Hematology and Oncology Disorders
Anemia: Acute
Christine A. Schindler
Background/Definition
Anemia is a reduction in red blood cell (RBC) mass or blood hemoglobin concentration that is more than two standard deviations below the mean for the reference population. Most commonly defined by reduction in either hematocrit or hemoglobin.
Etiology/Types
Increased red cell destruction (hemolysis) caused by hemoglobinopathies, membrane and enzyme defects, autoimmune hemolytic anemia, drug-associated hemolytic anemias, disseminated intravascular coagulation (DIC), and hemolytic uremic syndrome (HUS).
Excessive blood loss (hemorrhage).
Deficient red cell production (ineffective hematopoiesis).
Disorders of heme and globin production such as non-nutritional disorders of hemoglobin synthesis, thalassemia syndromes, lead poisoning, iron deficiency, chronic inflammatory diseases, chronic infections, chronic renal disease, and hyper/hypothyroidism.
Pathophysiology
RBCs develop in the bone marrow and circulate for approximately 100 to 120 days in the body before their components are recycled by macrophages.
Rate of RBC destruction exceeds the rate of production, resulting in hemolysis.
Rate of blood loss exceeds rate of production from hemorrhage.
Ineffective hematopoiesis: Rate of RBC production is slower than the rate of destruction.
Transient Erythroblastopenia of childhood: transient or temporary red cell aplasia; typically presents following viral illness, with anemia in the range of 6 to 8 mg/dL (although can be lower) and reticulocytopenia.
Clinical Presentation
Weakness, fatigue, confusion, and palpitations.
Pallor, tachycardia, flow murmur, diminished peripheral pulses, and sometimes jaundice.
Diagnostic Evaluation
Marked decrease in hematocrit and hemoglobin.
RBC indices and morphology.
Increased reticulocyte count and low mean corpuscular volume (MCV) includes hemoglobinopathies (e.g., thalassemia syndromes).
Increased reticulocyte count and normal MCV indicates Membrane, Enzyme, or Immune disorders, Microangiopathic anemias, DIC, infection-induced hemolysis or chronic blood loss.
Low, normal, or slightly elevated reticulocytes and low MCV: iron deficiency anemia, lead toxicity, Thalassemia trait, Sideroblastic anemia, or anemia of chronic disease.
Low, normal, or slightly elevated reticulocytes, and high MCV: congenital hypoplastic or aplastic anemia, acquired hypoplastic or aplastic anemia (malignancies), aplastic crisis with underlying hemolytic anemia (HbSS), megoblastic anemia (Folate or B12 deficiency), immune disorders, Hypersplenism, anemia of chronic disease.
Management
Treat underlying cause, maintain oxygenation.
If hypovolemic shock present, volume expansion with packed RBC (PRBC) transfusion is indicated.
Dietary counseling; in iron deficiency anemia and iron supplement.
Aplastic Anemia
Christine A. Schindler
Background/Definition
Aplastic anemia is a life-threatening disease of bone marrow failure resulting in decreased production of hematopoietic stem cells that results in peripheral pancytopenia and bone marrow aplasia. Rare condition; 0.6 to 6.1 cases per 1 million population.
Etiology/Types
Congenital aplastic anemia occurs in approximately 20% of cases.
Acquired aplastic anemia occurs in approximately 80% of cases. Acquired aplastic anemia may be a result of exposure to drugs, chemicals, ionizing radiation, or viruses.
Pathophysiology
The causative injury in aplastic anemia is thought to be a direct injury to the pluripotent stem cells.
Clinical Presentation
History: mucosal/gingival bleeding, headaches, fatigue, easy bruising, rash, fever, mucosal ulcerations, or recurrent viral infections.
Symptoms: pallor, tachycardia, petechial rash, purpura, ecchymoses, or jaundice.
Symptom severity depends on the level of pancytopenia.
Diagnostic Evaluation
Decrease in hemoglobin, white blood cell (WBC) count, and platelet count.
Reduction in or absence of the absolute number of reticulocytes.
Peripheral blood smear; no abnormal cells.
Reduction or absence of hematopoietic elements from bone marrow aspirate.
Management
Transfusions of RBCs and platelets.
Antibiotic therapy.
Bone marrow transplantation (BMT).
Immunosuppressive therapy if unable to receive a BMT.
Diamond-Blackfan Anemia (Diamond-Blackfan Anemia)
Christine A. Schindler
Background/Definition
A rare congenital hypoplastic anemia resulting in constitutional bone marrow failure.
Etiology/Types
Mutation for Diamond-Blackfan is on chromosome 19, which encodes for a ribosomal protein known as RPS19.
Pathophysiology
The definitive cause is unknown; hypothesized that it is an autosomal dominant disorder of faulty ribosome biogenesis that results in proapoptotic erythropoiesis, leading to marrow failure.
Clinical Presentation
Symptoms: pallor, fatigue, irritability, syncope, and dyspnea during feeding.
Physical examination: irregular heartbeat, hypotonia, short stature, and evidence of failure to thrive.
Associated with physical defects including craniofacial, hands, upper limbs, cardiac, or genitourinary.
Diagnostic Evaluation
Profound macrocytic anemia; WBCs and platelet count generally normal.
Reticulocytopenia.
Increased percentage of hemoglobin F for age.
Elevated erythrocyte adenosine deaminase activity.
Decreased or absent erythroid precursors in bone marrow aspirate.
Genetic screening; Diamond-Blackfan anemia—mutation in RPS19.
Management
Corticosteroids, frequent blood transfusion, BMT in some cases.
Hematology, BMT, and endocrinology team involvement.
Coagulation Disorders
Disseminated Intravascular Coagulation (DIC)
Sheree H. Allen
Background/Definition
DIC, also referred to as defibrination syndrome or consumptive coagulopathy, is a life-threatening complication of systemic or localized tissue injury causing a disturbance of the normal coagulation cascade that results in uncontrolled intravascular coagulation coupled with the consumption of coagulation factors and platelets, which triggers concurrent thrombosis and hemorrhage.
