Anemias generally are classified either by the mechanism resulting in the hemoglobin deficit—decreased production, accelerated destruction, or loss of erythrocytes—or by the morphologic appearance of the erythrocyte (Box 81-1).² Decreased RBC production may result from a variety of causes, including congenital defects, such as Fanconi anemia and Diamond-Blackfan anemia, or from postnatal causes, including acquired aplastic anemia, erythropoietin deficiency associated with renal disease, bone marrow suppression secondary to drugs or infectious agents, nutritional deficiencies, and bone marrow infiltration.

Box 81–1 Physiologic Classification of Anemia

RBC loss may stem from enhanced destruction as seen with erythrocyte membrane defects, (e.g., hereditary spherocytosis); with deficits in RBC enzymes such as glucose 6-phosphate dehydrogenase; and with microangiopathic processes, including hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and disseminated intravascular coagulation (DIC). Antibody-mediated red cell destruction, whether autoimmune, alloimmune, or drug related, may result in profound anemia. Blood loss secondary to trauma, surgery, hemorrhage, or even frequent phlebotomy may also lead to severe anemia.

Morphologic classifications of anemia are based on either erythrocyte size, as defined by mean corpuscular volume and mean corpuscular hemoglobin concentration, or by abnormalities in the erythrocyte shape (Box 81-2).² The normal values for mean corpuscular volume and mean corpuscular hemoglobin concentration vary with the child’s age. A wide variety of conditions, some intrinsic to the erythrocyte and others related to extrinsic factors, may result in abnormal RBC morphology.

Box 81–2 Classification of Anemias Based on Red Cell Size

The more common causes of profound anemia encountered in the pediatric intensive care setting are reviewed below. These causes include hemorrhagic anemia, decreased RBC production, and hemolytic anemia. Chapter 84, “Hemoglobinopathies,” provides a discussion of sickle cell anemia, other hemoglobinopathies, and their complications.

Bleeding may be either acute or chronic. Chronic bleeding generally causes anemia through depletion of iron stores.³ In response, patients adapt mechanisms to increase O₂ delivery and to avoid hypovolemia permitting them to tolerate hemoglobin levels well below the normal range, with mild clinical findings. Signs and symptoms of acute hemorrhage result from poor end-organ perfusion, with consequent diminished O₂ delivery. However, diagnosis of the presence and degree of blood loss may be difficult in an otherwise healthy child. Signs of impending shock, such as pallor, anxiety, and tachypnea, may be subtle.⁴ Signs of significant cardiovascular compromise may not become evident until the child has lost at least 25% of total blood volume. Patients who have lost more than 25% of blood volume usually manifest age-related systolic hypotension.⁴ Initial management should include achieving hemostasis, establishment of a secure airway, maintenance of ventilation, and initiation of volume replacement via an adequate intravenous catheter.⁵ Either crystalloid or colloid solutions are effective in restoring circulating volume, but an important debate currently exists over appropriate fluids and timing of resuscitation in acute traumatic hemorrhage that is beyond the scope of this chapter.

RBC transfusion should be given if O₂ delivery to the end organ is impaired.⁶ Either whole blood or packed RBCs can be used, but the former has many difficulties related to storage and transport. If packed RBCs or plasma-poor red cells are used to correct O₂-carrying capacity during massive blood loss, deficits of coagulation factors develop earlier than during transfusion of whole blood. Hypofibrinogenemia generally develops first, followed by deficits in other clotting factors and later by thrombocytopenia. Fresh-frozen plasma should be used to treat coagulopathy that develops during replacement of massive blood loss with RBCs. Transfusion of platelets should be guided by serial platelet counts.⁷

Central venous pressure should be monitored to allow for rapid administration of RBCs and volume replacement while decreasing the risks of hypervolemia. Blood and other fluids may be administered very rapidly until central venous pressure rises to between 6 and 7 mm Hg. Chapter 29 discusses the diagnosis and management of shock.

