Systemic Lupus Erythematosus

Juvenile Idiopathic Arthritis (Rheumatoid Arthritis)

Anemia in rheumatoid arthritis is caused typically by both anemia of chronic disease and iron-deficiency anemia. A high incidence of iron deficiency has historically been seen in children with juvenile idiopathic arthritis (JIA), because of gastrointestinal blood loss secondary to long-standing use of aspirin and nonsteroidal analgesics in the symptomatic treatment of this disease. The severe inflammatory nature of this disorder makes it a model for anemia of chronic disease, a sideropenic anemia with reticuloendothelial iron overload. Iron is not only loaded inappropriately into the reticuloendothelial system but also accumulates in the involved joint, possibly playing a role in joint destruction.

Microcytosis is very common in juvenile chronic forms of arthritis, with a rate of occurrence of about 40%. The degree of microcytosis relates directly to disease activity. Occasionally, macrocytic anemia develops in patients with JIA. Although abnormal vitamin B ₁₂ metabolism has been suggested as a cause, this is not seen in children. Folate metabolism may, however, be abnormal. Some children with rheumatoid arthritis have diminished plasma and red blood cell folate levels. Increased folic acid plasma clearance and reduced protein binding have also been observed.

A few patients have had mild shortening of red blood cell survival as a result of an extracorpuscular defect. More severe hemolytic anemia is much less common than in other collagen vascular diseases. Erythroid aplasia responsive to corticosteroid therapy has been reported in a child with juvenile rheumatoid arthritis. Circulating inhibitors of erythropoiesis have also been noted.

Leukocytosis and neutrophilia are common during acute flare-ups of JIA; however, this is uncommon in the adult form of the disorder. Neutrophil chemotaxis may be mildly diminished. Phagocytosis is normal or mildly impaired. Nitroblue tetrazolium dye reduction may be increased during active phases of this disease. These minimal alterations in white blood cell function do not produce any clinical disturbances. Wound healing, for example, is normal even after surgery in patients who have not been receiving high-dose corticosteroid therapy. A peripheral blood eosinophil count greater than 5% has been noted in slightly more than 50% of children with JIA. Some will also demonstrate basophilia and plasmacytoid lymphocytes.

Secondary thrombocytosis is common in JIA, as part of the inflammatory response. A consumptive coagulopathy may be seen in association with systemic JIA. Acquired circulating inhibitor to factor VIII has been described in JIA and may cause bleeding. However, clinical problems related to coagulation abnormalities in this disorder are rare.

Felty Syndrome

Felty originally described the triad of rheumatoid arthritis, splenomegaly, and neutropenia in 1924. Whether Felty syndrome occurs with JIA is unclear. Splenomegaly is seen in about 20% of all children with JIA, especially in those with the acute extraarticular exacerbations of this disease. However, splenomegaly alone does not suggest Felty syndrome.

The etiology for the neutropenia of Felty syndrome is multifactorial. The neutropenia is not always a consequence of hypersplenism per se because only 60% of adults who undergo splenectomy experience resolution of their neutropenia. In 50% of patients, a maturation arrest bone marrow pattern is demonstrated, possibly from immune humoral or cellular mechanisms. Neutropenia in association with cytotoxic lymphocytes directed against granulocyte progenitors has also been reported, as have lower than normal levels of granulocyte colony-stimulating factor (G-CSF) activity. The neutropenia of Felty syndrome may also be immunologic in origin, because some patients have IgG antibodies directed against neutrophils.

The neutropenia may be associated with serious infections. Recombinant human G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF) both effectively raise the neutrophil count in essentially all patients with Felty syndrome. The neutrophil count decreases again once the growth factor treatment is stopped, but often it stabilizes at a level higher than it was before treatment. The drug can be used long term and may be cost-effective in selected patients with a high incidence of infections and repeated hospitalizations. Methotrexate treatment in Felty syndrome can be effective in correcting the neutropenia. Splenectomy may be indicated in those in whom G-CSF or GM-CSF is ineffective or rapid blood cell improvement is desired. A rise in the neutrophil count after splenectomy is experienced by 50% to 80% of patients.

Polyarteritis Nodosa

Microangiopathic hemolytic anemia can be associated with renal disease or hypertensive crises in polyarteritis nodosa. The hemolytic process in these circumstances parallels disease activity. Anemia of chronic disease is common in polyarteritis nodosa.

Neutropenia occurs and is associated with the presence of antineutrophil cytoplasmic antibodies. Neutrophilia and eosinophilia are also common. The eosinophilia may be marked, particularly in those patients with clinically apparent pulmonary involvement.

Wegener Granulomatosis

Wegener granulomatosis, characterized by necrotizing vasculitis (particularly in the lungs and kidneys), is rare but can affect children. The disease can also occur in the neonatal period. The course of the disease is marked by fever, cough, hemoptysis, epistaxis, nasal discharge, obliteration of the nasal sinuses, and nodular pulmonary infiltrates. Renal failure may occur. A microangiopathic hemolytic anemia can develop. An associated anemia of chronic disease is common.

The white blood cell count is elevated, often coupled with an eosinophilia. The disease is characterized by marked thrombocytosis. Autoantibodies directed against cytoplasmic components of neutrophil granulocytes and monocytes have been described as a disease-specific marker for Wegener granulomatosis.

Ehlers-Danlos Syndrome

Most Ehlers-Danlos subtypes are caused by mutations in fibrillar collagens. The elastic tissue defects result in an increased bleeding tendency. Different forms of Ehlers-Danlos have been associated with platelet and coagulation defects, including disorders of platelet aggregation and factor deficiencies. It is not clear whether these hematologic defects are sporadic associations in individual patients or true associations with the subtypes of Ehlers-Danlos.

In Ehlers-Danlos syndrome, the bleeding symptoms are typically easy bruising, gingival bleeding, prolonged bleeding with surgical or dental procedures, and menorrhagia. Other common clinical findings include skin hyperextensibility, “cigarette paper–like” scars, and joint hypermobility. The vascular Ehlers-Danlos syndrome, type IV, is an autosomal dominant disorder caused by mutations in the collagen type III alpha 1 (COL3A1) gene. Type IV Ehlers-Danlos is associated with small and large vessel bleeding, including arterial bleeding, and spontaneous ruptures of the bowel, uterus, and lungs. Nonemergent surgical interventions are to be avoided in these individuals owing to the high risk for perisurgical bleeding and complications. With serious bleeding in Ehlers-Danlos syndrome patients, efficacy of desmopressin and of factor VIIa has been reported.

Other Inherited Connective Tissue Disorders

Marfan syndrome is not associated with fragility of capillaries or small to medium-sized arteries or veins. However, many Marfan syndrome patients report easy bruising, which has not been explained. A defective fibronectin has been proposed as the cause of the hypermobility and platelet dysfunction in some patients. Easy bruising has also been reported in individuals with osteogenesis imperfecta.

Red Blood Cell Disturbances

The anemia of chronic disease is common to all infections. Even common childhood infections, especially those associated with inflammation, will cause a decline in hemoglobin concentration. During active inflammation, the hemoglobin concentration declines about 13%, usually within 1 week, followed by an increase of nearly 25% during resolution of the active inflammation. The actions of hepcidin probably deprive microorganisms of iron, which is an essential nutrient for microbial replication, and may be a component of host immunity against infection. Serum levels of iron decrease after a bacterial challenge, and the lactoferrin released from stimulated granulocytes is a conduit for this iron to return to reticuloendothelial cells. Many examples of bacterial pathogenicity being dependent on iron availability (e.g., Neisseria gonorrhoeae, Neisseria meningitidis ) support the hypothesis that the anemia of infection is the body’s compromise in an attempt to deprive invading microorganisms of iron.