Etiology
Acquired condition resulting from single or multiple underlying conditions or disease processes.
Associated with significant mortality and may not resolve with treatment of the underlying cause.
Infection—most common cause (approximately 35% of all cases).
Gram-negative (most commonly associated with DIC) or gram-positive sepsis.
Viral processes.
Fungal infection.
Severe pancreatitis.
Trauma; penetrating brain injury, burns, or multiple trauma.
Hematologic malignancies; hemolytic processes.
Acute respiratory distress syndrome.
Obstetrical complication.
Necrotizing enterocolitis.
Extra Corporeal Membrane Oxygenation.
Graft-versus-host disease (GVHD).
Pathophysiology
Acute or chronic process in which there is concurrent acceleration of the clotting cascade and the fibrinolytic system causing simultaneous hemorrhage and microvascular clotting.
Uncontrolled, intravascular coagulation secondary to:
Excessive fibrin and platelets deposited into microvascular system causing microfibrin threads and thrombi.
Consumption of platelets—thrombocytopenia.
Intravascular thrombosis, purpura, petechiae, end organ ischemia, and infarction.
Hemorrhage secondary to:
Depletion of coagulation factors and platelets.
Prolonged protime (PT).
Prolonged activated partial thromboblastin time (PTT).
Activation of fibrinolytic system—increased plasmin production and release of fibrin degradation products.
Hemorrhage causes a rapid release of procoagulant into circulation, causing further depletion of coagulation factors, and ultimately results in increased bleeding.
Multiple organ system failure secondary to microinfarction, tissue ischemia and necrosis, end organ failure, and shock.
Clinical Presentation
No predictable pattern. DIC is not a primary disorder, but is always a complication preceded by a significant illness or injury.
Symptoms: headache, altered level of consciousness, bleeding, disproportionate bruising.
Findings: diffuse bleeding; often initial symptom, petechiae, ecchymosis, purpura, and hematoma, gingival bleeding and epistaxis, hematuria, hematemesis and melena, intrahepatic hemorrhage, signs and symptoms of shock, thrombosis can be present, cool mottled skin, pallor, poor perfusion, tissue necrosis, and gangrene.
Multiorgan system failure can occur related to ischemia and/or necrosis, resulting in respiratory insufficiency or failure, renal failure, and altered level of consciousness.
Diagnostic Evaluation
Laboratory testing—may change depending on the length of illness; there is not one confirmatory laboratory study to diagnose DIC. The following findings are consistent with DIC:
Prolonged PT.
Prolonged activated partial thromboblastin time.
Increased international normalized ratio (INR).
Decreased fibrinogen and platelet count.
Schistocytes (fragmented RBCs) on complete blood count (CBC) smear.
Elevated fibrin split product (FSP).
Positive/elevated D-dimer (marker is sensitive to endogenous generation of thrombin and plasmin).
Management
Supportive therapy should target specific organ symptoms affected while maintaining perfusion of vital organs until DIC is controlled.
Monitor vital signs, central venous pressure, and oxygen saturation.
Administer oxygen as needed; additional respiratory strategies as needed.
Antibiotics—organism specific for presumed or identified infectious etiology.
Fluid and electrolyte balance; correct acidosis and shock.
Administer vitamin K as indicated.
Frequent evaluation of laboratory studies—coagulopathy profile, CBC, chemistry, and acid-base balance (arterial or venous blood gases).
Blood product administration and replacement.
Cryoprecipitate—provides fibrinogen, factor VIII, and vonWillebrand factor.
Consider anticoagulation (e.g., heparin); controversial and not widely recommended; inhibits thrombin generation; efficacy has not been demonstrated in clinical trials.
Antithrombin III (ATIII)—An a2-globulin that inhibits coagulation.
Consider Aprotinin—slows fibrinolysis, but not routinely used.
PEARLS
Thrombocytopenia is the most common laboratory finding in DIC.
Differential diagnosis includes liver disease, which produces similar coagulopathies. However, in liver disease, factor VII is significantly decreased, and factor VIII may be normal or increased.
Early detection and prompt management of DIC may prevent complications and death.
Hemolytic Uremic Syndrome
Sheree H. Allen
Background/Definition
HUS, a disease of the microcirculation, is characterized by hemolytic anemia, thrombocytopenia, and acute renal failure (ARF). Occurs most frequently in children <4 years of age and is the most common cause of ARF.
Etiology
Contamination of water, meat, fruits, and vegetables with infectious bacteria; peak incidence during summer.
E. coli 0157:H7 is the most common etiology of postdiarrheal (D+) HUS.
Types
D+ HUS—Postdiarrheal or typical HUS; occurs in previously healthy children who have had recent gastroenteritis. Mortality rate is 3% to 5%; associated with renal failure in 50% to 70% of patients affected. Bacterial verotoxins, absorbed through intestinal mucosa, are produced by E. coli O157:H7 infection (Shiga toxin; most common cause), Shigella dysenteriae, Citrobacter freundii, and other subtypes of E. coli (also Shiga toxin).
D–HUS—Atypical or sporadic HUS is less common and more severe than D+HUS with an approximately 25% mortality rate. It is associated with end-stage renal disease in approximately 50% of cases. More common in adulthood, atypical D–HUS infection may have a familial link and may also begin in the neonatal period; occurs year round with no gastrointestinal (GI) prodrome. Causative factors include Inherited factor H deficiency (10%-20%); inhibits complement activation, Membrane cofactor protein mutations, Streptococcus pneumoniae infection, medications including Cyclosporine and Tacrolimus.
Pathophysiology
D+HUS occurs as a result of verotoxins, especially Shiga toxin, absorbed by the intestinal mucosa, which damage endothelial cells and erythrocytes, producing a prodrome of hemorrhagic enterocolitis.
