these can be classified into three major groups (Table 41–8). Type I is the most common and is a partial quantitative disease, type II is a qualitative (abnormal function) disease, and type III is a severe and almost complete deficiency of vWF (this type is a rare autosomal recessive form). vWF is a glycoprotein that, as opposed to most other coagulation factors, is synthesized, stored, and then secreted by the vascular endothelial cells. It is a cofactor for platelet adhesion and the carrier protein for factor VIII.

Clinical Findings

Symptoms and Signs

Bleeding symptoms are common in people with von Willebrand disease, particularly in children and adolescents. Symptoms include recurrent epistaxis, gingival bleeding, unusual bruising, gastrointestinal bleeding, and menorrhagia in young women. Hemarthrosis is not typical unless severe disease is present. In mild cases of von Willebrand disease, patients may be unaware of the disease until they undergo a surgical procedure or experience a traumatic event. Von Willebrand disease is relatively common, and its presence influences the treatment of other medical problems, because patients with this disease should not take medications with known antiplatelet effects, including aspirin, NSAIDs, antiplatelet agents, heparin, and some antibiotics.

Laboratory Findings

Common abnormalities on hemostatic testing include a prolonged bleeding time, low or normal vWF antigen, and low vWF activity. The PT is usually normal, but this can be variable, as can the factor VIII level. This variability sometimes makes von Willebrand disease difficult to differentiate from mild hemophilia A. The patient’s blood type affects the vWF level; blood type O has as much as a 30% reduction in vWF levels compared to the other blood types.

Treatment

Desmopressin has become a mainstay of therapy for many patients with type I von Willebrand disease and may work in conjunction with other plasma products that contain vWF for types II and III. In responsive individuals, desmopressin causes a transient two- to fourfold increase in vWF. It also seems to have an effect on the endothelium that promotes hemostasis. The dose is 0.3 μg/kg (maximum dose, 20 μg) administered subcutaneously or intravenously every 12 hours for a total of 3–4 doses; after 4 doses, tachyphylaxis develops. Desmopressin can also be used as an intranasal spray. For children older than 5 years, a single spray in a single nostril is adequate (150 μg total dose). For adolescents and adults, administer a single spray in each nostril (300 μg total dose).

Plasma derivatives that contain vWF are used for patients with type I disease that does not or no longer responds to desmopressin and for patients with type II or III disease. To be effective the chosen product must have vWF in the high-molecular-weight form. Cryoprecipitate meets this objective (contains factor VIII and vWF), but the potential for viral transmission is a concern. If cryoprecipitate is used, 10 bags every 12–24 hours will usually control bleeding. Humate-P is an intermediate-purity factor VIII concentrate that has significant amounts of vWF and can be used to treat bleeding episodes. Platelet transfusions may benefit patients with certain types of von Willebrand disease (especially type III) that do not respond to vWF-containing concentrates of cryoprecipitate.

Local measures to control bleeding in von Willebrand disease include (1) intranasal application of porcine strips (eg, Surgicel), porcine strips sprinkled with microfibrillar collagen (eg, Avitene), or cauterization for epistaxis, (2) birth control pills to help raise vWF levels and limit the degree of menstrual bleeding, and (3) EACA for dental injury or planned intraoral procedures.

Liver Disease

Clinical Findings

Acute and chronic diseases of the liver can be associated with many hemostatic abnormalities. Hepatocytes synthesize all of the coagulation factors and related regulatory proteins, with the exception of factor VIII. Malabsorption of vitamin K can occur with processes that interfere with the absorption of fat-soluble vitamins, including impaired bile acid metabolism (ie, primary biliary cirrhosis), intrahepatic or extrahepatic cholestasis, and treatment with bile acid binders.

Thrombocytopenia in severe liver disease is most often due to portal hypertension, which leads to congestive hypersplenism and splenic sequestration. Patients with significant liver disease have increased fibrinolysis due to decreased synthesis of α2-plasmin inhibitor. In some patients with liver disease, abnormal fibrinogen molecules are synthesized, which, when cleaved to fibrin monomers, do not polymerize correctly.