Although some infections, particularly viral ones, such as parvovirus, cause transient bone marrow aplasia or selective erythroid aplasia, anemia from this cause is rare because of the long life span of red blood cells. In contrast, patients with chronic hemolytic anemias may experience a rapid decrease in hemoglobin concentration or an “aplastic” crisis during viral and some bacterial infections.

Severe hemolytic anemia may be observed in certain types of infections. Clostridial infections may result in a high titer of hemolysins and cause severe anemia. A similar severe anemia may result from sepsis related to other bacterial organisms, including staphylococci, streptococci, pneumococci, and Haemophilus influenzae. Immune hemolytic anemia mediated by a cold agglutinin may be observed with Listeria and Mycoplasma infections and occasionally with infections by other organisms such as Epstein-Barr virus.

Many viral illnesses may be associated with what appears to be a mild hemolytic anemia for which no pathologic mechanism has been defined. The most common morphologic finding in these circumstances is poikilocytosis. Certain viruses, such as most strains of influenza virus, contain neuraminidase activity, which is, at least theoretically, capable of affecting the sialic acid content of the red blood cell membrane. Whether this plays any significant role in the hemolysis associated with some viral diseases is not known.

Many congenital infections, including cytomegalovirus, herpes simplex, rubella, toxoplasmosis, and syphilis, produce profound hemolytic anemia in the neonatal period, even though these same agents may not significantly alter red blood cell survival at other times of life.

White Blood Cell Disturbances

The white blood cell count may be normal, low, or high with infection. Viral illnesses may be associated with leukocyte counts lower than 5000 cells/mm ³ , although bacterial diseases of certain types or overwhelming sepsis of any type may also cause leukopenia. The most common viral illnesses associated with leukopenia are infectious hepatitis, infectious mononucleosis, rubella, measles, and, occasionally, influenza. Of the bacterial infections, shigellosis may produce leukopenia with a marked increase in band cell forms. Sepsis caused by meningococci, pneumococci, staphylococci, and a few other bacterial pathogens may also cause leukopenia.

Neutrophilia, with or without an increase in band cell count, is a common result of bacterial infection. White blood cell and neutrophil counts do not differ between children of different races with bacteremia. Occasionally, viral illness also initially will be manifested as neutrophilia. A variety of morphologic changes may appear in the neutrophils of patients with infection. Döhle bodies ( Fig. 37-1 ), which are pale blue cystlike inclusion bodies usually located in the periphery of the cytoplasm of neutrophils, may appear in bacterial infections. They are occasionally associated with viral illness but are also commonly seen in patients with burns, massive trauma, and cancer, as well as in pregnancy and after the use of cyclophosphamide. In addition, Döhle bodies are seen in the May-Hegglin anomaly. Increased size of neutrophil granules (“toxic granulation”) may be found in both bacterial and viral illnesses, as well as in many of the other disorders associated with the presence of Döhle bodies. Vacuolization of the cytoplasm of neutrophils is the next most common morphologic abnormality of neutrophils in patients with significant bacteremia. In overwhelming sepsis, the organisms are frequently evident in the vacuoles of the polymorphonuclear cells. In a study of the neutrophils of patients with bacteremia, Zipursky and associates found toxic granulation, Döhle bodies, and vacuolization in 75%, 29%, and 24%, respectively, of the patients studied.

Döhle bodies.

Increased neutrophil alkaline phosphatase activity and nitroblue tetrazolium dye reduction may also occur, but neither of these characteristics is specific for bacterial infection. Infections may be associated with development of the Pelger-Huët anomaly ( Fig. 37-2 ), in which granulocytes and eosinophils have one or two lobes per nucleus and assume a round, dumbbell, or peanut shape.

Pelger-Huët anomaly.

In neonates, especially those born prematurely, an increase in total white blood cell or mature neutrophil counts may not be seen in the presence of infection. In fact, a decrease in the neutrophil count often occurs. The most helpful signs of septicemia in this age group are an increase in the band cell count and the presence of toxic granulations and Döhle bodies.

Leukocytosis may result from lymphocytosis. The most common infections producing the greatest increases in lymphocyte counts are infectious mononucleosis, cat-scratch disease, and pertussis. Many other viral illnesses, such as cytomegalovirus, rubella, mumps, and hepatitis, may also cause an increase in the lymphocyte count. Lymphopenia of T lymphocytes is a common finding after measles infection.

Eosinophilia may reflect the presence of parasitic infections. In the United States, the most common cause of marked elevations in eosinophil counts is Toxocara infestation, which is often accompanied by high titers of isohemagglutinins. Other parasites commonly causing eosinophilia include organisms belonging to Trichinella, Echinococcus, Filaria, Strongyloides, Schistosoma, Enterobius, and Ancylostoma and tapeworms other than Echinococcus. Allergic sensitization to mites may cause eosinophilia, as well as fungal infections, especially aspergillosis. Eosinophilia is not specific for infestation. Marked degrees of eosinophilia may occur in association with prematurity. An absolute eosinophilia may be expected in about 75% of low-birth-weight infants. In some, the eosinophilia is marked (3000 cells/mm ³ ) and the maximal increase seems to occur at about the time that birth weight is regained, although this is not true in all infants.

Monocytosis is occasionally reported with specific infections, especially tuberculosis, syphilis, and subacute bacterial endocarditis. Monocytosis is often noted early in the course of many infections and again on recovery, particularly if it is associated with granulocytopenia.

Basophilia is rarely seen in infection but has been reported with tuberculosis, influenza, and hookworm infestation.

Clotting Abnormalities and Thrombocytopenia

DIC may be triggered by infectious processes. Of the infectious causes, gram-negative septicemia is probably most common. Meningococcus, Escherichia coli, Proteus, Pseudomonas, Aerobacter, and Klebsiella are among the most common etiologic agents recovered from the bloodstream. Gram-positive septicemia can cause a similar picture. The most common offender is Streptococcus pneumoniae, especially in asplenic individuals. Other gram-positive agents causing DIC include Staphylococcus aureus, other streptococcal species, and Clostridium. A wide range of viral infections may cause a consumptive coagulopathy that often leads to purpura fulminans. Among the most common agents are those that cause infectious hepatitis, measles, rubella, varicella, and infectious mononucleosis. Less common causes of DIC are severe mycoplasmal, rickettsial, and malarial infections.

Thrombocytopenia occurring separately from a true disseminated consumptive process is quite common in many infectious processes, especially in association with infectious mononucleosis, cytomegalovirus, rubella, measles, gram-negative bacteremia, and rickettsial diseases. Congenital viral infections and congenital syphilis and toxoplasmosis, if clinically apparent, are almost invariably associated with increased platelet turnover with or without thrombocytopenia. Pediatric immune thrombocytopenia is commonly associated with viral infections. Immune thrombocytopenia may also occur after immunization with the measles, mumps, and rubella vaccine. Corrigan found that thrombocytopenia without consumptive coagulopathy is an extremely common finding in infants and children with septicemia. In contrast, thrombocytosis is often present during the active phases of infectious processes. The platelet distribution width and mean platelet volume may be helpful in predicting whether the thrombocytopenia is due to infection. In the late neonatal period, thrombocytopenia associated with an infection dramatically increases the mean platelet volume and platelet distribution width as determined by electronic counting equipment.

