Audra L. McCreight
Jonathan E. Wickiser
• Aggressive treatment of hemophilia patients with head trauma is imperative as signs and symptoms of intracranial bleeding may be delayed. Even though initial imaging studies may be normal, factor replacement is indicated and careful monitoring of the patient is crucial to detect subtle changes in mental status.
• Patients with hemophilia and inhibitors remain challenging management cases and are best cared for in conjunction with a hematologist.
• Treatment of bleeding episodes in von Willebrand patients may include desmopressin (DDAVP), cryoprecipitate, or factor VIII concentrates rich in von Willebrand factor (vWf).
• Treatment options for ITP are based on the clinical severity of bleeding. Consultation with a hematologist is indicated for patients with bleeding complications or platelet counts <20,000.
Hemophilia is an X-linked recessive disorder of coagulation caused by deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B), occurring in one in 5000 men.1 The percentage of factor present determines the severity of disease. Six to forty percent factor activity levels denotes mild disease with no tendency for spontaneous hemorrhage and bleeding occurs usually only with surgery or severe trauma. Two to five percent implies moderate disease with bleeding following mild trauma. Less than 1% is severe disease with proclivity to spontaneous hemorrhage. Two-thirds of male patients with hemophilia have severe disease. In both hemophilia A and B, the prothrombin time (PT) is normal and partial thromboplastin time (PTT) is prolonged. The same types of bleeding occur in both factor VIII and factor IX deficiency. Bruising, hemarthroses, and intramuscular hematomas predominate. Intracranial hemorrhage is less common but can be devastating. It is important to listen to the patient and their parents as the initial presentation of bleeding may not be dramatic.
Knees, elbows, ankles, hips, and shoulders are the most commonly affected joints (Fig. 105-1). Older patients may be aware of a bleed prior to the onset of pain and swelling, whereas younger patients may present with new onset limp or limited range of motion. It is generally agreed that even if joint bleeding cannot be confirmed, treatment is indicated. This philosophy is based on the potentially crippling sequelae of hemarthrosis. Intraarticular bleeding provokes a strong synovial inflammatory reaction causing erosion of the cartilage, synovial hypertrophy, and friability. Muscle atrophy around the joint leads to instability, which increases the likelihood of more frequent hemarthroses. Unless treated early and adequately, repeated bleeding into a “target joint” can lead to complete cartilaginous destruction causing secondary osteoarthritis. Joint swelling that is persistent and associated with fever may indicate a septic joint. Aspiration preceded by appropriate factor replacement may be necessary but should only occur after discussion with the child’s hematologist. Joint aspiration is not recommended for most cases of bleeding.
FIGURE 105-1. A 5-year-old with severe factor VIII deficiency and acute left knee hemarthrosis.
Symptomatic treatment of hemarthroses consists of splinting, ice, immobilization, elastic bandages, and analgesia with acetaminophen with or without codeine. A single factor infusion to raise levels to 30% to 50% is usually sufficient to terminate bleeding. A joint that has bled repeatedly may require several doses of factor. Range of motion and physical therapy are instituted as soon as possible. Bleeding into the hip is especially worrisome because pressure within the joint can lead to aseptic necrosis of the femoral head. Factor replacement to 80% to 100% levels with subsequent daily replacement to 50% may be necessary.
Such hemorrhage usually affects the large weight-bearing muscles such as the iliopsoas, calf, gluteal, and forearm muscles, but can affect any muscle of the body. Bleeding is often slow, occurring over extended periods of time before symptoms of pain, tenderness, and swelling appear. Therefore, such hemorrhages often present as a large hematoma. Treatment consists of factor replacement to a level of 30% to 50%. Forearm, calf, and hand bleeding can result in a compartment syndrome. Vascular compromise or nerve paralysis may occur if not treated promptly with factor replacement. Iliopsoas hemorrhage, which can be massive, presents with flexion of the thigh, groin, or iliac fossa pain, and paresthesias along the anterior thigh from femoral nerve compression. This characteristic triad of symptoms is secondary to femoral nerve compression by the swollen iliopsoas muscle as it passes under the anterior ligament. Ultrasound or computed tomography (CT) can confirm the diagnosis. Compartment syndromes and psoas hemorrhages are treated with correction to achieve factor levels of 80% to 100% and require admission for observation and continued factor replacement. Surgical intervention should be avoided if at all possible.