Endothelial swelling of the glomerular arterioles in the kidneys results in a decrease in glomerular filtration rate, proteinuria, and hematuria.
This characteristic microangiopathy precipitates the release of clotting factors, platelet aggregation, and fibrin deposition in the small vessels of the kidney, gut, and central nervous system (CNS), resulting in hemolytic anemia; shearing of RBC’s as they pass through narrowed vessels, renal cortical injury and ARF, and thrombocytopenia.
Clinical Presentation (Typical D+HUS)
Previously healthy child with exposure to contaminated source, incubation period 3 to 5 days.
Symptoms: abdominal pain; watery, nonbloody diarrhea, fever, weakness, lethargy, irritability.
Progression to hemorrhagic colitis occurs 5 to 7 days after onset of diarrhea.
Findings: pallor, petechiae, ecchymoses, hematuria, oliguria, azotemia, hypertension; may progress to anuria, hepatomegaly, splenomegaly, hematemesis, edema.
Tremor and seizures (approximately 20% of cases).
Diagnostic Evaluation
HUS diagnosis is supported by patient history and the presence of microangiopathic hemolytic anemia, thrombocytopenia, and ARF.
Reticulocytosis and abnormal RBC morphology.
Schistocytes, burr, and helmet cells on smear; fragmented erythrocytes.
Anemia; decreased plasma haptoglobin.
Thromobocytopenia.
Leukocytosis is common.
Coagulation profile is often normal.
Stool cultures are often positive for E. coli 0157:H7, or other toxin-producing bacteria; however, not always detected.
Serum ELISA testing—should be done at diagnosis and repeated 2 weeks later (determines presence of antibodies to Shiga toxin E. coli serotypes).
Elevated BUN, serum creatinine, bilirubin, and potassium.
Coombs negative.
Microscopic hematuria, proteinuria, and casts on urinalysis.
Management
Typical D+HUS.
Supportive therapy—90% of patients survive the acute phase.
Greater than 50% recover full renal function.
Antibiotics are not indicated (may stimulate the bacteria to release more toxins that can damage platelets, blood vessels, and kidneys).
Dialysis—(approximately 50% of patients).
Correct electrolyte imbalances, azotemia, manage fluid overload.
Maintain adequate nutrition and caloric intake while observing renal protective diet.
Correct anemia—75% of patients require PRBC transfusion.
Control hypertension.
Oral calcium channel blocker (e.g., nifedipine).
Intravenous (IV) calcium channel blocker (e.g., nicardipine) or nitroprusside.
Long-term follow-up:
Monitor blood pressure (BP) and urinalysis.
Complications are uncommon; however, proteinuria, decreased glomerular filtration rate, and hypertension may recur up to 1 year later.
Atypical D–HUS.
Plasmapheresis—consider for patients with factor H deficiency; may limit renal involvement temporarily, but does NOT prevent progression to end-stage renal disease and has not been shown to prevent recurrence of D–HUS.
Kidney transplantation—8% to 30% if recurrence persists.
Long-term follow-up with monitoring of BP and urinalysis.
Proteinuria, decreased glomerular filtration rate, and hypertension may recur up to 1 year later.
Hemophagocytic Lymphohistiocytosis
Daniel K. Choi
Etiology/Types
Primary hemophagocytic lymphohistiocytosis (HLH): primarily in newborns and young children.
Often associated with a family history of HLH and/or in patients with genetic mutations associated with specific immune cell defects that lead to HLH.
Gene defects associated with increased risk of HLH: Perforin (PRF), MUNC (UNC13D), Syntaxin 11 (STX11), and SAP (SH2-D1A).
Secondary HLH: Older children, usually secondary to an underlying medical condition with an underlying immune system defect that acts as a “trigger.”
Conditions associated with malignancy, autoimmune disease, immune deficiency, and specific infections (e.g., Ebstein-Barr virus, cytomegalovirus [CMV]).
Pathophysiology
Complex immune dysregulation; molecular mechanism not completely understood.
When the immune system is activated, critical immune cells (e.g., T-cells, macrophages) are not downregulated appropriately.
Overactivated critical immune cells (e.g., T-cells/macrophages) stimulate other immune cells to release additional inflammatory cytokines, leading to a self-perpetuating “cytokine storm.”
End organ damage occurs from immune cell damage and inflammation.
Clinical Presentation
Variable presentation; often appear quite ill.
Most “common” presentation is prolonged high fever (≥38.5°C), hepatosplenomegaly, hepatitis, and cytopenias (at least two cell lines).
Can affect any organ system; notable systems include the skin, pulmonary, and CNS.
A high index of suspicion is needed; the diagnosis can often be confused with malignancy, Kawasaki Disease, and severe infection.
Diagnostic Evaluation
Criteria first proposed in 1994, and updated in 2004, and are often referred to as the HLH-2004 Criteria:
A molecular diagnosis consistent with HLH: pathologic mutations of PRF1, UNC13D, Munc18-2, Rab27a, STX11, SH2D1A, or BIRC4; or
Five out of the eight criteria listed below are fulfilled:
Fever ≥38.5°C.
Splenomegaly.
Cytopenias (affecting at least two of three lineages in the peripheral blood):
Hemoglobin <9 g/dL (in infants <4 weeks: hemoglobin <10 g/dL).
Platelets <100 × 103 cells/mL.
Neutrophils <1 × 103 cells/mL.
Hypertriglyceridemia (fasting >265 mg/dL) and/or hypofibrinogenemia (<150 mg/dL).
Hemophagocytosis in bone marrow or spleen or lymph nodes or liver.
Low or absent NK-cell activity.
Ferritin >500 ng/mL (usually much higher in HLH).
Elevated Soluble CD25 (alpha chain of soluble IL-2 receptor).
Important to note that these are suggested criteria, and that a high clinical suspicion and consultation with a pediatric hematologist/oncologist is warranted.
Management
Children are often acutely ill, and usually require close pediatric intensive care unit support and monitoring.