Bone Marrow Abnormalities

The bone marrow frequently contains clues as to the source of infectious diseases. Histoplasmosis ( Fig. 37-3 ), tuberculosis, kala-azar, Salmonella typhi, and Candida ( Fig. 37-4 ) all have been identified in marrow macrophages. Marrow granulomas may be a marker of disseminated tuberculosis or histoplasmosis ( Fig. 37-5 ). Histoplasmosis, tuberculosis, brucellosis, and Salmonella can be successfully cultured from the marrow aspirate.

Histoplasmosis in the bone marrow.

Candida albicans.

Bone marrow granuloma.

Bacterial Infections

Clostridial Sepsis.

Clostridium perfringens septicemia is seen in a variety of clinical situations but must particularly be considered in patients with penetrating wounds, septic abortions, peritonitis after a perforated viscus, or cholecystitis or cholangitis; in immunosuppressed patients with gastrointestinal or hematologic malignancies; and in neonates with necrotizing enterocolitis. In patients with clostridial sepsis, severe, rapidly progressive intravascular hemolysis and microspherocytosis may occur ( Fig. 37-6 ). Hemolysis of the entire red blood cell mass has been reported. Complications include shock, acute renal failure, and death. Transfusion therapy may be ineffective. Antibiotics and hyperbaric oxygen occasionally have been used successfully to treat clostridial infections.

Peripheral blood in Clostridium perfringens septicemia demonstrating microspherocytes, neutrophils with toxic granulation, vacuolization, and Döhle bodies and erythrophagocytosis.

The mechanism of red blood cell damage is uncertain and may vary between patients. The bacteria produce several hemolytic toxins including α-toxin, a 43-kD protein that contains an NH ₂ -terminal phospholipase domain and a COOH-terminal domain required for hemolysis, and θ-toxin, a 54-kD cholesterol-binding protein that aggregates and forms membrane pores leading to colloid osmotic hemolysis. α-Toxin appears to induce hemolysis through the activation of sphingomyelin metabolism. C. perfringens contains a neuraminidase that cleaves terminal sialic acids from red blood cell glycoproteins in some patients. The underlying galactose residues form the Thomsen-Friedenreich cryptoantigen (or T antigen). Anti-T antibodies are present in almost all adult plasma; thus T-antigen activation can lead to significant hemolysis. In infected infants and children who lack T antibodies, transfusion may lead to massive hemolysis and death. Rarely, T-antigen activation may precede the intravascular hemolysis, leading to early detection of clostridial sepsis and lifesaving therapeutic intervention.

Babesiosis.

In healthy individuals, a mild hemolytic anemia is caused by Babesia microti and Babesia divergens microorganisms. Occasional cases of combined B. microti babesiosis and Lyme disease are described, attributable to the shared geographic locale of the tick vectors for these diseases. The disease can also be acquired by transfusion. Babesiosis is not life threatening except in asplenic subjects in whom the parasitized red blood cells are not contained. Then, the infection can be rapidly progressive and life threatening. In extreme cases, nearly all the red blood cells may be parasitized ( Fig. 37-7 ). Patients may have malaise, headache, fever, shaking chills, profuse sweating, jaundice, and dark urine. There may be intravascular hemolysis and, occasionally, pancytopenia and hemophagocytosis. Diagnosis is made by finding the parasites in blood smears or by serologic tests or amplification of parasitic DNA using the polymerase chain reaction (PCR) assay. Current treatment of symptomatic cases is quinine plus clindamycin, but treatment failures have been reported in asplenic patients. Exchange transfusion may reduce the parasite load and be beneficial.

Babesiosis in the peripheral red blood cells.

Anaplasmosis (Ehrlichiosis).

A variety of hematologic manifestations are found in infections with Ehrlichia chaffeensis, the causative bacteria of human monocytic ehrlichiosis (HME, Fig. 37-8 ), and Anaplasma phagocytophilum, the causative bacteria of human granulocytic anaplasmosis (HGA, Fig. 37-9 )). The disease is transmitted through tick bites, typically through the Lone Star tick or Ixodes scapularis, the shared tick vector of Lyme disease and babesiosis. Transmission has also been reported through blood transfusions. Symptoms are variable but are most severe in immunocompromised individuals. The obligate intracellular bacteria grow within membrane-bound vacuoles in leukocytes. General symptoms can include fever, headache, rash, and neurologic symptoms. Thrombocytopenia and leukopenia are common, often with both lymphopenia and neutropenia. Lymphopenia can be followed by an atypical lymphocytosis in the later stages of disease. Intraleukocytic morulae detected on review of the peripheral blood smear or buffy coat can be seen in up to 50% to 70% of infected individuals. Diagnosis can also be made through serologic tests or PCR assay. Doxycycline is the treatment of choice; however, rifampin has been reported to be effective in young patients.

Intramonocytic morula in human monocytic ehrlichiosis.

Morula-infected neutrophil in human granulocytic anaplasmosis.

Viral Infections

Infectious Mononucleosis.

Infectious mononucleosis is caused by the Epstein-Barr virus (EBV) and historically associated with the triad of (1) the classic clinical picture, (2) atypical lymphocytosis, and (3) positive results on a heterophil antibody test. Serologic testing for EBV is now often used in addition or instead of the heterophil antibody test to confirm acute infection.

Epidemiology.

EBV infection is acquired at an early age in lower socioeconomic groups. In economically privileged children, infection is often delayed until adolescence and young adulthood. About 40% of American children are seropositive for EBV by 5 years of age. In a report from the U.S. Military Academy at West Point, 63.5% of entering cadets had EBV antibody, indicative of previous infection. During the college years, the infection rate among susceptible individuals is 12% to 15% per year.

The pattern of infection in different groups of susceptible persons is probably best explained by transmission of this virus in throat secretions. EBV is present in the saliva of most patients with infectious mononucleosis, in up to 20% of healthy persons with EBV antibodies, and in 50% or more of seropositive patients receiving immunosuppressive drugs. The ease with which EBV is recovered from the oral secretions of persons with primary or reactivated EBV infection suggests that a cell type that freely permits EBV replication exists in the oropharynx. The oropharyngeal epithelial cell may be the target cell type that is productively infected in infectious mononucleosis. Transmission requires intimate contact. Intrafamilial spread, however, does occur frequently, and, in this setting, an incubation period of 4 to 6 weeks has been demonstrated. Another possible route of transmission of EBV is transfusion through white blood cells.

Clinical Manifestations.

The classic clinical manifestations of infectious mononucleosis are generally seen only in adolescents and young adults. Younger children rarely exhibit the typical findings of this disease, and most generally have only a mild viral respiratory illness.

The onset of typical illness is usually a subtle prodrome consisting of fatigue, malaise, sweating, feverishness, and anorexia. Headache, nausea, and vomiting are seen frequently. The most common symptom during this period is a sore throat, which begins slowly and increases in intensity over a 1-week period. The usual findings of infectious mononucleosis then follow ( Table 37-1 ). The course of fever often follows a specific pattern, with no temperature elevation in the morning but daily afternoon or evening peaks of 38.3° C to 39.4° C (101° F to 103° F). Occasionally, higher temperatures are observed. The fever usually lasts about 2 weeks.

