ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Increased frequency of infections.
Ulceration of oral mucosa and gingivitis.
Decreased absolute neutrophil count; normal numbers of red cells and platelets.
Neutropenia is an absolute neutrophil (granulocyte) count of less than 1500/μL in childhood, or less than 1100/μL between ages 1 month and 2 years. During the first few days of life, an absolute neutrophil count of less than 3500/μL may be considered neutropenia in term infants. Neutropenia results from absent or defective myeloid stem cells; ineffective or suppressed myeloid maturation; altered production of hematopoietic cytokines or chemokines or abnormalities in their receptors; decreased marrow release; increased neutrophil apoptosis; destruction or consumption; or, in pseudoneutropenia, from an increased neutrophil marginating pool (Table 30–5). A decrease in neutrophil mass diminishes delivery of these cells to areas where the balance favors bacterial proliferation and invasion.
Table 30–5.Classification of neutropenia in childhood. ||Download (.pdf) Table 30–5. Classification of neutropenia in childhood.
Congenital neutropenia with abnormalities of stem cells or committed myeloid progenitor cells
Chronic idiopathic neutropenia of childhood
Severe congenital neutropenia (SCN 1-5 and X-linked)
Organic acidemias (eg, propionic, methylmalonic)
Neutropenia with immunodeficiency disorders (SCID, Hyper-IgM)
Acquired neutropenias affecting stem cells
Malignancies (leukemia, lymphoma) and preleukemic disorders
Drugs or toxic substances
Acquired neutropenias affecting committed myeloid progenitors or survival of mature neutrophils
Ineffective myelopoiesis (vitamin B12, folate, and copper deficiency)
Immune (neonatal alloimmune or autoimmune, autoimmune, or chronic benign neutropenia of childhood)
The severity of neutropenia may be characterized by the level of peripheral neutrophils, the number and severity of infections, and the production of mature neutrophils in the marrow. Also important is whether the neutropenia is acute (< 3 months) or chronic (> 3 months). The most severe types of chronic neutropenia include reticular dysgenesis (congenital aleukocytosis), Kostmann syndrome or severe congenital neutropenia, SCN (severe neutropenia with maturation defect in the marrow progenitor cells associated with specific gene defects), Shwachman syndrome (neutropenia with pancreatic insufficiency), neutropenia with immune deficiency states, cyclic neutropenia, and myelokathexis or dysgranulopoiesis. Genetic mutations for Chédiak-Higashi syndrome (LYST (CHS1), Whim syndrome (CXCR4), SCN 1-5 (ELANE, GFl1, HAX1, G6PC3, VPS45, as well as WASP and GCSF3R), Shwachman syndrome (SBDS), and cyclic neutropenia (ELANE) have been identified. Neutropenia may also be associated with storage (GSD-Ib) and metabolic diseases, immunodeficiency states, and other disorders. At least 17 genes have been implicated in all these disorders. In many cases, race, neutropenia represents the sole manifestation but sometimes the disorder is also associated by multisystem involvement. The most common causes of acute neutropenia are viral infection or drugs, resulting in decreased neutrophil production in the marrow, increased peripheral turnover, or both. Severe bacterial infections may be associated with neutropenia. Although not commonly identified, neonatal alloimmune neutropenia can be severe and associated with infection. Autoimmune neutropenia occurs with chronic benign neutropenia of childhood, immunodeficiency syndromes, autoimmune disorders, or, in the newborn, as a result of passive transfer of antibody (alloimmune) from the mother to the fetus. Malignancies, osteopetrosis, marrow failure syndromes, and hypersplenism usually are not associated with isolated neutropenia.
Acute severe bacterial or fungal infection is the most significant complication of neutropenia. Although the risk is increased when the absolute neutrophil count is less than 500/μL, the actual susceptibility is variable and depends on the cause of neutropenia, marrow reserves, and other factors. The most common types of infection include septicemia, cellulitis, skin abscesses, pneumonia, and perirectal abscesses. In addition to local signs and symptoms, patients may have chills, fever, and malaise. Sinusitis, aphthous ulcers, gingivitis, and periodontal disease also cause significant problems in chronic neutropenia. In most cases, the spleen and liver are not enlarged. Staphylococcus aureus and gram-negative bacteria are the most common pathogens.