Anemia Secondary to Bone Marrow Failure

Several hematologic diseases are associated with diminished blood cell production. Acquired aplastic anemia, characterized by pancytopenia and hypocellular or acellular bone marrow, is defined by at least two of the three following: granulocytes less than 500/μL, platelets less than 20,000/μL, and anemia with a corrected reticulocyte count less than l%, in conjunction with markedly hypocellular bone marrow.⁸ The majority of cases have no definable cause but the pathophysiology appears related to immune mediated with destruction of blood-forming cells by lymphocytes. Excessive production of interferon-γ, tumor necrosis factor, and interleukin-2 has been noted.⁹ Altered immunity results in CD34 cell death and in intracellular pathways leading to cell cycle arrest.¹⁰ A minority of cases follows chemical or drug exposure. Post-hepatitis aplastic anemia typically occurs in young males, with pancytopenia presenting several weeks after severe liver inflammation.¹¹ Serologic testing for known hepatitis viruses generally reveals no pathogen.¹²

Acquired aplastic anemia can be distinguished from bone marrow failure resulting from Fanconi anemia by specific assays for chromosomal susceptibility to chemical cross-linking agents that characterize Fanconi anemia.¹³ Other constitutional syndromes may be suspected based on the presence of a pedigree of typical physical stigmata. Cytogenetic studies usually are normal in aplastic anemia, whereas aneuploidy or structural abnormalities are relatively common in myelodysplasia.¹⁰ Myelodysplasia may evolve in patients treated for aplastic anemia. Some patients with paroxysmal nocturnal hemoglobinuria develop bone marrow failure; conversely, paroxysmal nocturnal hemoglobinuria may evolve years after aplastic anemia is diagnosed.¹⁰ In paroxysmal nocturnal hemoglobinuria, flow cytometry shows a deficiency of CD59 on erythrocytes and leukocytes.

Irrespective of the etiology of bone marrow failure, life-threatening complications may arise from blood cytopenias. The most common causes of death are bacterial sepsis and fungal infection secondary to refractory granulocytopenia.¹⁴ Broad-spectrum antibiotics should be used to treat suspected infection in the granulocytopenic patient. Historically, gram-negative organisms were the most frequent cause of fulminant infection in this patient population. With the increased use of central venous catheters, gram-positive organisms now predominate.¹⁵ Antifungal therapy should be instituted in patients who fail to defervesce within 3 to 5 days of treatment with antibiotics. Persistent, unexplained fever requires thorough evaluation to look for evidence of invasive fungal infection.

Platelet transfusions should be used judiciously in an effort to avoid alloimmunization to platelet antigens, generally being reserved for episodes of active bleeding. Similarly, RBC transfusions should be reserved for patients whose oxygen delivery may be compromised as a result of profound anemia. The patient should not receive blood products donated by family members to avoid sensitization to leukocyte and platelet antigens of potential bone marrow donors. All blood products should be irradiated and leukodepleted to decrease the risk of graft-versus-host disease.¹⁵ Treatment of severe acquired aplastic anemia involves either the use of immunosuppressive therapy or replacement of bone marrow through stem cell transplantation. The patient and immediate family members should undergo human leukocyte antigen typing. The treatment of choice, bone marrow or peripheral blood stem cell transplantation from a histocompatible sibling, produces long-term survival rates of 75% to 80%.¹⁶ Unfortunately, up to 70% of patients may lack a suitably matched sibling donor. Stem cells are harvested from matched unrelated donor, or umbilical cord blood, produce poorer outcomes because of the higher rate of graft-versus-host disease. For these patients, immunomodulation, which usually includes a combination of antithymocyte globulin, cyclosporin, and corticosteroids, often with use of hematopoietic growth factors, has resulted in response rates of 70% to 80%.^17,¹⁸ Not all responders achieve a complete remission, however; late relapses, as well as evolution to myelodysplasia and leukemia, are reported.¹⁹

Hemolytic Anemia

Hemolysis, the destruction of RBCs with liberation of hemoglobin, may occur either within the blood vessels (intravascular hemolysis) or the reticuloendothelial system (extravascular hemolysis). Anemia results when the rate of RBC destruction exceeds new RBC production in the bone marrow.²⁰ Laboratory findings in patients with hemolytic anemia usually include increased reticulocyte count and elevated serum concentrations of unconjugated bilirubin and lactate dehydrogenase. Intravascular hemolysis usually results in decreased serum haptoglobin concentrations.

