Hematologic manifestations of systemic illness

Intravascular hemolytic anemia may occur following cardiac procedures using prosthetic valves or synthetic patches for correction of valvular disease and anatomic defects, respectively. Aberrant mechanical forces generated by regurgitant flow, impaired endothelialization, or valve calcification mediate red cell lysis.

• Laboratory findings indicative of intravascular hemolysis include elevated serum lactate dehydrogenase (LDH), reduced serum haptoglobin, hyperbilirubinemia with an increased indirect component, and hemoglobinuria.

• Chronic intravascular hemolysis may lead to iron deficiency secondary to shedding of hemosiderin within renal tubular cells into the urine.

• Treatment relies on surgical repair of dysfunctional prosthesis in cases of severe hemolysis.

An uncommon cause of autoimmune hemolytic anemia occurs following cardiac surgeries such as heart transplantation and may also be associated with additional immune cytopenias including acquired Glanzmann thrombasthenia and idiopathic thrombocytopenic purpura (ITP).

• A 4-week course of weekly intravenous (IV) rituximab 375 mg/m ² demonstrated efficacy in a series of pediatric transplant patients with autoimmune cytopenias postcardiac transplant.

Infective endocarditis mediates anemia through intravascular hemolysis and anemia of inflammation. Rarely, infective endocarditis may cause pancytopenia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by easy bruisability, epistaxis, and respiratory and gastrointestinal (GI) bleeding due to abnormal blood vessels ( i.e. telangiectatic lesions). Chronic blood loss from these lesions may result in an iron deficiency anemia (IDA) and infrequently (approximately 5% of patients) causes severe hemorrhage manifesting as a normocytic anemia. Treatment for HHT-associated anemia includes:

• Oral or IV iron supplementation;

• Trials are underway exploring medical treatments, including the vascular endothelial growth factor (VEGF) inhibitor bevacizumab; and

• Packed red blood cell (RBC) transfusion as indicated.

Congenital heart disease (CHD)-associated hypoxemia produces a compensatory elevation in erythropoietin (EPO) and secondary erythrocytosis (see Chapter 10: Primary and Secondary Erythrocytosis).

• Secondary erythrocytosis predisposes patients to cerebrovascular accidents secondary to hyperviscosity as well as symptomatic hypoglycemia (especially in the neonatal period).

• The use of partial exchange transfusion has been suggested, although the long-term value of exchange has been challenged.

• In general, serious consideration for dehydration and iron deficiency must be considered. Unlike many situations relieved by therapeutic phlebotomy, iron deficiency secondary to phlebotomy may actually increase the chance of viscosity-related injury and must be avoided. Any therapeutic phlebotomy in these patients should be performed in well-hydrated and iron-replete patients with no sign of iron deficient maturation defect in their red cells.

• Hydroxyurea at an initial dose of 10–13 mg/kg/day escalated by 5 mg/kg/day every 8 weeks resulted in symptomatic relief in a small series of patients with persistent CHD. However, large studies are lacking, and the potential for myelosuppression should be considered.

Cardiac anomalies, particularly situs inversus , may be associated with hyposplenism and the blood smear may show Howell–Jolly and Pappenheimer bodies.

Idiopathic pulmonary hemosiderosis is a rare chronic disease characterized by recurrent intraalveolar microhemorrhages with pulmonary dysfunction, hemoptysis, and hemosiderin-laden macrophages, which results in IDA.

• Idiopathic pulmonary hemosiderosis associated with celiac disease is referred to as Lane–Hamilton syndrome.

• Variant associated with hypersensitivity to cows’ milk (Heiner’s syndrome) and one that occurs with a progressive glomerulonephritis (Goodpasture syndrome).

• Bronchoscopy with bronchoalveolar lavage or gastric aspirates containing siderophages establishes the diagnosis.

• The mainstray of treatment involves protecting hemoglobin levels with transfusion when necessary and iron supplementation. Alternative therapies are also being used to prevent further hemorrhage, including high-dose steroids, rituximab, and chemotherapy immunosuppression such as cyclophosphamide.

Hypoxia secondary to pulmonary disease results in secondary erythrocytosis.

Pediatric IDA after the age of 5 years must suggest the possibility of GI blood loss. IDA may occur as a manifestation of gastroesophageal reflux disease, Meckel’s diverticulum, inflammatory bowel disease (IBD), polyps, or HHT, and therefore, endoscopy may be required in unexplained iron deficiency.