Therapy is generally initiated even if there are coinciding infections.
Human leukocyte antigen (HLA) typing is usually sent early in the treatment course for possible stem cell transplantation.
Induction therapy is generally with dexamethasone, etoposide +/- cyclosporine, with treatment weaning over 8 weeks.
In patients with genetic/familial predisposition or recurrent/refractory disease, an allogeneic stem cell transplant with a HLA-matched donor is indicated.
Risk of recurrence is much higher in this patient population.
Caution must be used with a HLA-matched sibling, as they may also have the genetic/familial predisposition to HLH.
Hemophilia
Sheree H. Allen
Background/Definition
Hemophilia is an X-linked, recessive coagulation disorder that occurs most commonly in males and is caused by specific clotting factor deficiencies. Females may rarely be affected, as in the case of a carrier mother and affected father. There is no racial or ethnic predilection for hemophilia. The majority of cases are diagnosed at birth due to a positive family history. Approximately one-third of hemophilia patients have no family history of hemophilia and develop the disease as a result of a new gene mutation.
Etiology
Hemophilia A—“Classic hemophilia”— is a deficiency of Factor VII, occurring 1 in 5,000 male births.
The most common and severe form; 80% to 85% of all hemophilia.
Hemophilia B—“Christmas disease” is a deficiency of Factor IX deficiency.
1 in 30,000 male births.
Pathophysiology
When injury occurs, both intrinsic and extrinsic pathways of the clotting cascade are activated to form a stable fibrin clot
and achieve secondary hemostasis. The severity of bleeding is dependent upon the degree of factor deficiency.
Severe disease—persons with <1% of normal factor activity; may experience spontaneous or excessive bleeding following minimal trauma. Risk for trauma-induced hemorrhage.
Moderate disease—persons with 2% to 5% of normal factor activity; typically bleed with trauma or surgery.
Mild disease—persons with greater than 5% of normal factor activity; generally, experience only delayed clotting/bleeding associated with significant hemostatic challenges.
Clinical Presentation
Symptoms: slow, persistent bleeding after minor injury, hematemesis or melena, epistaxis, hematuria, joint pain, swelling, and decreased range of motion due to bleeding into the joints (especially knees, ankles, and elbows), causing hemarthroses, ecchymosis, and subcutaneous hematoma.
Uncontrollable bleeding after injury.
30% to 50% of patients experience earliest symptom during and after circumcision.
Neonatal considerations include cephalohematoma, subdural, and periosteal bleeding during delivery, and intracranial hemorrhage (up to 2% of infants).
Diagnostic Evaluation
Factor assay to determine deficiency.
Hemophilia A: factor VIII assay decreased, prolonged PTT, normal platelets.
Hemophilia B: factor IX assay decreased, prolonged PTT.
Hematocrit may be decreased in presence of excessive bleeding, normal platelet count.
PT will be normal, and PTT prolonged >60 seconds.
Management
Blood Product Administration: fresh frozen plasma (FFP), Cryoprecipitate, PRBC.
Factor Administration.
Prompt factor replacement minimizes the morbidity from hemorrhage.
Major bleeding—100% factor replacement.
Minor bleeding into muscles and joints—50% to 60% factor replacement.
Mucocutaneous bleeding—30% to 50% replacement.
Factor VIII—(half-life 8-12 hours).
Factor IX—(half-life 12-24 hours).
1-deamino-8-D-arginine vasopressin (DDAVP) for mild to moderate hemophilia A.
Parenteral DDAVP or Intranasal DDAVP.
Patients should be pretreated with 100% recombinant clotting factor concentrate prior to any surgical or invasive procedure.
Patient and Family Education
Genetic counseling.
Avoid medications that inhibit platelets or coagulation factors including NSAIDS, aspirin, anticoagulants, and certain antibiotics.
Contact sports are not recommended.
Vaccination for hepatitis A and hepatitis B is recommended.
Maintain a healthy weight, exercise to increase muscle strength and protect joints.
Annual evaluation at a Hemophilia Treatment Center.
Immune Thrombocytopenic Purpura
Sheree H. Allen
Background/Definition
ITP is an acquired autoimmune disorder that results in destruction of platelets, which presents in healthy children. Peak age for presentation is from 2 to 6 years of age, with equal distribution between males and females until adolescence, when there is an increase in females with ITP.
Etiology
Cause is unknown; may be acute or chronic.
Frequently precipitated by a viral illness.
Estimated incidence is 4 to 8 cases per 100,000 population per year (United States).
Acute ITP is self-limiting in children <12 years of age; resolves within 6 months.
Approximately 10% of children will develop chronic ITP.
Pathophysiology
Antibodies develop.
IgG, IgA, or IgM autoantibodies coat the platelets.
Platelets are destroyed in the spleen with resulting splenic sequestration.
Antibodies contribute to immature platelet production by the bone marrow.
New platelets are destroyed within hours.
Bleeding may occur as platelet count falls.
Clinical Presentation
Bruising and petechiae, epistaxis, GI bleeding, hematuria, menorrhagia, spontaneous bleeding from mucous membranes and gingiva.
Intracranial bleeding and splenomegaly are possible.
Diagnostic Evaluation
Platelet count <100,000; large platelets on smear.
PT and PTT (normal), Fibrinogen (normal), Fibrin degradation products (normal).
Diagnosis may be confirmed by bone marrow aspiration; normocellular result with elevated megakaryocytes.
Management
Acute ITP—goal is to restore the platelet count.
Oral corticosteroids; course may be weeks to months.
IV gamma globulin (IVIG) OR Anti D immunoglobulin (WinRho-D).
Recurrent monitoring of platelet count guides therapy.
Avoid NSAIDS and aspirin.
Chronic ITP—(ITP lasting longer than 6 months).
Regular administration of IVIG or WinRho-D.
Splenectomy.