Neutrophils are absent or markedly reduced in the peripheral blood. In most forms of neutropenia or agranulocytosis, the monocytes and lymphocytes are normal and the red cells and platelets are not affected. The bone marrow usually shows a normal erythroid series, with adequate megakaryocytes, but a marked reduction in the myeloid cells or a significant delay in maturation of this series may be noted at various stages of myeloid maturation. Total cellularity may be decreased.
In the evaluation of neutropenia (eg, persistent, intermittent, cyclic), attention should be paid to the duration and pattern of neutropenia, the types of infections and their frequency, and phenotypic abnormalities on physical examination. A careful family history and blood counts from the parents may be useful. If an acquired cause, such as viral infection or drug, is not obvious as an acute cause, no other primary disease is present, and the neutropenia is chronic, WBC counts, white cell differential, and platelet and reticulocyte counts should be completed twice weekly for 6 weeks to determine the pattern of neutropenia. Bone marrow aspiration and biopsy including cytogenetic analysis are most important to characterize the morphologic features of myelopoiesis. Measuring the neutrophil counts in response to corticosteroid infusion may document the marrow reserves. Other tests that aid in the diagnosis include measurement of neutrophil antibodies, immunoglobulin levels, antinuclear antibodies, and lymphocyte phenotyping to detect immunodeficiency states. Culture of bone marrow may define myeloid progenitors or the presence of inhibitory factors. Cytokines in plasma or by mononuclear cells can be measured directly. Some neutropenia disorders have abnormal neutrophil function, but severe neutropenia may preclude collection of sufficient cells to complete assays. Analysis for gene mutations noted above may help confirm the diagnosis of a severe neutropenia syndrome. Increased apoptosis in marrow precursors or circulating neutrophils is a general characteristic described in several congenital or genetic disorders.
Underlying disorders should be identified and treated or associated agents should be eliminated. Infections should be aggressively assessed and treated. Prophylactic antimicrobial therapy is not indicated for afebrile, asymptomatic patients, but may be considered in rare cases with recurrent infections. Recombinant G-CSF will increase neutrophil counts in most patients; GM-CSF may be considered, but is less extensively used. For patients with neutrophil counts 500/μL or less G-CSF (Filgrastim) may be started at 3–5 mcg/kg/day subcutaneously or intravenously once a day, and the dose adjusted to keep the absolute neutrophil count > 500/μL and < 10,000/μL. The use of long-acting G-CSF (pegfilgrastim) has been used in a few patients with chronic neutropenia. In a small number of patients, G-CSF therapy has been shown to be safe for mothers throughout pregnancies and for newborns without evidence of teratogenicity. Some patients maintain adequate counts with G-CSF given every other day. Treatment will decrease infectious complications but may have little effect on periodontal disease. However, not all patients with neutropenia syndromes require G-CSF (eg, chronic benign neutropenia of childhood). Patients with cyclic neutropenia may have a milder clinical course as they grow older. Immunizations should be given if the adaptive immune system is normal. Hematopoietic stem cell transplant may be considered for patients with severe complications, especially those with severe congenital neutropenia.
The prognosis varies greatly with the cause and severity of the neutropenia. In severe cases with persistent agranulocytosis, the prognosis is poor in spite of antibiotic therapy; in mild or cyclic forms of neutropenia, symptoms may be minimal and the prognosis for normal life expectancy excellent. G-CSF has the potential to prolong life expectancy. Up to 50% of patients with Shwachman syndrome may develop aplastic anemia, myelodysplasia, or leukemia during their lifetime. Patients with other SCNs also have a potential for leukemia, as do patients with neutropenia associated with some immune disorders. Hematopoietic stem cell transplant may be the only curative therapy for some disorders.