TABLE 37-1

Approximate Rate of Occurrence of Various Signs and Symptoms of Infectious Mononucleosis in Young Adults

Symptom or Sign	%
Adenopathy	100
Malaise and fatigue	90-100
Fever	80-95
Sweats	80-95
Sore throat, dysphagia	80-95
Pharyngitis	65-85
Anorexia	50-80
Nausea	50-70
Splenomegaly	50-60
Headache	40-70
Chills	40-60
Bradycardia	35-50
Cough	30-50
Periorbital edema	25-40
Palatal enanthema	25-35
Liver or splenic tenderness	15-30
Myalgia	12-30
Hepatomegaly	15-25
Rhinitis	10-25
Ocular muscle pain	10-20
Chest pain	5-20
Jaundice	5-10
Arthralgia	5-10
Diarrhea or soft stools	5-10
Photophobia	5-10
Rash	3-6
Conjunctivitis	5
Abdominal pain	5
Gingivitis	3
Pneumonitis	3
Epistaxis	3

 

From Finch SC: Clinical symptoms and signs of infectious mononucleosis. In Carter RL, Penman HG, editors: Infectious mononucleosis, Oxford, 1969, Blackwell Scientific, p. 35.

Lymphadenopathy is seen in all patients. Symmetric, moderately enlarged, discrete, slightly tender nodes, especially in the posterior cervical region, are most characteristic. Adenopathy is common in the axillary, epitrochlear, and inguinal areas. The nodes are not matted and do not show signs of heat, redness, or fluctuation. Rarely, enlargement of the mediastinal glands constitutes the only evidence of adenopathy and may be confused with a lymphomatous process.

Splenomegaly occurs in more than 50% of patients with infectious mononucleosis. The spleen is usually just barely palpable but on rare occasion may be quite large. It is smooth, soft to firm, and sometimes slightly tender. In some patients, splenomegaly persists for months, but the most common situation is resolution by 2 to 3 weeks after onset of the illness.

Hepatomegaly occurs in about 20% of patients, and clinical jaundice is seen in 10%. The jaundice is invariably mild. Despite the low rate of occurrence of apparent hepatic dysfunction, virtually all patients with infectious mononucleosis demonstrate abnormal liver enzyme levels. Except in rare patients with acute liver failure, the hepatitis associated with this illness is self-limited. There is no evidence that chronic liver disease or cirrhosis results from infectious mononucleosis.

Rashes occur occasionally, and their manifestation follows no particular pattern. The rash may be a diffuse, faint, erythematous or maculopapular eruption, or it may be urticarial, scarlatiniform, petechial, or herpetiform. In general, the rashes of infectious mononucleosis have no unique features and are of little or no help for diagnosis. Circulating immune complexes and complement sequence activation occur only when rashes are present. If ampicillin is administered to patients with infectious mononucleosis, a rash will develop in 69% to 100%. Other penicillins may cause this response but less often. This rash is not an allergic reaction, and these antibiotics may be administered subsequently without ill effect.

Only a few patients with infectious mononucleosis have no pharyngitis. Almost all demonstrate hyperplasia of the pharyngeal lymphoid follicles. The presence of an exudate is common, and membrane formation occurs frequently. The inflammation may be severe enough to cause respiratory obstruction. Peritonsillar abscesses may complicate the course of the illness. A palatal enanthema is seen in about a third of patients and consists of crops of sharply circumscribed petechiae, symmetrically distributed at the junction of the soft palate. Unfortunately, such petechiae are not specific for infectious mononucleosis and have been described in rubella and other viral disorders. In fact, the entire pharyngeal manifestation of infectious mononucleosis is clinically indistinguishable from that of streptococcal disease.

Periorbital edema is not rare and occasionally leads to the erroneous suspicion that renal disease or hypoproteinemia is present. The edema is self-limited and lasts only a few days.

Complications.

Much attention is paid to the complications associated with infectious mononucleosis, although their overall occurrence is low ( Table 37-2 ). Hematologic complications of infectious mononucleosis include disturbances resulting in anemia, granulocytopenia, thrombocytopenia, and occasional coagulation defects. The rate of occurrence of these hematologic abnormalities is shown in Table 37-3 .

TABLE 37-2

Reported Complications of Infectious Mononucleosis

Type of Complication	Diagnosis or Description of Abnormalities
Neurologic	Bell palsy, cerebellar syndrome, encephalitis, encephalomyelitis, encephalomyelopathy, Guillain-Barré syndrome, meningitis, meningoencephalitis, myelitis, optic neuritis, peripheral neuritis, psychosis, radiculoneuritis, ataxia, positive Babinski sign, coma, convulsions, diplopia, extraocular palsy, facial diplegia, hemiplegia, hyperesthesia, meningismus, mental confusion, nystagmus, papilledema, psychotic reaction, ptosis, respiratory paralysis, positive Romberg sign, seizure, status epilepticus, scotomas
Cardiac	Electrocardiographic changes, myocarditis, pericarditis
Ocular	Conjunctivitis, diplopia, cyclic edema, hemianopia, lacrimal pericyclitis, nystagmus, optic neuritis, ptosis, retinal edema, retinal hemorrhage, retroorbital pain, scotomas, uveitis
Respiratory	Laryngeal obstruction, peritonsillar abscess, pharyngeal edema, pleural effusion, pleuritis, pneumonitis
Hematologic	Acquired hemolytic anemia, agranulocytosis, eosinophilia, fibrinolysis, pancytopenia, splenic rupture, thrombocytopenia
Digestive	Esophageal varices, gingivitis, hepatic dysfunction, hepatic necrosis, jaundice, melena
Renal	Hematuria, hemoglobinuria, nephritis, nephrotic syndrome, porphyrinuria, proteinuria
Other	Bullous myringitis, endocervicitis, orchitis, otitis media, pancreatitis, porphyria, rashes

 

From Finch SC: Clinical symptoms and signs of infectious mononucleosis. In Carter RL, Penman HG, editors: Infectious mononucleosis, Oxford, 1969, Blackwell Scientific, p. 35.

TABLE 37-3

Infectious Mononucleosis—Laboratory Features

Findings	% Positive
Lymphocytosis, relative and absolute	100
Atypical lymphocytes, definite *	100
Epstein-Barr virus antibody in serum	100
Heterophil antibody	80-100
Liver enzyme abnormalities	80-100
Leukocytosis	60-80
Neutropenia	60-80
Hyperbilirubinemia	30-50
Bone marrow granulomas	50
Slight thrombocytopenia	25-50
Increased cold agglutinins	10-50
Occult hemolysis	20-40
Hyperuricemia	15-20
Leukopenia	10-20
Severe thrombocytopenia with bleeding	Rare
Positive direct Coombs test results	Rare
Significant anemia (usually caused by hemolysis)	Rare

 

* Twenty percent or more of white blood cells in peripheral blood.

AIHA can occur with EBV infection and developed in approximately 3% of West Point cadets with infectious mononucleosis. When hemolysis does occur, it usually begins 1 to 2 weeks into the course of the illness. The majority of occurrences terminate in less than 1 month, and chronic hemolysis is rare. Although usually mild, hemolysis occasionally occurs rapidly and can then result in severe anemia. Jenkins reported the first instance of hemolytic anemia in infectious mononucleosis that was mediated by the temporary induction of a high-thermal amplitude cold agglutinin of anti-i specificity. Since then, several series have verified the high incidence of anti-i antibody as the cause of immune-mediated hemolysis in infectious mononucleosis. It should be noted that although hemolysis is not common in infectious mononucleosis, the presence of anti-i is seen in as many as 50% of all patients. Not all instances of immune hemolysis in infectious mononucleosis are caused by anti-i antibodies. Anti-N antibodies have also been reported, and in some patients the nature of the antibody has not been identified.