Intracranial bleeding may be traumatic or spontaneous. Minor trauma may present with neurologic changes days after the event. Symptoms include headache, lethargy, loss of consciousness, vomiting, and seizures. Forceful blows to the head, regardless of symptoms, are empirically treated with factor replacement. If intracranial hemorrhage is suspected, immediate factor replacement to a 100% level is necessary. Factor infusion should not be delayed for imaging studies.
OTHER BLEEDING MANIFESTATIONS
Subcutaneous hemorrhage, abrasions, and lacerations that do not require sutures do not require factor replacement. However, factor replacement is necessary prior to laceration repair, lumbar puncture, surgery, and dental extractions. Men with hemophilia can also present with painless, gross hematuria. An anatomic source of the bleeding is often not found and treatment with factor may or may not be necessary. Prednisone is advocated by some to decrease the duration and degree of hematuria. In cases such as this, close consultation with the child’s hematologist is invaluable. Intramuscular injections, aspirin, and jugular and femoral venipuncture are to be avoided in this patient population. Simple peripheral venipuncture is followed by at least 5 minutes of pressure to the site.
Factor replacement for hemophilia A or B is accomplished by transfusion with a variety of factor VIII or IX concentrates, respectively. These products are made from either pooled donor plasma-derived or recombinant proteins. The purest of the plasma-derived products are monoclonal antibody purified. Recombinant products may contain human albumin and are not necessarily superior. The amount of factor to be delivered will be dependent on the nature and severity of the bleeding episode. For minor bleeding, target factor level is 30% to 40%. For major bleeding or prior to surgery a minimum of 50% factor level is required. For life- or limb-threatening bleeds, 80% to 100% factor level is needed, and treatment with factor replacement is required every 12 hours or by continuous infusion until healing occurs.2
The following formulas may be used to calculate factor replacement:
• Factor VIII (units) = weight (kg) × 0.5 × desired increment (percent) of factor VIII level (i.e., 1 U/kg of factor VIII raises the level by 2%).
• Example: To achieve 50% factor VIII level in an 80-kg patient 80 × 0.5 × 50 = 2000 units of factor VIII given as a bolus
• Factor IX (units) = weight (kg) × 1.0 × desired increment (percent) of factor IX level (i.e., 1 U/kg of factor IX raises the level by 1%–1.5%).
• Example: To achieve a 50% factor IX level in an 80-kg patient 80 × 1.0 × 50 = 4000 units of factor IX given as bolus
Patients and parents often present with their home supply of factor, and this may be utilized. Always give an entire vial of factor even if it results in a higher than calculated dose per weight, as any leftover factor must be wasted.
Approximately 30% of patients with severe factor VIII deficiency develop an inhibitory IgG antibody against factor VIII.3 Treatment of patients with inhibitors can be problematic, as the infused factor VIII is immediately neutralized by the circulating antibody. Treatment of bleeding episodes in these children depends on inhibitor titer and the severity of the bleeding. Children with low titers and serious hemorrhage may respond to large doses (up to 100–200 U/kg) of factor VIII. Some children with inhibitors demonstrate an anamnestic response (high responders) with high titers of antibody appearing rapidly after factor VIII administration. Alternatives for treating patients with high titers of inhibitor include prothrombin complexes (which bypass the need for factor VIII through the presence of factors II, VII, and X), and recombinant factor VIIa. Recombinant activated factor VII a (rFVIIa) has a very short half-life and must be given every 2 hours. The response to these therapies is judged by the patient’s clinical response.