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Neutrophilia is an increase in the absolute neutrophil count in the peripheral blood to greater than 7500–8500/μL for infants, children, and adults. To support the increased peripheral count, neutrophils may be mobilized from bone marrow storage or peripheral marginating pools. Neutrophilia occurs acutely in association with bacterial or viral infections, inflammatory diseases (eg, juvenile rheumatoid arthritis, inflammatory bowel disease, Kawasaki disease), surgical or functional asplenia, liver failure, diabetic ketoacidosis, azotemia, congenital disorders of neutrophil function (eg, chronic granulomatous disease, leukocyte adherence deficiency), and hemolysis. Drugs such as corticosteroids, lithium, and epinephrine increase the blood neutrophil count. Corticosteroids cause release of neutrophils from the marrow pool, inhibit egress from capillary beds, and postpone apoptotic cell death. Epinephrine causes release of the marginating pool. Acute neutrophilia has been reported after stress, such as from electric shock, trauma, burns, surgery, and emotional upset. Tumors involving the bone marrow, such as lymphomas, neuroblastomas, and rhabdomyosarcoma, may be associated with leukocytosis and the presence of immature myeloid cells in the peripheral blood. Infants with Down syndrome have defective regulation of proliferation and maturation of the myeloid series and may develop neutrophilia. At times this process may affect other cell lines and mimic myeloproliferative disorders or acute leukemia.
The neutrophilias must be distinguished from myeloproliferative disorders such as chronic myelogenous leukemia and juvenile chronic myelogenous leukemia. In general, abnormalities involving other cell lines, the appearance of immature cells on the blood smear, and the presence of hepatosplenomegaly are important differentiating characteristics.
DISORDERS OF NEUTROPHIL FUNCTION
Neutrophils play a key role in host defenses. Circulating in the laminar flow of blood vessels, they adhere to capillary vascular endothelium adjacent to sites of infection and inflammation. Moving between endothelial cells, the neutrophil migrates toward the offending agent. Contact with a microbe that is properly opsonized with complement or antibodies triggers ingestion, a process in which cytoplasmic streaming results in the formation of pseudopods that fuse around the invader, encasing it in a phagosome. During the ingestion phase, the oxidase enzyme system assembles in the phagosomal membrane and is activated, taking oxygen from the surrounding medium and reducing it to form toxic oxygen metabolites critical to microbicidal activity. Concurrently, granules from the two main classes (azurophil and specific) fuse and release their contents into the phagolysosome. The concentration of toxic oxygen metabolites (eg, hydrogen peroxide, hypochlorous acid, hydroxyl radical) and other compounds (eg, proteases, cationic proteins, cathepsins, defensins) increases dramatically, resulting in the death and dissolution of the microbe. Complex physiologic and biochemical processes support and control these functions. Defects in any of these processes may lead to inadequate cell function and an increased risk of infection.
Table 30–6 summarizes congenital neutrophil function defects. Recently reported is variant CGD with p40phox deficiency manifested by inflammatory bowel disease. Also described is a syndrome of severe neutrophil dysfunction and severe infections associated with a mutation in a GTPase signaling molecule, Rac2 (gene, RAC2). New syndromes of innate immune dysfunction include defects in interferon and interleukin (IL)-12 receptor and signaling pathways, leading to monocyte and macrophage dysfunction and defective toll-like receptor signaling pathways (IL-1 receptor-associated kinase 4 [IRAK-4] deficiency) associated with recurrent bacterial infections. Leukocyte adhesion deficiency (LAD) III is a disorder characterized by severe bleeding, impaired leukocyte adhesion, and endothelial inflammation, and is associated with mutations of FERMT3 gene, which encodes for a protein, Kindlin-3, critical for intracellular function of β integrins and perhaps other adhesion strategies. Other congenital or acquired causes of mild to moderate neutrophil dysfunction include metabolic defects (eg, glycogen storage disease Ib, G6PC3 deficiency, other congenital neutropenia syndromes (eg, Chediak Higashi syndrome and Shwachman Diamond Syndrome), diabetes mellitus, renal disease, and hypophosphatemia, viral infections, and certain drugs. Neutrophils from newborn infants have abnormal adherence, chemotaxis, and bactericidal activity. Cells from patients with thermal injury, trauma, and overwhelming infection have defects in cell motility and bactericidal activity similar to those seen in neonates.