Henoch-Schönlein Purpura
Sheree H. Allen
Background/Definition
An acute, systematic, immune complex mediated, small-vessel vasculitis, which is self-limiting and resolves within about 4 weeks, considered the most common vasculitis of childhood. Incidence of 10 to 20 cases per 100,000 children. Peak age at presentation is between 2 and 8, affecting more males than females and occurring primarily in fall, winter, and spring months. Renal impairment is the most serious complication.
Etiology
Usually precipitated by an upper respiratory tract infection, medication, or other environmental trigger.
Associated with many infectious agents, with most prevalent organism group A streptococcus; approximately 50% of patients with Henoch-Schönlein purpura have antistreptolysin O antibodies.
Pathophysiology
Pathogenesis is not completely understood.
IgA complexes are deposited in the small vessels of the renal glomeruli, skin, and GI tract, causing petechiae, purpura, GI bleeding, and glomerulonephritis.
Clinical Presentation
Recent upper respiratory tract infection and prodrome of fever and fatigue.
Commonly presents with tetrad of symptoms:
Rash: nonpruritic, erythematous papules or wheals that progress to petechiae, and nonblanching, palpable, purpuric lesions >10 mm diameter; found in dependent areas of body that are subject to pressure and extensor surfaces of the extremities. Trunk is usually spared, and lesions fade over 10 to 12 days.
Polyarthralgias: pain, swelling, decreased range of motion; Lower extremity joints most frequently involved.
“Bowel angina” – diffuse, colicky abdominal pain with me-lena and vomiting; approximately 70% of patients.
Renal symptoms with hematuria, proteinuria, and hypertension; approximately 20-60 % of patients weeks to months after initial presentation
Mild renal impairment may progress to nephrotic syndrome and ARF.
Renal biopsy consistent with focal and proliferative glomerulonephritis.
Diagnostic Evaluation
Based on clinical features and presenting symptoms; renal function should be evaluated at baseline.
Platelets normal or elevated.
BUN and creatinine may be elevated.
Normal coagulation studies.
Immune antibody panel—Presence of IgA antibodies in the blood, skin, or glomeruli may help to confirm diagnosis.
Urinalysis for evaluation of blood and protein.
Management
Rest and activity limitations, with symptomatic management of systemic complications, NSAIDS.
Oral prednisone; indicated for patients with kidney involvement.
Henoch-Schönlein purpura resulting in severe kidney disease may require plasma exchange, high-dose IV immunoglobulin (IVIG), or immunosuppressant agents.
Long-term management of hypertension may be required.
PEARL
Differential diagnosis should include IgA nephritis; evaluation for autoimmune conditions including systemic lupus erythematosus, acute hemorrhagic edema of infancy, septicemia, and other forms of vasculitis.
Heparin-Induced Thrombocytopenia
Melanie Muller
Background
Heparin-induced thrombosis (HIT) occurs in approximately 2% to 3% of pediatric patients who receive heparin.
Definition
An immune mediated drug reaction that places the patient at a higher risk of thrombosis development.
Pathophysiology
Presence of heparin in the body causes the formation of IgG antibodies that recognize platelet factor 4 (PF4), a protein on the surface of the platelet that is bound to the heparin.
The IgG antibodies attach to the PF4-heparin complex, resulting in platelet activation and subsequent thrombin generation and formation of thrombosis.
Thrombocytopenia results from increased platelet aggregation and consumption.
Etiology
Exposure to heparin.
Duration and extent of exposure.
Clinical Presentation
Thrombocytopenia; platelets decrease by >50% within the first 4 to 14 days after initiation of heparin.
Occasionally, development of thrombosis is the first sign of HIT, more commonly venous thrombosis.
In some patients, rapid onset of thrombocytopenia, occurring within minutes to hours after heparin exposure. This usually occurs as a result of heparin exposure in the previous 100 days.
Diagnostic Evaluation
Diagnosis is made based on clinical presentation.
Serotonin release assay, heparin-induces platelet activation test, and flow cytometric tests to detect platelet microparticle release may be used
Evaluating for other etiologies of thrombocytopenia, including cardiopulmonary bypass within the last 48 hours, presence of bacteremia or fungemia, recent chemotherapy administration, and DIC due to other etiologies.
Management
If suspected, immediate removal of heparin and low molecular weight heparin from all sources.
If ongoing anticoagulation is needed, use vitamin K antagonist or direct thrombin inhibitor.
Platelet recovery and disappearance of antibodies can take weeks once heparin is discontinued.
PEARL
In cases of suspected HIT, do not delay treatment while awaiting confirmatory testing
Glucose-6-Phosphate Dehydrogenase Deficiency
Myra Cleary
Background/Definition
G6PD deficiency is a partial or complete deletion of G6PD, an enzyme that is crucial in aerobic glycolysis. Children who have G6PD-deficient RBCs are susceptible to oxidative damage and hemolysis during certain conditions of stress, exposure to certain medications, foods, or chemicals. Occurs most often in males.
Etiology/Types
Three forms have been described.
Variant 1: G6PD activity is less than 10% of normal, resulting in severe neonatal jaundice or congenital nonspherocytic hemolytic anemia.
Variant 2: G6PD activity is typically less than 30% of the normal range, resulting in an asymptomatic steady state. Individuals who carry this mutation are at risk for neonatal jaundice, acute hemolytic anemia, and favism.
Variant 3: Enzyme activity is greater than 85% of the normal reference range, resulting in no clinical manifestations. Considered the “wild type” disease.
X-linked inherited disease that affects primarily men.
Pathophysiology
G6PD is the first enzyme in the hexose monophosphate shunt. This enzyme is required for the production of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH).
NADPH is critical in preventing oxidative damage.
RBCs are susceptible to oxidative damage since they carry oxygen.
Reactive oxygen radicals damage the RBC membrane and hemoglobin resulting in hemolysis of the RBC.
Clinical Presentation
Children with G6PD deficiency are clinically and hematologically normal for the majority of their lifetime.