Aplastic anemia has been reported to follow the onset of infectious mononucleosis. Aplastic anemia caused by EBV infection has also been reported after bone marrow transplantation. Localization of EBV in the bone marrow of some patients with aplastic anemia supports a causative role of the virus in these aplastic anemia patients.

Granulocytopenia is common during the acute phase of infectious mononucleosis. It is rarely severe but, on occasion, is associated with a secondary bacterial infection. Bone marrow myeloid hyperplasia with myeloid arrest is the most typical finding. Spontaneous resolution is the rule.

Immune thrombocytopenia occurs rarely in infectious mononucleosis. Most occurrences of thrombocytopenia are mild. The signs and symptoms of severe occurrences are similar to those of primary ITP. Severe hemorrhagic complications are rare. Treatment of the thrombocytopenia of infectious mononucleosis in children is guided by bleeding symptoms. Treatment approaches are similar to primary ITP with first-line therapies with corticosteroids and/or intravenous immune globulin.

The incidence of the neurologic complications reported varies from 0.37% to 7.3%, depending on the series. A rare occurrence in adolescence is the “Alice in Wonderland” phenomenon in which objects are visualized in a very distorted fashion, with exaggerations in size, being either too large or too small. A transverse myelopathy characterized by a sudden onset of profound weakness of the lower extremities and urinary retention may complicate the clinical course of infectious mononucleosis.

Cardiac complications are rare and occur in 1% to 6% of reported series. They usually consist of only nonspecific T-wave changes or minor conduction abnormalities. Myocarditis and pericarditis are rare. Liver function abnormalities are rarely severe, although enzyme changes are common. Primary EBV infection has been associated with a Reye syndrome–like illness. Severe liver dysfunction causing death is a common complication of EBV infection in the X-linked lymphoproliferative syndrome. Hepatic dysfunction is uniformly present with this disorder at the time of death and is the cause of death in about a third of such patients. An unusual manifestation of infectious mononucleosis is intense jaundice. It generally results from a combination of hemolysis and mild hepatitis. Spontaneous rupture of the spleen may occur.

Respiratory difficulties usually consist of upper airway obstruction. Transient interstitial infiltrations, some with effusions, have been recorded. Infectious mononucleosis should be considered in the differential diagnosis of any child with pleural effusions. Renal complications of infectious mononucleosis generally consist of hematuria associated with a mild nephritis. Not all occurrences have been clearly separated from poststreptococcal glomerulonephritis. Severe rhabdomyolysis can be associated on rare occasion with EBV infection. Eye findings in infectious mononucleosis are unusual but may be significant when they do occur. Severe retinochoroiditis is such an ocular complication. In some patients with infectious mononucleosis, lethargy, particularly daytime lethargy, is seen for prolonged periods, often longer than a year.

X-linked lymphoproliferative syndrome is associated with fatal or severe infectious mononucleosis, acquired hypogammaglobulinemia, and malignant lymphoma. Details about X-linked lymphoproliferative syndrome can be found in Chapter 24 .

A variety of malignancies have been linked to EBV, including clonal T-cell proliferations. In patients who undergo transplantation, a spectrum of lymphoproliferative diseases may occur as a result of activation of EBV. These diseases may vary from an infectious mononucleosis–like polyclonal B-cell proliferation to a monoclonal B-cell lymphoma. EBV infection can also result in a hemophagocytic syndrome. The total spectrum of the rare complications and unusual syndromes associated with EBV infection have been reviewed by Timár and colleagues.

Laboratory Diagnosis.

Atypical lymphocytosis is the hallmark of infectious mononucleosis ( Fig. 37-10 ). Several attempts have been made to classify these abnormal cells on morphologic grounds, the best known method being that of Downey and McKinlay. However, it is clear that atypical lymphocytes cannot be easily classified into separate categories and that a spectrum of cell types exists. In general, the atypical lymphocytes of infectious mononucleosis are large, but they vary in size considerably. Their outlines are irregular, and many cells show a characteristic tendency to flow around adjacent erythrocytes. Nuclei are large and usually eccentrically located and pleomorphic, with abundant coarse chromatin and occasional nucleoli. The cytoplasm is generally abundant and typically basophilic. Cytoplasmic vacuoles may be seen. These types of cells are not morphologically specific for infectious mononucleosis and can be seen in other viral infections and after administration of a number of medications.

Atypical lymphocytes (Downey cells) in infectious mononucleosis.

The vast majority of atypical lymphocytes from patients with infectious mononucleosis are thymus derived. These atypical cells possess human T-lymphocyte–specific antigens, as well as sheep erythrocyte receptors. T lymphocytes appear to lack receptors for EBV, and it would appear that only B lymphocytes are infected by this virus. A possible unifying interpretation of the role of T lymphocytes is that these cells represent an immune reaction that protects against this potentially oncogenic virus. Increased numbers of B cells are found during the first week of illness and decline to normal levels in 3 weeks. T lymphocytes reach their peak later, usually 10 to 14 days after the onset of symptoms, and remain elevated for 5 weeks. There may be an early reversal of the ratio of T to B lymphocytes, with a subsequent increase in the percentage of T cells during the second through fifth weeks of illness. It is possible that both T and B cells may be “transformed” into atypical lymphocytes—B cells by infection with EBV and T cells by an immunologic response to viral antigen itself—or the B cells may respond to altered antigens on their surface. EBV-infected B lymphocytes account for only a minority of the atypical lymphocytes found in peripheral blood. In the very early stages of symptomatic illness, however, nearly 20% of all B cells in the circulation may be infected with the virus. The majority of atypical lymphocytes are T lymphocytes. Natural killer (NK) cell activity has been shown to be present during the acute phase of infectious mononucleosis. Interferons, which are inducers of NK cell activity, may have an inhibitory effect on the outgrowth of EBV-infected B lymphocytes in vitro. Significant anergy and diminished lymphocyte responsiveness in vitro to mitogens and antigens exist during the first week of illness. These lymphocyte changes are reflected in a great increase in uric acid turnover, with 55% of infected patients having serum uric acid levels of 8 mg/dL or higher.

Patients with infectious mononucleosis have lymph node pathologic findings that are easily confused with lymphoma. The nodal architecture is distorted by large, dark lymphoid cells, and the capsule may be infiltrated. Reed-Sternberg cells have been reported on several occasions. Pathologic changes are not confined to lymphoid tissue, however. Perivascular cuffing of the brain vasculature, inflammation of the liver, and inflammatory infiltration of the kidney and bone marrow have been repeatedly observed.

The heterophil antibody is so named because the antigen to which the antibody reacts is found in more than one species. The antibody, like anti-i, is an IgM macroglobulin. It agglutinates sheep red blood cells and can be removed completely from serum by preincubation with beef red blood cells but not with guinea pig kidney. Heterophil antibody titers usually increase after the third day of illness, peak at 2 weeks, and may remain positive for several months before ultimately becoming negative (unlike the antibody specific for EBV). This traditional Paul-Bunnell serologic agglutination method has been largely replaced for screening purposes by the spot test, in which finely ground guinea pig kidney or beef red blood cell stroma is added to serum on a slide, followed by a drop of horse cells. Results of the test are considered positive if agglutination occurs in the presence of guinea pig kidney (which absorbs out Forssman antibody but not heterophil antibody) but are negative with beef red blood cell stroma. The spot test requires only 2 minutes and is 96% to 99% accurate. Results of both the Paul-Bunnell test and the spot test are usually negative in preschool-aged children, in whom heterophil antibody production is limited. This age group does produce diagnostic levels of EBV-specific antibody.