Premature destruction of RBCs may result from intrinsic RBC abnormalities, such as hemoglobinopathies or red cell membrane defects, or from a variety of extrinsic factors (Figure 81-1).² Numerous hemoglobin variants resulting in shortened RBC survival have been identified. Individuals with sickling hemoglobinopathies may suffer a variety of complications that require treatment in an ICU (see Chapter 84). Abnormalities in the structure of the RBC membrane, as in hereditary spherocytosis, or decreased quantities of RBC enzymes, as in G6PD deficiency, also decrease red cell survival. Hemolysis in these settings occurs primarily extravascularly. Mechanical disruption of the red cell membrane secondary to factors extrinsic to the RBC may lead to macroangiopathic hemolytic anemia, as with turbulent flow around a prosthetic heart valve, or microangiopathic hemolytic anemia, caused by fibrin deposition in the microvasculature. The latter process is seen in consumptive disorders, including DIC, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura.²¹ In these entities, hemolysis is primarily intravascular. Schistocytes are characteristically seen on the blood smear.

Figure 81–1 Causes of premature destruction of the red blood cell. CU, Copper; DIC, disseminated intravascular coagulation; G6PD, glucose 6-phosphate dehydrogenase; HS, hereditary spherocytosis; PK, pyruvate kinase; PNH, paroxysmal nocturnal hemoglobinuria.

The hemolytic processes that result from abnormal interactions between erythrocytes and the immune system are known collectively as autoimmune hemolytic anemia (AIHA).² AIHA can be classified as either primary, in which there is no identifiable systemic illness except possibly a history of a recent viral-like illness, or secondary, in which the hemolytic anemia is present in the context of another illness. AIHA has been reported as a manifestation of autoimmune disorders (e.g., lupus erythematosus), immunodeficiency disorders, malignancies, specific infections, or as a drug reaction (Box 81-3).²¹ AIHA also may be classified by the thermal sensitivity of the autoantibodies. The most common form is the result of warm-reactive immunoglobulin (Ig) G autoantibodies directed against RBC membrane proteins. Extravascular hemolysis occurs, with sensitized erythrocytes cleared primarily in the spleen. Cold-agglutinin disease, the second most common form of AIHA, most frequently occurs with Mycoplasma pneumoniae infections, but it also is associated with other infectious agents, including Epstein-Barr virus, cytomegalovirus, and mumps virus. In this disorder, IgM autoantibody binds to the RBC and fixes complement. The erythrocytes may undergo intravascular hemolysis, or they may be cleared by the reticuloendothelial system, primarily in the liver. Paroxysmal cold hemoglobinuria, a rare variant of AIHA in which an IgG autoantibody binds at cold temperature to the P-antigen of the erythrocyte, fixing complement (the Donath-Landsteiner antibody) and producing intravascular hemolysis. It usually follows a viral illness.²¹ Although drug-induced autoantibodies occur uncommonly in children, they may follow exposure to some antibiotics, including penicillins and cephalosporins.^22,²³ Mechanisms of drug-induced hemolysis may include autoantibody formation and adsorption of the drug onto the red cell membrane, with immune complex formation with IgG or IgM.²⁴

^∗ Occurs in the majority of affected children and often follows a nonspecific viral-like syndrome, but in the absence of another systemic illness.