Table 30–6.Classification of congenital neutrophil function deficits. ||Download (.pdf) Table 30–6. Classification of congenital neutrophil function deficits.
|Disorder ||Clinical Manifestations ||Functional Defect ||Biochemical Defect ||Inheritance (Chromosome; Gene) |
|Chédiak-Higashi syndrome ||Oculocutaneous albinism, photophobia, nystagmus, ataxia. Recurrent infections of skin, respiratory tract, and mucous membranes with gram-positive and gram-negative organisms. Many patients die during lymphoproliferative phase with hepatomegaly, fever, which may be a viral-associated hemophagocytic syndrome secondary to Epstein-Barr virus infection. Older patients may develop degenerative CNS disease. ||Neutropenia. Neutrophils, monocytes, lymphocytes, platelets, and all granule-containing cells have giant granules. Most significant defect is in chemotaxis. Also milder defects in microbicidal activity and degranulation. ||Gene (CHS1/LYST) deficit identified. Alterations in membrane fusion with formation of giant granules. Other biochemical abnormalities in cAMP and cGMP, microtubule assembly. ||Autosomal recessive (1q42.1-.2; CHS1) |
|Leukocyte adherence deficiency I ||Recurrent soft-tissue infections, including gingivitis, otitis, mucositis, periodontitis, skin infections. Delayed separation of the cord in newborn and problems with wound healing. ||Neutrophilia. Diminished adherence to surfaces, leading to decreased chemotaxis. ||Absence or partial deficiency of CD11b/CD18 cell surface adhesive glycoprotein. Defect in expression CD18 (gene, TGB2) ||Autosomal recessive (12q22.3; ITGB2) |
|Leukocyte adherence deficiency II ||Recurrent infections, mental retardation, craniofacial abnormalities, short stature. ||Neutrophilia. Deficient “rolling” interactions with endothelial cells. Red cells have Bombay phenotype. ||Deficient fucosyl transferase (gene, SLC35C1) results in deficient sialyl-Lewis-X antigen, which interacts with P selectin. P selectin on endothelial cells is required for neutrophil rolling, a prerequisite for adherence and diapedesis. ||Autosomal recessive (11p11.2; SLC35C1) |
|Chronic granulomatous disease ||Recurrent purulent infections with catalase-positive bacteria and fungi. May involve skin, mucous membranes. Patients also develop deep infections (lymph nodes, lung, liver, bones) and sepsis. ||Neutrophilia. Neutrophils demonstrate deficient bactericidal activity but normal chemotaxis and ingestion. Defect in the oxidase (Nox2) enzyme system, resulting in absence or diminished production of oxygen metabolites toxic to microbes. || |
Several molecular defects in oxidase components. Absent cytochrome b558 with decreased expression of either (1) or (2):
(1) gp91-phox (gene, CYBB)
(2) p22-phox (gene, CYBA)
Absent p47-phox (gene, NCF1) or p67-phox (gene, NCF2) both ar cytosolic components.