EBV is a herpeslike DNA virus. It is a relatively complex virus, and a variety of virus-associated antigens have been described. Antibodies to viral capsid antigen (VCA) and early antigen (EA) are detected early after the onset of EBV-associated infectious mononucleosis. Levels of antibodies to VCA reach their peak at about 3 weeks after the onset of clinical illness. Their levels decline somewhat thereafter, but they remain for life. Antibodies to EA usually last 2 to 4 months. EA has two components that are differentiated by their immunofluorescent staining: “D” for diffuse and “R” for restricted staining. A technique for determining EBV-specific IgM has been described. EBV-specific IgM almost always occurs in the acute phase of infectious mononucleosis. It rarely persists more than 2 to 3 months. During this period, virus shedding from the oropharynx is easily demonstrable.

Figure 37-11 shows the characteristic antibody patterns observed in young adults with EBV-induced infectious mononucleosis. Before infection, no antibodies are present. During the acute phase of illness, high titers of IgM and IgG antibodies to VCA are seen. IgM antibodies are transient and disappear after 1 to 2 months. Antibodies appearing against EA disappear after a few weeks to months. Antibodies against Epstein-Barr nuclear antigen are the last to appear and are seen 1 to 2 months after the illness. In young infants, VCA IgM is found in only 60% of patients and EA antibody is identified in only 50%. The only persistent antibody response should be VCA IgG and antibodies to Epstein-Barr nuclear antigen.

Characteristic Epstein-Barr virus–specific antibody response observed in young adults with acute infectious mononucleosis.

(Modified from Henle W, Henle GE, Horwitz CA: Epstein-Barr virus specific diagnostic tests in infectious mononucleosis. Hum Pathol 5:551–565, 1974; and Sullivan JL: Epstein-Barr virus and the X-linked lymphoproliferative syndrome. Adv Pediatr 30:365–399, 1984.)

Treatment.

There is no evidence that bed rest or rest in general shortens the clinical course of infectious mononucleosis. Patients will determine their own level of activity. The most significant risk during acute illness is splenic rupture, but its incidence is extremely low.

Corticosteroid therapy is often used for infectious mononucleosis. Although these agents may produce improvement of symptoms, enhancement of general well-being, and reduction of fever, their use for these purposes should be restricted. Less controversial is the use of corticosteroid therapy for patients with airway obstruction secondary to tonsillar hypertrophy, severe hemolytic anemia, or thrombocytopenia and bleeding.

Infections in the Developing World

A detailed review of the prevalent infections in developing countries, including malaria, visceral leishmaniasis (kala-azar), schistosomiasis, trypanosomiasis, hookworm, bartonellosis, and dengue can be found in Chapter 38 .

Anemia

Anemia is a common finding in acute and chronic renal disease and is often so severe in these conditions that it constitutes the major morbidity of renal disease. Although the anemia is often multifactorial, the main cause is erythropoietin deficiency. Progressive renal disease is accompanied by an erythropoietin decline that results in a hypoproliferative, usually normochromic, normocytic anemia. However, other factors can intervene to impair erythropoietin responsiveness and aggravate already low levels of the hormone. These include infection and inflammation (anemia of chronic disease), inadequate dialysis, and secondary hyperparathyroidism. In patients treated with erythropoietin, deficiencies of cobalamin (vitamin B ₁₂ ), folic acid and, especially, iron may limit response. Transfusion support frequently becomes a necessary intervention, although elevated 2,3-DPG levels and a right-shifted oxygen dissociation curve make the red blood cells of uremic subjects more effective in the delivery of oxygen than normal red blood cells. The anemia usually develops when the creatinine clearance decreases below 35 to 45 mL/min, although no direct correlation is found between the severity of the anemia and the degree of renal impairment. The hemoglobin level is generally in the 7- to 8-g/dL range in uremic states.

Decreased red blood cell production is the major cause of the anemia of chronic renal failure. Although deficiency in erythropoietin production is the primary cause of decreased red blood cell production in renal failure, suppression of hematopoiesis by serum inhibitors may be a contributing factor. In patients with acute or chronic renal failure as a result of nephrectomy, normal or even increased erythropoietin production can be maintained. Several series have documented improved hematocrits and erythrocyte volumes proportional to the intensity of dialysis treatments, which may remove the inhibitors.

In addition, excess parathyroid hormone is also an inhibitor of erythropoiesis in uremia, a defect that renal failure states share with primary hyperparathyroidism. The mechanism of this contribution to anemia is likely due to the replacement of the marrow cavity by fibrous tissue in hyperparathyroid states. Removal of hypertrophied parathyroid glands improves the osteitis fibrosa of involved marrows and the anemia that accompanies this abnormality. Treatment with 1,25-dihydroxycalciferol also decreases marrow fibrosis and diminishes the anemia of renal failure. The role of parathyroid hormone in these anemias is in remodeling the environment in which hematopoiesis takes place; the more advanced states of bone disease seen in patients with uremia may even lead to splenomegaly secondary to extramedullary hematopoiesis.

In renal disease, unlike many other chronic disease states, close correlation exists between erythrocyte mass and erythrocyte survival. This implies that shortening of red blood cell survival has an important role in the development of anemia in these patients. About 70% of patients with renal disease have shortened red blood cell survival related to a host of potential alterations. These cells demonstrate increased mechanical fragility, autohemolysis, diminished deformability, and a variety of metabolic defects.

A circulating inhibitor of red blood cell metabolism accumulates in some but not all uremic patients. This inhibitor diminishes recycling of glucose through the hexose monophosphate shunt, a defect that may be clinically important. There are several reports of severe hemolytic disease in uremic patients given sulfa drugs. Because of this problem, caution in the use of oxidant drugs is advised in those with azotemia. The decreased shunt activity may be secondary to a metabolic defect within the shunt itself or due to a block within the main glycolytic pathway. Other incidental causes of hemolysis may be observed during hemodialysis. Contaminants such as copper, nitrate, and chloramines in hemodialysis baths may cause varying degrees of hemolysis.

The erythrocytes of patients with renal disease are generally normochromic and normocytic without any distinguishing morphologic characteristics. Occasionally, scalloped or burr cells are observed, usually in association with uremia secondary to specific causes or related to specific syndrome complexes such as hemolytic uremic syndrome ( Fig. 37-13 ). In diseases associated with microangiopathic hemolytic anemia, red blood cell fragmentation is common. It may be observed in patients with malignant hypertension, renal cortical necrosis, polyarteritis nodosa, hemolytic uremic syndrome, SLE, and TTP.

Burr cells caused by uremia.

Anemia associated with megaloblastic changes in bone marrow is not uncommon in chronic renal failure. This anemia is usually due to folate deficiency caused by poor dietary intake, hemodialysis, peritoneal dialysis, or the effects of immunosuppressive drugs. In addition, defective protein-mediated folate transport may be present. Serum from uremic patients may contain an increased concentration of folic acid–binding protein. Folate deficiency is usually suspected when large numbers of macroovalocytes are seen in association with hypersegmentation of polymorphonuclear leukocytes on the peripheral blood smear. The anemia of renal disease can also be worsened in dialyzed patients by superim­position of iron deficiency due to blood loss during hemodialysis.