Adjuncts to therapy in hemophilia are available in certain situations. Some centers use corticosteroids for the management of hematuria or recurrent joint bleeds. Epsilon aminocaproic acid (Amicar) and tranexamic acid (Cyklokapron) are clot stabilizers used for the prevention or treatment of oral hemorrhage. Both can be administered orally or intravenously. DDAVP increases factor VIII levels in patients with mild hemophilia and may be useful for minor bleeds in patients who have shown prior adequate response to this therapy. DDAVP is administered intravenously over 30 minutes (0.3 μg/kg) or intranasally (150 μg or one metered dose for children <50 kg and 300 g or two metered dose sprays for children >50 kg).
VON WILLEBRAND DISEASE
The carrier protein in plasma for factor VIII is vWf, and it also acts as a bridge between platelets and subendothelial collagen fibers.4 Von Willebrand disease exists when there are decreased levels of or defective vWf proteins. The condition is heterogeneous with respect to its genetic, molecular biology, clinical manifestations, and laboratory values. Unlike the sex-linked hemophilias, von Willebrand disease is typically transmitted as an autosomal dominant trait showing variable expression and penetrance. Classification systems separate quantitative deficiencies of vWf (type 1, classic) from qualitative abnormalities (types 2A and 2B) and type 3 in which plasma vWf and factor VIII levels are not measurable or are <5 U/dL.
Most patients present as young adults with clinical manifestations including epistaxis, easy bruising, menorrhagia, prolonged oozing from superficial cuts, and bleeding after dental extraction. Posttraumatic and postsurgical hemorrhage can occur, but hemarthroses are uncommon. Many people exhibit no clinical problems with bleeding in spite of biochemical abnormalities. Typical laboratory findings include a normal PT and platelet count, with a prolonged bleeding time and a PTT that may be normal or prolonged. Measurement of antigenic vWf (vWf:Ag) and ristocetin cofactor (vWf:RCo) activity can usually confirm the diagnosis. Both are decreased in most von Willebrand patients.
Of the subtypes, approximately 80% of patients have Type I von Willebrand disease, which is often amenable to DDAVP therapy. DDAVP stimulates the endogenous release of vWf. The dose is 0.3 μg/kg intravenously infused over 20 to 30 minutes. This can be repeated every 4 to 6 hours for continued bleeding. Stimate (1.5 mg/mL) is a concentrated intranasal preparation of DDAVP that has demonstrated effectiveness. In teens and adults, the dose is 150 μg/nostril, with a total dose of 300 μg. For children <50 kg, the total dose is 150 μg.
Treatment with a factor VIII concentrate rich in vWf is sometimes necessary for patients who do not respond to DDAVP or in whom its use is contraindicated. Loading dose of concentrate is 40 to 60 IU/kg of vWf with follow-up doses administered every 12 to 24 hours to maintain vWf:RCo activity >0.5 IU/mL. All currently available concentrates are plasma derived and undergo a viral inactivation step making it unlikely to transmit viruses such as hepatitis and HIV.
Acquired abnormalities of coagulation include vitamin K deficiency, liver disease, disseminated intravascular coagulation (DIC), thrombocytopenia, and platelet dysfunctions. Vitamin K deficiency leads to decreases in the vitamin K-dependent factors (II, VII, IX, and X) and prolongation of the PT. It can be seen in malabsorption syndromes, such as cystic fibrosis and celiac disease, biliary obstruction, and prolonged diarrhea. Children with poor nutrition who receive broad-spectrum antibiotics are also at risk. Drugs, such as diphenylhydantoin, phenobarbital, isoniazid, and coumadin may cause vitamin K deficiency as a side effect. Vitamin K deficiency can lead to hemorrhagic disease of the newborn unless supplementation is provided routinely at delivery. Administration of vitamin K is safest by the subcutaneous route. A dose of 10 mg of vitamin K given subcutaneously will correct the PT within 24 hours. Rare but severe anaphylactoid reactions are described with intravenous infusion. The liver is the primary site of production of clotting factors, and severe liver disease may lead to coagulation defects that can mimic DIC.