Fourth cytosolic component defect described, p40phox deficiency (gene, NCF4)
X-linked in 60%–65% of cases (Xp21.1; CYBB)
Autosomal recessive in < 5% of cases (16q24; CYBA)
Autosomal recessive in 30% of cases (7q11.23; NCF1 and 1q25; NCF2, respectively)
|Myeloperoxidase deficiency ||Generally healthy. Fungal infections when deficiency associated with systemic diseases (eg, diabetes in poor control). ||Diminished capacity to enhance hydrogen peroxide-mediated microbicidal activity. Decreased killing of Candida. ||Diminished or absent myeloperoxidase; posttranslational defect in processing protein. ||Autosomal recessive (17q22-23) |
|Specific granule deficiency ||Recurrent skin and deep tissue infections. ||Neutropenia. Neutrophils have band-shaped or bilobed nuclei. Decreased chemotaxis and bactericidal activity. ||Failure to produce specific granules or their contents during myelopoiesis. Defect in transcription factor (gene, C/EBP-epsilon). ||Autosomal recessive (14q11.2; CEBPε) |
Recurrent bacterial or fungal infections are the hallmark of neutrophil dysfunction. Although patients will have infection-free periods, episodes of pneumonia, sinusitis, cellulitis, cutaneous and mucosal infections (including perianal or peritonsillar abscesses), and lymphadenitis are frequent. As with neutropenia, aphthous ulcers of mucous membranes, severe gingivitis, and periodontal disease are also major complications. In general, S aureus or gram-negative organisms are commonly isolated from infected sites; other organisms may be specifically associated with a defined neutrophil function defect. In some disorders, fungi account for an increasing number of infections. Deep or generalized infections, such as osteomyelitis, liver abscesses, pneumonitis, sepsis, meningitis, and necrotic or gangrenous soft-tissue lesions, occur in specific syndromes (eg, leukocyte adherence deficiency or chronic granulomatous disease). Patients with severe neutrophil dysfunction may die in childhood from severe infections and associated complications. Table 30–6 summarizes pertinent laboratory findings.
The mainstay of management of these disorders is anticipation of infections and aggressive attempts to identify the foci and the causative agents. Surgical procedures to achieve these goals may be both diagnostic and therapeutic. Broad-spectrum antibiotics covering the range of possible organisms should be initiated without delay, switching to specific antimicrobial agents when the microbiologic diagnosis is made. When infections are unresponsive or they recur, granulocyte transfusions may be helpful.
Chronic management may include prophylactic antibiotics. Trimethoprim-sulfamethoxazole and some other antibiotics (eg, rifampin) enhance the bactericidal activity of neutrophils from patients with chronic granulomatous disease. Some patients with Chédiak-Higashi syndrome improve clinically when given ascorbic acid. Recombinant γ-interferon decreases the number and severity of infections in patients with chronic granulomatous disease. Demonstration of this activity with one patient group raises the possibility that cytokines, growth factors, and other biologic response modifiers may be helpful in other conditions in preventing recurrent infections. Bone marrow transplant has been attempted in most major congenital neutrophil dysfunction syndromes, and reconstitution with normal cells and cell function has been documented. Combining genetic engineering with autologous bone marrow transplant may provide a future strategy for curing these disorders.
For mild to moderate defects, anticipation and conservative medical management ensure a better outlook. For severe defects, excessive morbidity and significant mortality still exist. In some diseases, the development of noninfectious complications, such as the lymphoproliferative phase of Chédiak-Higashi syndrome or inflammatory syndromes in chronic granulomatous disease, may influence prognosis.
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From the first week up to the fifth year of life, lymphocytes are the most numerous leukocytes in human blood. The ratio then reverses gradually to reach the adult pattern of neutrophil predominance. An absolute lymphocytosis in childhood is associated with acute or chronic viral infections, pertussis, syphilis, tuberculosis, and hyperthyroidism. Other noninfectious conditions, drugs, and hypersensitivity and serum sickness–like reactions cause lymphocytosis.
Fever, upper respiratory symptoms, gastrointestinal complaints, and rashes are clues in distinguishing infectious from noninfectious causes. The presence of enlarged liver, spleen, or lymph nodes is crucial to the differential diagnosis, which includes acute leukemia and lymphoma. Most cases of infectious mononucleosis are associated with hepatosplenomegaly or adenopathy. The absence of anemia and thrombocytopenia helps to differentiate these disorders. Evaluation of the morphology of lymphocytes on peripheral blood smear is crucial. Infectious causes, particularly infectious mononucleosis, are associated with atypical features in the lymphocytes, such as basophilic cytoplasm, vacuoles, finer and less-dense chromatin, and an indented nucleus. These features are distinct from the characteristic morphology associated with lymphoblastic leukemia. Lymphocytosis in childhood is most commonly associated with infections and resolves with recovery from the primary disease.