Acute exacerbations may occur with the ingestion of fava beans (favism), during the course of an infection, and exposure to oxidative drugs (e.g., antimalarials, sulfa-containing drugs, aspirin, and quinolones).
Symptoms: fever, nausea, abdominal pain, diarrhea, and occasionally vomiting within 24 to 48 hours after oxidative challenge.
Findings: Dark brown or black discoloration of the urine is present within 6 to 24 hours after exposure (result of hemolysis); jaundice, pallor, tachycardia, hypovolemic shock, and hepatosplenomegaly may develop.
Diagnostic Evaluation
Severe anemia with marked variation in the size of the RBCs resulting in an increase in the RBC distribution width. WBC count may be elevated.
Large polychromatic cells with spherocytic morphology as well as markedly irregular-shaped cells known as poikilocytes on peripheral blood smear.
Increased reticulocyte count; may reach levels as high as 30%.
Heinz body stain: As the RBCs circulate through the spleen, Heinz bodies are removed, resulting in classic “bite cells.” Heinz bodies are identified with methyl violet staining and are denatured hemoglobin and a manifestation of the oxidative injury to the hemoglobin.
Hemoglobinuria may be present.
Management
Blood transfusion is indicated if the child is hemodynamically unstable or the hemoglobin level declines to <7g/dL.
If the hemoglobin is <9 g/dL with evidence of persistent brisk hemolysis with hemoglobinuria, blood transfusion may be indicated.
Dialysis may be indicated for acute kidney failure.
Neonatal jaundice related to G6PD deficiency is managed with observation for mild cases, phototherapy, and hydration for more significant cases, and exchange transfusion may be beneficial for severe cases.
Methemoglobinemia
Christine A. Schindler
Background/Definition
Methemoglobinemia is an uncommon cause of cyanosis in infants and children that is a result of the heme iron being in the ferric rather than ferrous state. Under these conditions,
oxygen binding to hemoglobin is severely impaired. A small amount of methemoglobin is normal (higher baseline levels in smokers); however, when a large portion of methemoglobin is present, cyanosis can result due to the inability of methemoglobin to carry oxygen.
Etiology/Types
Congenital methemoglobinemia is caused by diminished enzymatic reduction of methemoglobin back to functional hemoglobin. Patients may present with a cyanotic appearance, but may be aysmptomatic.
Acquired methemoglobinemia is generally caused from exposure to certain medications or agents that cause an increase in the production of methemoglobin.
Substances that have been implicated in the formation of methemoglobin include:
Oxidant drugs: Sulfonamide antibiotics, Quinones, Phenacetin, Benzocaine.
Domestic and environmental substances: foods containing nitrates or nitrites, well water with nitrates, aniline dyes, naphthalene (mothballs), soap enemas, certain industrial compounds (e.g., nitrobenzenes, nitrous gases, organic amines).
Pathophysiology
Methemoglobin is an altered state of hemoglobin in which the ferrous (Fe2+) irons of heme are oxidized to the ferric (Fe3+) state. The ferric hemes are unable to bind to oxygen, resulting in an inability of the methemoglobin-containing hemoglobin to carry oxygen. The ultimate result is impaired oxygen delivery to the tissues and cyanosis.
Clinical Presentation
Symptoms depend on the concentration of methemoglobin:
10% to 30% methemoglobin—cyanosis only.
30% to 50% methemoglobin—dyspnea, tachycardia, dizziness, fatigue, headache.
50% to 70% methemoglobin—severe lethargy and stupor.
>70% methemoglobin—death.
Oxygen administration fails to affect the cyanosis.
“Chocolate”-appearing blood with laboratory sampling.
Diagnostic Evaluation
Patients with methemoglobinemia and cyanosis may have normal oxygen saturation measurements on pulse oximetry.
Rapid screening test—A drop of the patient’s blood should be placed on filter paper. After the filter paper is waved in the air for 30 to 60 seconds, normal blood appears bright red, while blood from a patient with methemoglobinemia remains reddish-brown.
Spectrophotometric assays—used for confirmation of methemoglobinemia and for determination of the level of methemoglobin.
Arterial blood gas with co-oximetry to measure level of methemoglobin.
Management
Remove the causative substance.
Depends on clinical severity:
Mild symptoms—therapy unnecessary.
Severe symptoms—treatment is administration of Methylene blue.
Failure of methylene blue therapy may be a result of concomitant G6PD deficiency. Ascorbic acid may be of some value, but if severe symptoms persist, exchange transfusion or hyperbaric oxygen may be required.
Sickle Cell Disease
Nneka Okoye
Background/Definition
Sickle cell disease (SCD) encompasses a group of hemoglobinopathies in which an abnormal sickle hemoglobin gene is inherited. Sickling of blood cells causes increased hemolysis, anemia, and acute and chronic vasoocclusive complications that affect multiple organs of varying severity.
Etiology/Types
There are several different types of SCD ranging in severity, listed below from most to least common.
Sickle cell anemia (HbSS)—most common, majority of patients, and most severe form of disease.
Sickle hemoglobin C disease (HbSC)—typically milder disease.
Sickle β+ thalassemia (HbSβ+Thal)—typically milder disease.
Sickle β0 thalassemia (HbSβ0Thal)—typically severe disease.
Rare types of SCD—sickle hemoglobin D disease (HbSD), sickle hemoglobin E disease (HbSE), sickle hemoglobin O disease (HbSO). Variable severity.
Sickle cell trait (AS)—This is not a type of SCD, but an asymptomatic carrier state affecting 10% of African Americans.
Pathophysiology
Autosomal recessive inherited disorder.
Cause of SCD is the substitution of valine for glutamic acid at the sixth position of beta (β) globin. The immediate consequence of the mutation is that deoxygenated hemoglobin S polymerizes and distorts the shape of the RBC into a sickle shape.
Sickle hemoglobin also has adverse effects on the red cell membrane that causes oxidative damage, cellular dehydration, abnormal phospholipid asymmetry, and increased adherence to endothelial cells.