Chronic atrophic gastritis causes iron deficiency and may lead to megaloblastic anemia secondary to associated vitamin B ₁₂ malabsorption. Parietal cells play an important role in vitamin B ₁₂ absorption by producing intrinsic factor (IF).

• Pernicious anemia is a subtype of megaloblastic anemia resulting from autoantibodies against parietal cells and IF (see Chapter 4: Nutritional Anemias).

Gastric resection may result in iron deficiency or in vitamin B ₁₂ deficiency.

Zollinger–Ellison syndrome (increased parietal cell production of hydrochloric acid) may cause iron deficiency through mucosal ulceration.

Helicobacter pylori infection, although atypical in children, may cause chronic gastritis as well as initiate IDA and vitamin B ₁₂ deficiency.

• Standard treatment includes amoxicillin, clarithromycin, and a proton pump inhibitor.

Short bowel syndrome as a result of significant bowel resection may impair micronutrient absorption leading to iron, folate, and vitamin B ₁₂ deficiencies.

Celiac disease or tropical sprue may cause malabsorption of iron and folate. Other hematologic manifestations of celiac disease are discussed in later sections and in Table 2.1 .

IBD may cause anemia of chronic inflammation and iron deficiency from blood loss. Ulcerative colitis tends to appear as pure IDA, while Crohn’s disease often has a component of the anemia of inflammation.

Peutz–Jeghers syndrome (intestinal polyposis and mucocutaneous pigmentation) predisposes to adenocarcinoma of the colon.

Diarrheal illnesses of infancy can produce life-threatening methemoglobinemia. Most patients are at or below the 10th percentile for weight at the time the syndrome is discovered. There is evidence that this responds to methylene blue.

Hemorrhagic pancreatitis produces an acute normocytic, normochromic anemia. It may also be associated with disseminated intravascular coagulation (DIC).

Shwachman–Diamond syndrome (see Chapter 6: Bone Marrow Failure, and Chapter 11: Disorders of White Blood Cells) is characterized by congenital exocrine pancreatic insufficiency, metaphyseal bone abnormalities, and neutropenia. There may also be some degree of anemia and thrombocytopenia.

Pearson syndrome is characterized by exocrine pancreatic insufficiency and severe sideroblastic anemia.

Anemias of diverse etiologies occur in acute and chronic liver disease. Red cells are frequently macrocytic [mean corpuscular volume (MCV) of 100–110 fL] having acquired additional surface area from lipid accumulation. Target cells and acanthocytes (spur cells) are frequently seen. Some of the pathogenic mechanisms of cirrhosis-related anemia include:

• Reduced red cell survival and red cell fragmentation (spur cell anemia) often occur in later-stage cirrhosis in the presence of dyslipidemia.

• Hypersplenism with splenic sequestration in the presence of secondary portal hypertension.

• IDA due to chronic blood loss or normocytic anemia secondary to acute hemorrhage from esophageal varices in portal hypertension.

• Normochromic normocytic anemia secondary to chronic illness.

• Megaloblastic anemia secondary to folate deficiency in malnourished individuals.

Aplastic anemia following acute hepatitis (typically seronegative) in certain immunologically predisposed hosts.

Chronic hemolysis, which is the presenting manifestation in 5–6% of patients with Wilson disease, induced by copper accumulation in RBC.

Renal insufficiency and chronic kidney disease (CKD) are frequently associated with anemia (and sometimes pancytopenia), and occur through multiple pathogenic mechanisms, including reduced serum EPO concentrations mediated by loss of EPO-producing interstitial cells in response to renal inflammation and fibrosis (90% of EPO synthesis occurs in the kidney), diminished circulating red cell lifespan, and decreased bone marrow erythropoiesis secondary to uremic toxins, altered iron homeostasis emanating from reduced reneal clearance if hepcidin, and iron and folate deficiencies induced by dialysis.

• Laboratory findings include:

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    hemoglobin as low as 4–5 g/dL;

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    normochromic and normocytic red cell morphology;

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    low reticulocyte count; and

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    decreased erythroid precursors in bone marrow aspirate.

• Evaluation and treatment [as per Kidney Disease: Improving Global Outcomes(KDIGO) guidelines]:

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    In children <15 years of age, hemoglobin concentrations <11.0 g/dL (0.5–5 years), <11.5 g/dL (5–12 years), and <12.0 g/dL (12–15 years) warrant an anemia workup.

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    In adolescents >15 years of age, hemoglobin <13 g/dL in males and <12 g/dL in females warrant an anemia workup.