Eosinophilia in infants and children is an absolute eosinophil count greater than 300/μL. Marrow eosinophil production is stimulated by the cytokine IL-5. Allergies, particularly those associated with asthma and eczema, are the most common primary causes of eosinophilia in children. Eosinophilia also occurs in drug reactions, with tumors (Hodgkin and non-Hodgkin lymphomas and brain tumors), and with immunodeficiency and histiocytosis syndromes. Increased eosinophil counts are a prominent feature of many invasive parasitic infections. Gastrointestinal disorders such as chronic hepatitis, ulcerative colitis, Crohn disease, and milk precipitin disease may be associated with eosinophilia. Increased blood eosinophil counts have been identified in several families without association with any specific illness. Rare causes of eosinophilia include the hypereosinophilic syndrome, characterized by counts greater than 1500/μL and organ involvement and damage (hepatosplenomegaly, cardiomyopathy, pulmonary fibrosis, and central nervous system injury). This is a disorder of middle-aged adults and is rare in children. Eosinophilic leukemia has been described, but its existence as a distinct entity is very rare.
Eosinophils are sometimes the last type of mature myeloid cell to disappear after marrow ablative chemotherapy. Increased eosinophil counts are associated with graft-versus-host disease after bone marrow transplant, and elevations are sometimes documented during rejection episodes in patients who have solid organ grafts.
Bleeding disorders may occur as a result of (1) quantitative or qualitative abnormalities of platelets, (2) quantitative or qualitative abnormalities in plasma procoagulant factors, (3) vascular abnormalities, or (4) accelerated fibrinolysis. The coagulation cascade and fibrinolytic system are shown in Figures 30–4 and 30–5.
The procoagulant system and formation of a fibrin clot. Vascular injury initiates the coagulation process by exposure of tissue factor (TF); the dashed lines indicate thrombin actions in addition to clotting of fibrinogen. The dotted lines associated with VIIa indicate the feedback activation of the VII-TF complex by Xa and IXa. Ca++, calcium; HK, high-molecular-weight kininogen; PK, prekallikrein; PL, phospholipid. (Reproduced with permission from Goodnight SH, Hathaway WE: Disorders of Hemostasis & Thrombosis: A Clinical Guide. 2nd ed. New York: McGraw-Hill; 2001.)
The fibrinolytic system. Solid arrows indicate activation; dashed line arrows indicate inhibition. ECM, extracellular matrix; FDP, fibrinogen-fibrin degradation products; MMP, matrix metalloproteinases; PAI, plasminogen activator inhibitor; TAFI, thrombin activatable fibrinolysis inhibitor; tPA, tissue plasminogen activator; uPA, urokinase; uPAR, cellular urokinase receptor. (Reproduced with permission from Goodnight SH, Hathaway WE: Disorders of Hemostasis & Thrombosis: A Clinical Guide. 2nd ed. New York: McGraw-Hill; 2001.)
The most critical aspect in evaluating the bleeding patient is obtaining detailed personal and family bleeding histories, including bleeding complications associated with birth and the perinatal period, dental interventions, minor procedures, surgeries, and trauma. Excessive mucosal bleeding is suggestive of a platelet disorder, von Willebrand disease (vWD), dysfibrinogenemia, or vasculitis. Bleeding into muscles and joints may be associated with a plasma procoagulant factor abnormality. In either scenario, the abnormality may be congenital or acquired. A thorough physical examination should be performed with special attention to the skin, oro- and nasopharynx, liver, spleen, and joints. Screening and diagnostic evaluation in patients with suspected bleeding disorders may include the following laboratory testing:
Prothrombin time (PT) to assess clotting function of factors VII, X, V, II, and fibrinogen.