The net result of these cellular abnormalities is a shortened red cell lifespan (e.g., hemolysis) and intermittent episodes of vascular occlusion that cause tissue ischemia and acute and chronic organ dysfunction.
Clinical Presentation
Clinical manifestations are widely variable in all forms of SCD, ranging from asymptomatic, mildly affected, to severely affected.
See clinical presentation table below (Table 10.1).
TABLE 10.1 Clinical Presentation and Management of Sickle Cell Disease | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Diagnostic Evaluation
SCD can be identified through newborn screening in all 50 US states.
Confirmatory testing is done with hemoglobin electrophoresis.
Prenatal diagnosis is available via amniocentesis or chorionic villus sampling.
Management
The only cure for sickle cell anemia is BMT.
Hydroxyurea is the only disease-modifying medication to treat SCD; increases fetal hemoglobin levels, resulting in decreased incidence of complications.
Other supportive care includes:
Initiation of penicillin prophylaxis by 2 months of age and continued to at least 5 years of age.
Additional vaccines (i.e., pneumococcal and meningococcal) given at age 2 and 5 years of age.
Blood transfusions, either simple, exchange, or chronic.
Thalassemia
Cathy Haut
Background
Most common worldwide genetic disorder.
α-Thalassemia is typically seen in Southeast Asia, people of African descent, China, and Middle East. Greater than 50% of some populations carry the α-thalassemia gene.
β-Thalassemia is most common in people of Mediterranean descent; 1.7% of the world’s population has α- or β-thalassemia trait.
Must inherit defective genes from both parents to have thalassemia major.
Thalassemia minor is often found in an asymptomatic carrier.
Definition
Thalassemia is an autosomal dominant hematologic disorder that results in the production of an abnormal form of hemoglobin that results in destruction of RBCs.
Etiology/Types
α-Thalassemia major.
β-Thalassemia major, also called “Cooley Anemia.”
Thalassemia minor.
Pathophysiology
The thalassemias are classified according to the chain of the hemoglobin molecule that is affected. α-Thalassemia occurs when a gene or genes related to the α-globin protein are missing or changed (mutated). β-Thalassemia occurs when similar gene defects affect production of the β-globin protein. Both types result in excessive destruction of RBCs, causing anemia.
Clinical Presentation
Typical features: chipmunk facies with prominent frontal bossing, delayed pneumatization of the sinuses, marked overgrowth of maxillae.
Bones and ribs become “box-like,” premature fusion of epiphyses, and thinning of the cortex of the bone.
Findings: hepatomegaly, splenomegaly, enlarged kidneys with dilated renal tubules, dark urine, cardiac abnormalities, and delayed sexual development.
Diagnostic Evaluation
Anemia, typically found in the first year of life.
Hypochromic, microcytic anemia with decreased MCV, basophilic stippling, presence of Hgb A.
May have hyperuricemia.
Management
Primary treatment is blood transfusion and folate replacement.
BMT from a matched sibling donor is the best chance for cure.
Complications include iron overload from transfusions, congestive heart failure, and early death.
Thromboembolytic Disorders
Christine Guelcher
Background
Although relatively uncommon in pediatric patients, the incidence of venous thromboembolism is increasing as a result of advances in surgical and medical care for previously fatal illnesses. Thrombotic complications in pediatric patients are often a result of therapies, including central venous catheters.
Definition
Thrombosis is pathological formation of a blood clot (thrombus) in a blood vessel affecting blood flow. The thrombus may be occlusive or nonocclusive and either provoked or unprovoked. Embolism occurs when the thrombus travels through the blood vessels to the lungs, brain, or elsewhere, causing significant life-threatening acute events.
Most pediatric thrombotic events are associated with at least one risk factor, which can include genetic (e.g., inherited thrombophilia) or acquired (e.g., sepsis, trauma, dehydration, use of oral contraceptives).
Pathophysiology
According to Virchow’s triad concept, thrombosis is caused by a disruption of one of the three elements in this triad: changes in the vessel wall, alteration in blood flow, or increased coagulability of the blood.
Etiology/Risk Factors
Acquired risk factors: obesity, smoking, cancer, and medications including L-Asparginase and estrogen-based hormones.
Increased risk in pregnancy related to elevations of procoagulant factors and relative deficiency of anticoagulant factors.
Trauma can lead to vessel damage; can be compounded by venous stasis secondary to bed rest during recovery.
Antiphospholipid antibodies.
Presence of antiphospholipid antibodies on two occasions (separated by 12 weeks) and a thrombotic event is considered antiphospholipid syndrome.
Significantly increased risk for recurrent thrombosis.
Consider indefinite anticoagulation to prevent repeated thrombotic events.
Inherited risk factors.
Factor V Leiden mutation is the most common inherited thrombophilia, affecting 5% of Caucasians; rare in African or Asian populations. Factor V is not cleaved by activated protein C, resulting in resistance to activated protein C.
Prothrombin gene mutation is the second-most common inherited thrombophilia, more common in Caucasians, involving point mutation that results in increased levels of prothrombin (factors).
Protein S deficiency is rare (0.03%-0.13%).
Elevated factor VIII, an acute phase reactant, is increased by stresses to the system (e.g., trauma, surgery).
Presentation
Symptoms: impaired/absent blood flow in a deep vein. DVT in an extremity results in painful swelling of the extremity; symptoms depend on the location of the clot and the impact on blood flow to the distal vessels.
VT in the neck vessels can result in superior vena cava syndrome.
Pulmonary embolus can be life-threatening; symptoms may be more subtle in pediatric patients.
Cerebral sinus venous thrombosis is a thrombus in the deep veins of the head, resulting in persistent headache, blurred vision, neurologic signs, or seizures.
Renal vein thrombosis is associated with nephrotic syndrome, presenting with generalized edema.
Portal vein thrombosis causes splenomegaly with thrombocytopenia and anemia. Esophageal varices can result.