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    Recombinant human EPO (rHuEPO) administration ( Fig. 2.1 )

    

    There is a black box Food and Drug Administration warning for the use of EPO:

    • In contrast to adults, there is no exact hemoglobin threshold for rHuEPO initiation in children, but rather, is initiated based on clinical judgment and possible benefits to patient quality of life. However, one study demonstrated increased mortality in patients with hemoglobin <11 g/dL.

    • Initial dosing relies on the type of rHuEPO: 20–50 IU/kg three times per week for epoetin alfa/beta, and 0.45 μg/kg once weekly or 0.75 μg/kg every 2 weeks for darbepoetin-alfa.

    • Target hemoglobin increase is 1–2 g/dL over a 4-week period with optimal hemoglobin range between 11 and 12 g/dL (not to exceed 14 g/dL).

    • Titrate the dose:

      • if no response, increase rHuEPO up to 300 unit/kg/day subcutaneous (SC) three times a week;

      • if hematocrit (Hct) reaches 40%, stop rHuEPO until Hct is 36% and then restart at 75% dose;

      • if Hct increases very rapidly (>4% in 2 weeks), reduce dose by 25%.

    • Adverse effects from rHuEPO treatment include hypertension secondary to increased viscosity (30% of patients), increased risk of thrombosis, and increased mortality with high-dose erythropoiesis stimulating agent (ESA) (mean ESA equivalent dose of >6000 IU/m ² /week).

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    Iron administration and iron status monitoring:

    • For anemic CKD patients not on iron supplementation or rHuEPO, oral iron should be initiated in patients with a ferritin <100 ng/mL and transferrin saturation (TSAT) <20% or a soluble transferrin index >2. IV iron is used for patients on hemodialysis.

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    Folic acid 1 mg/day is recommended because folate is dialyzable.

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    Packed red cell transfusion is rarely required.

• Experimental ESAs include EPO mimetic peptides, EPO receptor modulators, molecules that prevent hydroxylation and subsequent degradation of hypoxia induced factor, hepcidin regulators, and EPO gene therapy.

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    These novel ESAs have shown efficacy in preclinical cellular and animal models, and many are currently in human clinical trials.

Anemia is frequently present in overt and subclinical hypothyroidism due to the importance of thyroid hormone signaling in erythroid precursor differentiation.

• Laboratory findings include:

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    Normochromic and normocytic anemia, but may present as hypochromic or macrocytic secondary to an associated iron or vitamin B ₁₂ deficiency, respectively

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    Bone marrow is characterized as fatty and hypocellular

• Of note, hypothyroidism with concomitant macrocytic anemia and megaloblastic bone marrow warrants investigation of underlying autoimmune processes ( i.e ., juvenile pernicious anemia with polyendocrinopathies)

In Addison disease, some degree of anemia is also present, but may be masked by coexisting hemoconcentration. The association between Addison disease and megaloblastic anemia raises the possibility of an inherited autoimmune disease directed against multiple tissues ( i.e ., juvenile pernicious anemia with polyendocrinopathies).

Hypercortisolism ( i.e. , Cushing syndrome) and congenital adrenal hyperplasia may produce secondary erythrocytosis mediated by excess androgens, which stimulate erythropoiesis.

Patients with extensive eczema and psoriasis commonly have anemia.

The anemia is typically normochromic and normocytic (anemia of inflammation), and mild in most cases, but severely affected individuals can have hemoglobin levels less than 9 g/dL.

Macrocytic anemia secondary to malabsorption.

Hyposplenism: Howell–Jolly bodies may be present on blood smear.

This disease is characterized by ectodermal dysplasia and aplastic anemia (see Chapter 6: Bone Marrow Failure).

The aplastic anemia is associated with high MCV, thrombocytopenia, and elevated fetal hemoglobin. This may occur before the onset of skin manifestations.

Mast cell disease or mastocytosis is associated with an abnormal accumulation of mastocytes (more closely related to monocytes or macrophages rather than to basophils) in the dermis (cutaneous mastocytosis) or in an internal organ (systemic mastocytosis).

The systemic form is rare in children.

In children, this condition is more common under 2 years of age.

It typically presents either as a solitary cutaneous mastocytoma or more commonly, as urticaria pigmentosa. Involvement beyond the skin is unusual in children, but splenomegaly and bone lesions have been reported.

No reports of bone marrow disease in either acquired or congenital mastocytosis have been reported.