Patients with AIHA usually present with pallor, jaundice, and splenomegaly on physical examination. The reticulocyte count is generally elevated, although initially it may be low or normal. Spherocytes and polychromasia are present on the peripheral blood film, and nucleated RBCs are frequently seen. RBC agglutination may be present in cold-reactive AIHA. The direct antiglobulin test (Coombs test) demonstrates the presence of antibodies or complement on the red cells. The indirect antiglobulin test measures the presence of unbound antierythrocyte antibodies in the patient’s serum.

Therapy depends on the type of AIHA and the severity of clinical symptoms. Profound anemia, usually with a hemoglobin level of less than 5 g/dL, may result in cardiovascular compromise and requires erythrocyte transfusion to increase O₂-carrying capacity. The presence of autoantibodies often makes cross-matching blood difficult, and the patient may require transfusion with “least incompatible” blood.²⁵ Significant hemolytic transfusion reactions are infrequent.²⁵ However, severe hemolysis occurs on rare occasions, with hemoglobinemia and hemoglobinuria resulting in renal failure. Therefore transfusions should be started at a slow rate, and both plasma and urine samples should be checked regularly for free hemoglobin.²¹ Patients with cold-reactive antibodies should be kept warm, and a blood warmer should be used for the transfused blood.²⁶ Even in the absence of transfusion, significant intravascular hemolysis may occur in patients with cold-reactive antibodies. Maintaining good renal blood flow and careful monitoring of urine output in this setting may help obviate renal injury.²⁷ Corticosteroids appear to slow the hemolytic process, particularly in patients with IgG autoantibodies, in whom they appear to inhibit Fc receptor-mediated clearance of sensitized erythrocytes.²⁸ The usual dosage is 1 to 2 mg/kg methylprednisolone given intravenously every 6 hours until the patient is clinically stable. The patient then can be switched to oral prednisone (2 mg/kg/day for 2 to 4 weeks, followed by a slow taper over 1 to 3 months).²¹

Corticosteroids may also be effective in cold agglutinin disease, although the response is less predictable.²⁹ High-dose intravenous γ-globulin (IVIG, 1 g/kg/day for 5 days), produces response in approximately one third of patients with warm-reactive disease.³⁰ Plasmapheresis and plasma exchange may be beneficial, particularly in patients with IgM autoantibodies.³¹ The overall prognosis for children with AIHA is good. Cold-reactive AIHA generally resolves completely. Some patients with warm-reactive antibodies have a chronic course, marked by remissions and exacerbations.²¹

Thrombocytopenia

Thrombocytopenia may be secondary to either decreased platelet production or increased platelet destruction. Decreased platelet production may result from primary bone marrow failure states or from bone marrow infiltration by malignant cells as in leukemia, lymphoma, and metastatic solid tumors. Bone marrow suppression, a common side effect of antineoplastic therapy including both chemotherapy and radiotherapy, frequently leads to periods of thrombocytopenia. Thrombocytopenia or platelet dysfunction may result in bleeding, usually involving the skin and mucous membranes. Clinical manifestations include petechiae and purpura, epistaxis, gastrointestinal bleeding, hematuria, and menorrhagia. Intracranial hemorrhage is an infrequent manifestation of thrombocytopenia.

Indications for platelet transfusion in these settings vary with the underlying cause of thrombocytopenia and the patient’s clinical status. Patients with primary bone marrow failure, who likely will experience prolonged thrombocytopenia, generally receive transfusions only for active bleeding because of the risk of alloimmunization. In addition, exposure to multiple platelet donors may jeopardize the success of bone marrow transplantation by increasing the risk of graft rejection.³² In the absence of other hemorrhagic risks, platelet counts of 10,000/dL or greater usually carry little risk of bleeding.³³ The threshold for transfusion may need to be set higher in patients with sepsis, decreased humoral coagulants, or other risk factors. In the perioperative setting, platelet counts should be maintained at higher than 50,000/dL and greater than 100,000/dL for neurologic or ophthalmologic surgery.³⁴ Use of ABO-compatible donors and leukoreduction diminishes the risk of platelet alloimmunization.³³ Single-donor apheresis units reduce donor exposure compared with pooled platelet concentrates, but whether such usage reduces the incidence of platelet alloimmunization remains unclear.³⁵