May-Thurner Syndrome is a vascular anomaly in the pelvis in which the right common iliac artery compresses the left common iliac vein; predisposes patients to left lower extremity DVT.
Paget-Schroetter syndrome is an upper extremity DVT that results from venous thoracic outlet syndrome, in which the axillary and subclavian veins are compressed at their exit site into the chest. Thrombosis is triggered by repetitive overhead arm motion (e.g., baseball pitching) that exacerbates the compression.
Diagnostic Evaluation
Imaging.
DVT—Doppler ultrasound can document the presence and extent of most DVTs (CT/MRI evaluate extension into the pelvis or head).
Pulmonary embolus—Spiral CT or ventilation-perfusion scan.
Cerebral sinus venous thrombosis—Contrast-enhanced MRI scan.
Renal vein thrombosis, portal vein thrombosis—Doppler US or Contrast CT scan.
Laboratory Evaluation
Evaluate for prothrombotic risk factors.
Some laboratory tests (e.g., protein C, protein S, ATIII) may be low with acute thrombosis.
Other laboratory tests may be elevated (e.g., factor VIII) with acute thrombosis.
Tests should be repeated if abnormal in the acute phase of disease.
Anticoagulation monitoring:
PTT is an indirect measurement of anticoagulation and should be correlated with patient’s anti-Xa level.
Anti-Xa is a more direct measure of heparin anticoagulation.
Anti-Xa levels for patients receiving low molecular weight heparin (e.g., Enoxaparin).
PT for patients receiving vitamin K antagonist (e.g., warfarin).
 FIGURE 10.1 • Coagulation Cascade. |
Management
The American College of Chest Physicians guidelines (2012) recommend that pediatric patients with a catheter-related thrombotic event undergo removal of a central venous access device within 3 to 5 days of starting anticoagulation. Follow protocols for continued therapy and prophylaxis if catheter is not removed.
For pediatric patients who have other risk factors that may resolve, the guidelines suggest anticoagulation treatment for at least 3 months or more with consideration of risk factor resolution (Figure 10.1).
Patients with occlusive thrombosis will develop collateral vessels, and some thrombi will never completely resolve. Anticoagulation therapy is designed to prevent propagation of the thrombus as fibrinolysis will occur to break down clot.
PEARLS
Identification of patients at risk is key to intervening and preventing thrombotic events.
Prevention of propagation of thrombus may require anticoagulation with heparin, warfarin, or low molecular weight heparin based on hematology recommendations.
Identify inherited risk factors in patients who develop thromboembolism.
Von Willebrand Disease
Christine Guelcher
Background
Von Willebrand disease (VWD) was first discussed in 1924 as a bleeding disorder that was associated primarily with mucosal membrane bleeding. Inheritance pattern is autosomal dominant. Affected patients had prolonged bleeding times, but normal clotting times. VWD affects between 0.1% and 1% of the world population.
Definition
A disease of either a quantitative deficiency or qualitative defect of the von Willebrand protein.
Etiology/Types
There are three main types of VWD that are characterized by the qualitative or quantitative defects in von Willebrand factor (VWF).
Pathophysiology
Some VWF is produced in Weibel-Pilade bodies and stored in epithelial cells that line the blood vessels.
VWF synthesized in macrophages and stored in α-granules
Binds to factor VIII in circulation.
Mobilized to site of vessel injury where it adheres to endothelium.
May be released from endothelial cells in response to injury.
Interacts with platelets to help with adherence and activation at the site of injury.
Patients who are deficient or have a defect of VWF are at risk for prolonged bleeding, particularly from the mucous membranes.
Clinical Presentation
Often diagnosed later in life.
History of easy bruising, frequent epistaxis (incidence can be 50% to 75%), heavy menstrual bleeding, or bleeding after a surgical/dental procedure.
Diagnostic Evaluation
Von Willebrand protein levels may fluctuate, so repeated laboratory testing may be needed for diagnosis.
Other screening tests can be used to identify coagulation factors and assist in diagnosis, but studies are complicated and not always reliable.
Management
Treatment capitalizes on interactions that occur during times of stress or with hormonal changes.
Desmopressin acetate (DDAVP).
Stimulates release of VWF and factor VIII.
Management of prolonged or refractory bleeding and prior to minor elective procedures.
Antifibrinolytic agents.
Used in managing recurrent bleeding in VWD, but do not stop active bleeding; slow the breakdown of clots to preventing rebleeding.
Aminocaproic acid (Amicar); contraindicated with hematuria.
Tranexamic acid (Lysteda): FDA-approved for menorrhagia.
VWF concentrates are derived from human blood donation.
The von Willebrand containing factors have both von Willebrand antigen and factor VIII.
PEARLS
A questionnaire has been adapted and studied for use as a pediatric screening tool for VWD.
Estrogen has been demonstrated to have an impact on VWF levels, so knowledge of hormonal contraception or pregnancy is important when evaluating adolescents.
DDAVP is not effective for all patients with VWD.
Transfusion Therapy
Cathy Haut
Background
Modern methods of blood transfusions began only in 1901, when blood types were discovered.
Pretransfusion typing is performed to determine the best match for minimal complications.
Definition
The transfer of blood or blood products from a donor to a recipient.
Physiology
The main function of blood is facilitation of delivery of oxygen and nutrients to tissues. Oxygen is carried by hemoglobin, an iron-containing protein. Blood also transports electrolytes, nutrients such as glucose, and waste products. The maintenance of immune surveillance is another function of blood.
FFP is extracted from whole blood and contains coagulation, fibrolytic, and complement systems that assist in the restoration of coagulation disorders such as DIC.
Platelets are responsible for hemostasis with resulting thrombus formation. Transfusion of platelets is used to restore abnormally low levels.
Cryoprecipitate is obtained by centrifuging plasma and removing the precipitate. It is not used as commonly as FFP, but can be used to replace low fibrinogen levels and when certain factors are not available for treatment of coagulation disorders.
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