DISSEMINATED INTRAVASCULAR COAGULATION
DIC is an acquired syndrome characterized by simultaneous activation of coagulation and fibrinolysis within the microvasculature. Microthrombi form in small blood vessels, leading to vessel occlusion, tissue ischemia, and end-organ damage. Excessive bleeding occurs due to thrombocytopenia, consumption of clotting factors, and fibrinolysis. In pediatric patients, the leading cause of DIC is overwhelming infection. However, conditions that can precipitate DIC are numerous and include tissue injuries, such as burns, multiple trauma and crush injuries, severe head trauma, placental abruption and eclampsia, tumors, hemolytic transfusion reactions, myocardial infarctions, giant hemangiomas, respiratory distress syndrome, snake bites, and heat stroke or hypothermia. Although bleeding is the predominant symptom, thrombotic damage can occur in most organ systems. Common ischemic complications include hemorrhagic necrosis of the skin, renal failure, seizures, coma, hypoxemia, and pulmonary infarcts. Laboratory findings in DIC are variable but usually include hemolytic anemia with schistocytes, thrombocytopenia, prolonged PT and PTT, and decreased levels of factor V, factor VIII, and fibrinogen with increased fibrin split products. There is also usually a marked decrease in protein C, protein S, and antithrombin III.
Management consists of treating the underlying disorder; antibiotics for sepsis, volume expanders for shock, and oxygen for hypoxemia. In addition, therapy is also directed to control the abnormalities of hemostasis. Therapeutic options include factor replacement, anticoagulants, and antifibrinolytics. Factor replacement may be accomplished with fresh frozen plasma (10–20 mL/kg) to keep the PT in the normal range. Cryoprecipitate provides increased concentration of fibrinogen, factor VIII, and vWf. Persistent oozing may be due to severe thrombocytopenia. Platelet transfusion may be considered to keep platelet counts >50,000.
Normally functioning platelets are a necessary component of the clotting process. Platelet activation, adherence, recruitment, and aggregation and binding of fibrinogen result in the cellular clot that is responsible for primary hemostasis following a disruption of a vessel wall. A deficit in platelet number or function can lead to excessive bleeding following injury. Congenital platelet dysfunction can affect a variety of platelet functions, such as receptor defects, platelet–vessel wall adhesion, platelet–platelet interactions to name just a few. Acquired platelet dysfunction is caused most commonly by aspirin, which inhibits production of thromboxane A2 and causes decreased platelet aggregation and vessel constriction. Patients with congenital platelet dysfunction typically present with severe bleeding diatheses early in life. Even minor platelet dysfunction can result in easy bruisability and significant bleeding from mucosal membranes.
Deficits in platelet number are much more common in pediatric patients. Thrombocytopenia is defined as a platelet count less than 150,000/μL, although it is rare to develop any abnormal bleeding with counts greater than 50,000/μL.
In the emergency department, thrombocytopenia is often an unexpected finding on a complete blood count obtained for unrelated reasons. Symptomatic patients may present as well-appearing children with a petechial or purpuric rash. At times the extensive ecchymoses in the absence of a history of significant trauma can wrongly suggest child abuse. With lower counts, patients may develop significant bleeding and bruising from minor trauma, mucosal bleeding, hematuria, or hematochezia. In addition to the skin findings, the physical examination should focus on evidence of systemic disorders such as recent weight loss, hypothyroidism, lymphadenopathy, and hepatosplenomegaly as these findings help establish the differential diagnosis. Involvement of other bone marrow elements also help guide the workup.
The differential diagnosis of thrombocytopenia is extensive, but the single most common cause in the well-appearing child is immune thrombocytopenic purpura (ITP). Other causes include autoimmune diseases such as systemic lupus erythematosus, in which anemia and lymphopenia are usually seen, and secondary immune destruction of platelets from infectious agents such as hepatitis B and Epstein–Barr viruses. Sepsis can cause destruction of platelets with or without the presence of DIC.