Patients with mild to moderate hepatic dysfunction frequently have subclinical hemostatic abnormalities. Patients with severe liver disease may have life-threatening bleeding. Laboratory studies should include a PT, aPTT, and platelet count. Also consider obtaining fibrinogen levels and measurement of fibrin degradation products (FDP) or d-dimer. In general, prolongation of the PT and a plasma fibrinogen level of less than 100 mg/dL is a poor prognostic sign in patients with liver disease.

Treatment and Disposition

Patients who have liver disease and laboratory abnormalities without clinically significant bleeding usually require only close observation. If clinically significant bleeding is present or an invasive procedure or surgery is pending, the coagulopathic state will need to be treated. Transfuse packed RBCs to maintain an adequate hemoglobin level and to maintain hemodynamic stability. Give oral or intravenous vitamin K to all patients. FFP can be used to replace coagulation factors temporarily, but the volume needed to completely replenish the coagulation factors may limit the amount given.

Cryoprecipitate may be used to replace fibrinogen in patients with fibrinogen levels less than 100 mg/dL. Platelet transfusions may be appropriate if platelet counts are low. Desmopressin (either 0.3 μg/kg subcutaneously or intravenously [maximum dose, 20 μg] or 300 μg intranasal spray) shortens the prolonged bleeding time in some patients with liver disease. Although controlled trials are lacking, there are few side effects.

Renal Disease

Patients with end stage renal disease typically develop complications due to two opposing hemostatic processes: bleeding and clotting. Platelet dysfunction is the main factor responsible for hemorrhagic disorders, although platelet counts are frequently normal. Platelet dysfunction occurs as a result of intrinsic platelet abnormalities such as impaired platelet adhesiveness and abnormal platelet–endothelial interaction. Anemia and complications from hemodialysis are major contributors to bleeding in advanced kidney disease.

Dialysis partially improves platelet function and may reduce bleeding likely due to the reduction of dialyzable toxins. Platelet function is optimized when the hematocrit is maintained at approximately 30% because anemia contributes to bleeding. Desmopressin administration intravenously or intranasally may improve the bleeding time in end stage kidney disease and can also be used prior to procedures that carry a risk of bleeding. Conjugated estrogen, 25 mg intravenously, also improves both bleeding time and clinical bleeding in more than 80% of uremic patients. Cryoprecipitate carries the risk of viral transmission, and platelet transfusions are relatively ineffective because the infused platelets quickly acquire the uremic defect.

Warfarin and Vitamin K Deficiency

General Considerations

The vitamin K-dependent coagulation factors produced in the liver are prothrombin factor II, VII, IX, and X, as well as the anticoagulant proteins C and S. Nutritional deficiency of vitamin K is rare in adults. However, patients with liver disease can have vitamin K deficiency due to a combination of poor nutrition and malabsorption. Additionally, deficiency of the vitamin K-dependent factors can occur in patients receiving antibiotics, particularly the third-generation cephalosporins that contain the N-methylthiotetrazole side chain (ie, moxalactam, cefamandole, cefotaxime, cefoperazone).

Warfarin, the major oral anticoagulant used in the United States, inhibits the production of the vitamin K-dependent coagulation factors. The half-life of warfarin is approximately 36 hours with normal hepatic function. The standard starting dosage is usually 5 mg/d with subsequent dose adjustment guided by the international normalized ratio (INR). Observable anticoagulation effect is expected in 2–7 days. The goal INR is 2.0–3.0 for all indications except in patients with prosthetic mechanical valves and with antiphospholipid antibody syndrome; these patients require a higher INR of 2.5–3.5. Maintenance dosage can be influenced by different variables, including the patient’s vitamin K stores, malnutrition, liver function, concurrent medical disorders, and numerous drug interactions.

Clinical Findings

The major adverse effects associated with warfarin treatment include warfarin embryopathy, warfarin-induced skin necrosis, and bleeding. Warfarin interferes with a vitamin K-dependent protein used to build the bone matrix, resulting in fetal bone abnormalities. This toxicity occurs with warfarin exposure during the 6th–12th weeks of gestation, but warfarin should be avoided during the entire pregnancy. Warfarin-induced skin necrosis is an uncommon complication occurring during the 1st week after initiating therapy. Some patients who develop this complication have a hereditary heterozygous protein C deficiency or protein S deficiency.

