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.
A child with ecchymosis associated with immune-mediated thrombo-cytopenia.
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.
Algorithm for the diagnosis and treatment of ITP during childhood.