The primary role of erythropoietin deficiency in the anemia of renal failure has been incontrovertibly confirmed with the successful trials of recombinant human erythropoietin in both dialyzed and nondialyzed renal failure patients (see Chapter 1 ). Administration of the hormone has eliminated the need for red blood cell transfusions or androgens, previously the mainstays in treating the anemia of renal failure. The therapeutic success of erythropoietin-stimulating agents (ESAs) has brought to a close any doubts concerning the major cause of the anemia of renal failure. The administration of ESAs may unmask iron and folate deficiency, their presence being signaled by an apparent refractoriness to erythropoietin administration. Controversy exists about the goal hemoglobin level in patients with renal insufficiency treated with ESAs, although most data support a lower hemoglobin level of 10 to 11 g/dL. Administering ESAs to reach higher target hemoglobin levels greater than 13 g/dL is associated with fewer red blood cell transfusions; however, higher hemoglobin levels are also associated with an increased risk for stroke, hypertension, and thrombosis. It remains unclear whether the higher hemoglobin is linked to these adverse outcomes or high doses of ESAs.

Polycythemia

Secondary erythrocytosis is a well-recognized complication of renal disorders. The increase in red blood cell mass is due to release of erythropoietin directly from renal tumor cells, renal ischemia, and hydronephrosis and in association with chronic glomerulonephritis, pyelonephritis, nephrosclerosis, and nephrotic syndrome in adults. Erythrocytosis is also a common finding after renal transplantation.

Esophagus

Plummer-Vinson syndrome (dysphagia, postcricoid webs, and iron deficiency) occurs in older individuals and is discussed in Chapter 11 . Iron-deficiency anemia may be the only manifestation of gastroesophageal reflux; thus endoscopy is important in the evaluation of unexplained iron-deficiency anemia. Chronic gastroesophageal reflux may cause Barrett esophagus with its attendant risk for the development of adenocarcinoma.

Stomach

The gastric mucosa is important in both vitamin B ₁₂ and iron absorption, and disorders of the gastric mucosa may cause defective absorption of either of these nutrients. The gastrointestinal causes of iron and vitamin B ₁₂ deficiency are reviewed in Chapters 10 and 11 .

Gastric resection may result in iron or vitamin B ₁₂ deficiency, the former from bleeding at sites of anastomosis and the latter, years later, from lack of intrinsic factor. Vitamin B ₁₂ deficiency may develop in infants breastfed by women who have undergone gastric or intestinal bypass procedures. Macrocytic, megaloblastic anemia resulting from vitamin B ₁₂ deficiency has been reported in association with gastric trichobezoars. This is presumed to be due to bacterial overgrowth of the upper gastrointestinal tract. In congenital intrinsic factor deficiency, gastric biopsy results are normal and no antibodies to parietal cells or intrinsic factor are present.

Small Intestine

Celiac disease and inflammatory bowel disease are both frequently associated with anemia and are covered in detail in Chapter 11 .

Crohn disease has also been associated with coagulopathy, particularly with acute flares. Low factor XIII levels have been observed in active disease associated with regional enteritis. An abnormality in arachidonic acid metabolism may occur in patients with chronic inflammatory bowel disease, including regional enteritis. This may result in alterations in platelet function. Diminished neutrophil function may be seen in both regional enteritis and other forms of inflammatory bowel disease. The condition may be identified by decreased oxidative metabolism and low superoxide dismutase content of neutrophils. Perinuclear antineutrophil cytoplasmic antibodies are commonly found in patients with inflammatory bowel disease. Inflammatory bowel disease, particularly during acute flares, is also associated with an increased risk for thrombosis.

Disorders such as tropical sprue, celiac disease, bowel lymphoma, amyloidosis, and connective tissue disturbances (including Ehlers-Danlos syndrome and pseudoxanthoma elasticum) may produce panselective or selective malabsorption. Certain disorders such as intestinal lymphangiectasia may cause protein loss of a magnitude sufficient to impair globin chain synthesis. Protein loss may also be associated with selective loss of T lymphocytes into the bowel lumen, which causes lymphopenia and altered delayed-type hypersensitivity. This lymphopenia may be associated with hypogammaglobulinemia.

Eosinophilic gastroenteritis is a disorder most often characterized by recurrent bouts of abdominal pain, nausea, vomiting, diarrhea, and an elevated peripheral blood eosinophil count for which there is no other explanation. The gut wall may be infiltrated by eosinophils.

Common diarrheal illnesses during infancy may result in life-threatening methemoglobinemia, especially if the diet has been high in nitrates.

Large Intestine

Ulcerative colitis is often associated with iron-deficiency anemia as a result of blood loss. AIHA identified by positive results of a Coombs test and immune thrombocytopenia are relatively rare complications of ulcerative colitis, however, and develop in less than 1% of patients. Occasionally, vitamin B ₁₂ deficiency occurs after many years if a “backwash” ileitis is present. Polymorphonuclear leukocytosis is common. Occasionally, an increase in plasma fibrinolytic activity will be observed. A significant decrease in antithrombin III levels may be found. Some clinicians have treated this complication with ε-aminocaproic acid. Platelet functional abnormalities may exist and are discussed in Chapter 34 . Alterations in T-cell subsets may also occur in children with inflammatory bowel disease.

Constipation has been reported to cause an increase in sulfmethemoglobin levels. It has been suggested that excess nitrite absorption from the gut may be present in some patients as a result of abnormal bowel function.

Symptoms of Peutz-Jeghers syndrome (gastrointestinal polyposis and mucocutaneous pigmentation) may occur in early childhood and are associated with an increased risk for intestinal cancer.

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) may result in iron deficiency from gastrointestinal bleeding. Alterations in hemostasis (DIC, platelet dysfunction, and factor XI deficiency) have been reported. An association between this disorder and von Willebrand disease may exist.

Red Blood Cell Disturbances

Anemia is common in acute and chronic liver disease and has a diverse etiology. Liver disease is often accompanied by increased portal pressures, with the resultant congestive splenomegaly potentially creating any combination of anemia, leukopenia, or thrombocytopenia. The marrow’s compensation for such hemolytic insults is frequently dampened or absent in the setting of liver disease because of concomitant vitamin nutritional deficiencies. In addition, portal hypertension and liver disease are associated with increased risk for bleeding and concomitant iron deficiency. Shortened red blood cell survival may be observed in some patients with no evidence of blood loss. The exact mechanism by which red blood cell survival is shortened is unclear.

Erythrocytes from patients with active liver disease have an increased tendency to form Heinz bodies after incubation with an oxidant chemical such as acetylphenylhydrazine or sodium ascorbate. This increase in Heinz body formation is associated with increased instability of red blood cell reduced glutathione, decreased hexose monophosphate shunt activity, and reduced glucose recycling through the hexose monophosphate shunt. Activation of superoxide dismutase and glutathione reductase may be observed in the red blood cells of patients with profound liver disease. This may partially explain the alterations in the antioxidant system noted with these disorders. The hemolytic anemia associated with liver disease secondary to Wilson disease is especially severe. The same is true of the hemolytic anemia related to protoporphyria.

The exact significance of these metabolic alterations has not yet been determined. Red blood cell metabolism appears to return to normal within a few weeks after an insult to the liver. All of the metabolic consequences of liver disease can be reproduced in normal intact red blood cells by prolonged incubation in plasma from patients with active liver disease. In patients with active liver disease, it may be wise to withhold any drug that has the potential to present an oxidant challenge to the red blood cell. Similar acquired abnormalities in hexose monophosphate shunt activity have been associated with drug-induced hemolysis in patients with uremia.

The red blood cells in liver disease are often macrocytic, with mean corpuscular volumes in the range of 100 to 110 fL. In patients with biliary obstruction, the red blood cell surface lipids increase and cause target cells. With severe hepatocellular damage, acanthocytes or spur cells are commonly observed ( Fig. 37-14 ). These morphologic abnormalities appear to be in direct proportion to the increase in red blood cell membrane cholesterol that accompanies hepatocellular liver disease. Increased osmotic resistance is a consequence of the increased red blood cell surface area. Stomatocytosis has been reported in alcoholic liver disease.