Treatment

Treatment of warfarin complications includes discontinuation of warfarin, heparinization if anticoagulation is required, vitamin K administration, and screening for protein C and protein S deficiencies. The fear of creating a hypercoagulable state in persons with undiagnosed protein C deficiency is unfounded, but persons with a known hypercoagulable state should receive anticoagulation therapy with heparin before starting warfarin.

Bleeding is the most common complication of warfarin treatment; the risk of bleeding is related directly to the degree of anticoagulation. Additionally, individual risk factors for bleeding include age greater than 65 years, hypertension, anemia, prior cerebrovascular disease, gastrointestinal lesions, and renal disease. Medications that increase warfarin activity and antiplatelet medications can also increase bleeding risks. Management of bleeding depends on the type of bleeding and the INR value (Table 41–9).

The anticoagulated state can be reduced by withholding warfarin, administering oral or intravenous vitamin K, or substitution of clotting factors such as (but not exclusive) FFP (widely used) or prothrombin complex concentrates (PCCs), which are increasingly being recommended and used.

Subcutaneous administration of vitamin K has an unpredictable and delayed response, whereas oral vitamin K is convenient to administer, is effective, and produces less resistance to subsequent warfarin use. Additionally, hypersensitivity reactions and anaphylaxis are uncommon with the oral administration of vitamin K. Intravenous administration of vitamin K results in the rapid reversal of hypercoagulation but is associated with anaphylaxis or hypersensitivity reactions, including flushing, diaphoresis, hypotension, dyspnea, and chest pain. Doses of vitamin K above 10 mg are associated with overcorrection of hypercoagulation and warfarin resistance for up to 1 week upon reinstitution of anticoagulation. In general, restrict the intravenous use of vitamin K to patients with life-threatening bleeding or to those with an INR greater than 20.

Two additional hemostatic agents are available for rapid correction of life-threatening bleeding. Recombinant factor VIIa (FVIIa) and PCC. FVIIa is a potent procoagulant agent that can generate thrombin even in the absence of tissue factor. It is a recombinant agent, it will not transmit viruses, and it will rapidly correct FVII deficiency. However, PCCs are now recommended for anticoagulation reversal in patients with life-threatening bleeding and an increased INR. Compared with FFP, PCCs provide quicker correction of the INR and improved bleeding control. Compared to FVIIa, PCCs correct not only the FVII deficiency but all of the warfarin-induced coagulation deficiencies, resulting in a true physiologic correction to normal.

Disseminated Intravascular Coagulation

General Considerations

Disseminated intravascular coagulation is characterized by both widespread activation of the coagulation system (resulting in fibrin formation and consumption of hemostatic factors) and activation of the fibrinolytic system (resulting in the breakdown of fibrin clots, consumption of coagulation factors, and bleeding). DIC is associated with a variety of disorders such as infection (usually bacterial and occasionally viral), malignancy (adenocarcinoma, acute leukemia, lymphoma), trauma (burns, fat embolism), liver disease, and environmental disorders (hyperthermia, envenomation). DIC may be acute and life-threatening or chronic and compensated.

Clinical Findings

Symptoms and Signs

Clinical features of DIC vary with the underlying precipitating medical illness. The clinical complications of DIC are bleeding, thrombosis, purpura fulminans, and multiple organ failure. Although hemorrhage and thrombosis may occur simultaneously, in an individual patient, one manifestation usually predominates and the most common one is bleeding. Bleeding can range from petechiae and ecchymoses to bleeding from the gastrointestinal tract, genitourinary tract, surgical wounds, mucocutaneous sites, and venipuncture sites. Intravascular coagulation and fibrin deposition can cause multiple organ failure. Clinical signs include mental status changes, focal ischemia or gangrene, oliguria, renal cortical necrosis, and adult respiratory distress syndrome. Purpura fulminans results when widespread arterial and venous thromboses occur and is most commonly seen with significant bacteremia. In chronic DIC, the pathophysiology of disease is essentially the same, but the destruction of coagulation factors and platelets is balanced by hepatic and bone marrow production.

Laboratory Findings