Immune Thrombocytopenia

Immune platelet destruction may be caused by autoantibodies, drug-dependent antibodies, or alloantibodies. Alloantibodies result from exposure to polymorphic epitopes expressed on foreign platelets to which the patient has been exposed (see previous section). Drug-induced thrombocytopenia may be suggested by the patient’s medication history. Laboratory tests for specific drug-associated antiplatelet antibodies are available.

In immune thrombocytopenia purpura (ITP), autoantibodies to platelets may be associated with other autoimmune disorders or immune deficiency states, or after viral illness or immunization.³⁶ The incidence of childhood ITP was found to range from 5 to 7 per 100,000 per year, with 25% of the children subsequently developing chronic ITP.³⁷ Frequently, no predisposing condition is identified (idiopathic thrombocytopenia purpura). Regardless of cause, the reticuloendothelial system removes antibody-coated platelets, with the bulk of the destruction occurring in the spleen. These children typically present with petechiae, purpura, and bleeding from mucous membranes and isolated thrombocytopenia. The bone marrow responds with increased platelet production. The rapid turnover in platelets results in younger, somewhat larger, platelets entering the blood. Hence, serious bleeding rarely occurs because of the increased effectiveness of platelets.³⁸ In a recent retrospective review, a low admission mean platelet volume value (<8 μL) and a history of viral prodrome were found to be independent prognostic variables that predicted durable remission.³⁹

The primary goal of therapy in children with ITP is to limit bleeding especially from the central nervous system. Therapy does not appear to affect the natural history of the illness. There is no consensus regarding the management of acute ITP and the need for intervention in the absence of significant hemorrhage remains the subject of debate.⁴⁰ Intracranial hemorrhage remains rare, and there are no data that treatment actually reduces the incidence of intracranial hemorrhage. Therapy is directed at slowing clearance of sensitized thrombocytes in the spleen and reducing antibody production. Initial medical management usually involves the use of corticosteroids (prednisone 2 mg/kg/day) or IVIG (1 g/kg/day for 1 to 2 days).^41,⁴² High-dose methyl-prednisolone (30 mg/kg/day intravenously for 3 days) also is effective.^43,⁴⁴ Bone marrow evaluation to rule out malignancy before corticosteroid therapy should occur. Infusion of anti-Rh(D) immunoglobulin (50 to 75 μg/kg) for individuals who have Rh(D)-positive RBCs prolongs survival of antibody-coated platelets in patients with ITP. As with IVIG, the major mechanism appears to include blockage of Fc receptors on reticuloendothelial cells.⁴⁵ Use of these agents usually halts bleeding and raises platelet counts to safe levels within a few days, although evidence indicating their influence on the course of the disease remains lacking.

Intracranial hemorrhage, the most devastating complication of ITP, although rare requires immediate intervention. Consequently, patients presenting with headaches, persistent vomiting, or neurologic symptoms require emergent computed tomography (CT) scan of the head. Therapy for intracranial hemorrhage usually includes, IVIG, corticosteroids, and emergency splenectomy.⁴⁶ Platelet transfusions in ITP rarely result in an increase in the platelet count because of rapid consumption of transfused platelets. Nevertheless, intermittent (2 to 4 IU/m² every 6 to 8 hours) or continuous (0.5 to 1 IU/m²/hr) platelet transfusions have been administered for life-threatening hemorrhage, with decreases in bleeding reported.^47,⁴⁸ Plasmapheresis may be beneficial in patients who do not respond to these interventions.⁴⁹ A splenectomy should be performed if a craniotomy is required, to maximize the perioperative platelet count.⁴⁷

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