Acanthocytes and target cells due to liver disease.

Coagulation Abnormalities

Because the liver is involved to some extent in the synthesis of most of the coagulation factors, it is not unexpected that liver dysfunction would be associated with the presence of abnormal clotting studies and bleeding. The coagulation abnormalities common in patients with fulminant hepatic failure have been reviewed in detail.

Patients with liver disease commonly manifest a spectrum of coagulation abnormalities that are highly suggestive of DIC. Findings consistent with DIC include hypofibrinogenemia, thrombocytopenia, increased fibrinogen catabolism, increased levels of fibrin degradation products, and depressed levels of other coagulation factors. This pattern of abnormalities is not specific for DIC and may simply reflect the severity of the hepatocellular disease process. For example, fibrinogen levels may be depressed on a synthetic basis alone. Increased catabolism of fibrinogen may reflect distribution in extravascular spaces, such as the formation of ascitic fluid or proteolysis by enzymes other than thrombin. Thrombocytopenia may occur for a variety of reasons and frequently is not present when other signs of DIC are seen. Changes in levels of factors V and VIII are varied and nonspecific. Because fibrin degradation products are cleared by the liver, severe liver dysfunction itself may cause elevations of these products without implicating DIC.

The acquired coagulation abnormalities of liver disease are discussed in detail in Chapter 35 .

Red Blood Cells

An unusual hemoglobin component in hemolysates prepared from the blood of some diabetic patients was first noted by Rahbar. A component that migrated near the position of fetal hemoglobin was described on agar gel electrophoresis at pH 6.2 in citrate buffers. This hemoglobin is present in normal individuals; it constitutes 5% to 7% of total hemoglobin and is called hemoglobin A _1c . Rahbar’s group observed a twofold increase in this hemoglobin fraction in some diabetic patients. Structurally, hemoglobin A _1c is a condensation product, by means of a Schiff base, between one molecule of hemoglobin A and one molecule of an aldehyde or ketone, linked at the amino-terminals. The aldehyde or ketone group appears to be one or more hexoses, thus making hemoglobin A _1c a glycohemoglobin. Bunn and Briehl have shown that the oxygen affinity of hemoglobin A _1c is little affected by the addition of 2,3-DPG, which leads to decreased oxygen affinity when added to hemoglobin A. Studies have shown highly significant relationships between the percentage of hemoglobin A _1c and the response to an oral glucose tolerance test and overall diabetic control, as reflected in quantitative urinary glucose determinations. In this sense, measurement of the glycohemoglobin provides an insight into diabetic control over many days.

Red blood cell survival, as measured by chromium ( Cr) labeling, may be mildly impaired during periods of poor diabetic control (mean erythrocyte half-life of 27 days). With improvement of diabetic control, red blood cell survival will increase (mean half-life of 31 days). During episodes of ketoacidosis, rapid shifts in the oxygen affinity of hemoglobin may also occur. A decrease in pH causes a shift to the right with an increase in oxygen unloading. Very rapid correction of pH may impede oxygen delivery. A prompt decrease in red blood cell 2,3-DPG levels occurs at these times. This decrease is probably compensatory—an attempt to correct the oxygen affinity disturbances caused by the acidosis. A decrease in red blood cell 2,3-DPG levels may also result from hypophosphatemia, if it occurs during insulin treatment.

Other red blood cell abnormalities have been found in diabetic subjects. The red blood cells of such individuals show evidence of lipid peroxidation and antiperoxidative enzyme changes when compared with those of healthy subjects. An increase in the glycosylated form of erythrocyte superoxide dismutase has been found in diabetic subjects and is related to nonenzymatic glycosylation of this enzyme. Erythrocytes from diabetic subjects also show sodium influx. Red blood cell sorbitol concentrations will increase in subjects with poorly controlled diabetes; the amount of red blood cell sorbitol is related to the degree of diabetic control. Finally, if electronic counting equipment is used to determine the mean corpuscular volume of red blood cells, artifactual elevations in mean corpuscular volume may be seen in subjects with hyperglycemia.

Thiamine-responsive megaloblastic anemia, diabetes mellitus, and sensorineural deafness is a rare autosomal recessive disorder that begins in childhood and is caused by defects in the high-affinity thiamine transporter-1 (SLC19A2), on chromosome 1q23.3. The anemia and diabetes respond to high-dose thiamine treatment, although the diabetes can relapse years later, despite continued thiamine treatment.

White Blood Cells

Polymorphonuclear cell function may be disturbed in diabetic patients. Leukocyte adherence is diminished in individuals with poor control of diabetes, as is phagocytic capacity. Chemotaxis may also be abnormal, but this does not correlate with the status of diabetic control. Impaired cellular metabolism and DNA synthesis have been reported in the lymphocytes of some patients with diabetes. Increased superoxide production by mononuclear cells is observed in patients with diabetes and hypertriglyceridemia.

Platelets

Many studies have emphasized the abnormalities in platelet adhesion and aggregation in patients with diabetes. The finding that enhanced platelet aggregation occurs before clinical evidence of diabetic vascular disease suggested that this defect may be acquired early in the natural history of diabetes and could underlie the vascular disease. Platelet aggregation in diabetic subjects is characterized by a shortened adenosine diphosphate–induced aggregation time. Increased platelet adhesiveness and platelet factor 3 and 4 activity also occur. Normal platelets incubated in the plasma of diabetic patients will become abnormal. This aggregation-enhancing activity is present in both plasma and serum and is nondialyzable and heat resistant. In patients with this plasma factor, von Willebrand factor activity is also increased, thus suggesting that the two are related. The enhanced in vitro responsiveness of platelets from diabetic patients can be decreased by prostaglandin synthetase inhibitors. Platelets from diabetic patients demonstrate increased activity of the prostaglandin synthetase system, which results in increased synthesis of prostaglandin endoperoxides and, therefore, of prostaglandin E ₂ . When induced to aggregate with arachidonic acid, the platelets of diabetic patients with vascular disease tend to produce more thromboxane A ₂ than those of normal subjects do. A lower prevalence and severity of diabetic retinopathy have been observed in a group of diabetic patients with concurrent rheumatoid arthritis who were taking high doses of aspirin. This finding suggests that inhibition of platelet aggregation and prostaglandin synthesis may be desirable in the management of diabetic patients. The increased glycosylation of connective tissue proteins in diabetic patients has been suggested to increase their aggregation potency.

Other Hematologic Findings in Diabetes Mellitus

A state of hypercoagulability associated with changes in clotting factors and platelet function has been postulated to be important in the increased thrombotic complications in diabetic patients. Approximately a third of patients with diabetes will show abnormally increased factor VIII coagulant activity and diminished antithrombin III levels. Abnormalities in fibrinolysis do not appear to be common. In addition to this, factor XI and factor XII levels are higher in some diabetic patients with evidence that the kallikrein-prekallikrein system has been activated. Ketoacidosis may be associated with DIC. Altered levels of factors V and VIII and diminished fibrinolytic activity have been reported in a few patients.

The hematologic consequences of diabetes also extend to infants born of diabetic mothers. An increased incidence of thrombosis or thromboembolic phenomena is well recognized in these infants. Complications such as renal vein thrombosis, peripheral gangrene secondary to vascular occlusion, and cerebral thrombosis may occur.