Bone marrow infiltration from leukemia, lymphoma, and other malignancies may initially present with thrombocytopenia but will often have associated hepatosplenomegaly, anemia, and abnormalities of the white blood cells. Cancer chemotherapy agents also cause suppression of all cell lines, including platelets. Thrombocytopenia may be the initial presentation of aplastic anemia. Idiosyncratic immune reactions leading to thrombocytopenia may be seen following administration of various agents, most commonly valproic acid, phenytoin, and trimethoprim/sulfamethoxazole.5
HEMOLYTIC UREMIC SYNDROME
Hemolytic uremic syndrome presents with a triad of acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia; it is discussed in more detail in Chapter 87. The thrombocytopenia is usually mild to moderate. The typical presentation is that of a pale, somewhat lethargic young child with a prodromal history of a gastrointestinal infection. Abdominal pain, vomiting, and bloody diarrhea are common, as are acute renal failure and neurologic manifestations. Laboratory examination typically reveals anemia with schistocytes, thrombocytopenia, electrolyte and acid–base disturbances, and elevated serum creatinine. Management consists of early dialysis to treat the effects of renal failure and reduce the fluid overload and hyperkalemia associated with the frequent blood transfusions that are necessary.
IMMUNE THROMBOCYTOPENIC PURPURA
ITP is the most common cause of thrombocytopenia in a well-appearing young child. The peak age of diagnosis is 2 to 4 years, occurring equally in female and male patients. Children typically have a history of a preceding viral illness, although the link to the development of antiplatelet antibodies is not clear. The platelet surface is covered with increased amounts of IgG and the spleen removes the affected platelets from the circulation. Platelet production is increased in the bone marrow, but not enough to offset the rapid destruction.
Patients present with the acute onset of bruising, petechiae, and purpura; they have normal physical examinations other than for skin findings (Fig. 105-2). Mucosal or gastrointestinal bleeding can occur. The most serious complication intracranial hemorrhage occurs in less than 0.1% to 0.5% of patients.
FIGURE 105-2. A child with ecchymosis associated with immune-mediated thrombocytopenia.
The diagnosis of ITP is likely when the complete blood count reveals thrombocytopenia in association with normal red and white blood cell numbers and morphology. Definitive diagnosis by bone marrow aspirate is not necessary in cases with thrombocytopenia and absence of signs, symptoms, or blood count results suggesting another diagnosis. Such children usually do not require hospitalization and can be followed up as outpatients. The natural history of the condition is that 85% of children make a full recovery within 6 months. Treatment of patients with ITP is controversial, consultation with a pediatric hematologist is recommended.6 An algorithm for the suggested management of ITP is provided in Figure 105-3. Therapeutic options include corticosteroids, intravenous immune globulin (IVIG), and anti-Rh(D) immunoglobulin (WinRho-SD). Corticosteroids or IVIG may promptly increase the platelet count in patients with profound thrombocytopenia. Both modalities are presumed to block reticuloendothelial destruction of platelets. However, there is currently no evidence that treatment diminishes the risk of major bleeding and, therefore, it is uncertain if the benefits of treatment outweigh its risks. Infusion of anti-Rh(D) immunoglobulin in Rh-positive individuals results in immune clearance of the antibody-coated red cells and coincident prolonged survival of autoantibody-coated platelets. Anti-D appears to be as safe and effective as IVIG in Rh-positive patients.3 Anti-D may only be administered in Rh-positive patients who have a normal hemoglobin level. Transfused platelets will be rapidly destroyed due to the immune response and have no role in the management of patients except in life-threatening hemorrhage. In that circumstance, platelet transfusion along with intravenous gamma globulin and high-dose intravenous steroids are administered. Emergency splenectomy may be required with life-threatening bleeding.
FIGURE 105-3. Algorithm for the diagnosis and treatment of ITP during childhood.
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6. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117:4190–4207.