Activated partial thromboplastin time (aPTT) to assess clotting function of high-molecular-weight kininogen, prekallikrein, XII, XI, IX, VIII, X, V, II, and fibrinogen.
Platelet count and size determined as part of a CBC.
Platelet functional assessment by platelet function analyzer-100 (PFA-100), template bleeding time, or whole blood platelet aggregometry.
Fibrinogen functional level by clotting assay.
The following laboratory tests may also be useful:
Thrombin time to measure the generation of fibrin from fibrinogen following conversion of prothrombin to thrombin, as well as the antithrombin effects of fibrin-split products and heparin. The thrombin time may be prolonged in the setting of a normal fibrinogen concentration if the fibrinogen is dysfunctional (ie, dysfibrinogenemia).
Euglobulin lysis time (ELT) to evaluate for hyperfibrinolysis if the preceding workup is nonrevealing despite documented history of bleeding. If the ELT is shortened, assess hyperfibrinolysis due to a congenital deficiency of the fibrinolytic inhibitors plasminogen activator inhibitor-1 and α2-antiplasmin. In ill patients, measurement of fibrin degradation products may assist in the diagnosis of DIC.
WE (eds): Disorders of Hemostasis & Thrombosis: A Clinical Guide, 2nd ed. McGraw-Hill, 2001:41–51.
ABNORMALITIES OF PLATELET NUMBER OR FUNCTION
Thrombocytopenia in the pediatric age range is often immune-mediated (eg, ITP, neonatal auto- or alloimmune thrombocytopenia), but is also caused by consumptive coagulopathy (eg, DIC, Kasabach-Merritt phenomenon), acute leukemias, or rarer disorders such as Wiskott-Aldrich syndrome and type 2b vWD, and artifactually in automated cytometers (eg, Bernard-Soulier syndrome), where giant forms may not be enumerated as platelets.
1. Idiopathic Thrombocytopenic Purpura
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Acute ITP is the most common bleeding disorder of childhood. It occurs most frequently in children aged 2–5 years and often follows infection with viruses, such as rubella, varicella, measles, parvovirus, influenza, EBV, or HIV. The thrombocytopenia results from clearance of circulating IgM- or IgG-coated platelets by the reticuloendothelial system. The spleen plays a predominant role in the disease by forming the platelet cross-reactive antibodies and sequestering the antibody-bound platelets. Most patients recover spontaneously within months. Chronic ITP (> 12 months duration) occurs in 10%–20% of affected patients.
Onset of ITP is usually acute, with the appearance of multiple petechiae and ecchymoses. Epistaxis is common at presentation. No other physical findings are usually present. Rarely, concurrent infection with EBV or CMV may cause hepatosplenomegaly or lymphadenopathy, simulating acute leukemia.
The platelet count is markedly reduced (usually < 50,000/μL and often < 10,000/μL), and large platelets are present in the peripheral blood smear, suggesting accelerated new platelet production. The white blood count and differential are normal, and the hemoglobin concentration is preserved unless hemorrhage has been significant.
Megakaryocyte hyperplasia with normal erythroid and myeloid cellularity.
3. Other laboratory tests
Platelet-associated IgG or IgM, or both, may be demonstrated on the platelets or in the serum. PT and aPTT are normal.
Table 30–7 lists common causes of thrombocytopenia. ITP remains a diagnosis of exclusion. Family history or the finding of predominantly giant platelets on the peripheral blood smear is helpful in distinguishing from hereditary thrombocytopenia. Bone marrow examination should be performed if the history is atypical (ie, the child is not otherwise healthy, or there is a family history of bleeding), if abnormalities other than purpura and petechiae are present on physical examination, or if other cell lines are abnormal on the CBC. Bone marrow examination prior to treatment with corticosteroids remains controversial.
Table 30–7.Common causes of thrombocytopenia. ||Download (.pdf) Table 30–7. Common causes of thrombocytopenia.
|Increased Turnover ||Decreased Production |
|Antibody-Mediated ||Coagulopathy ||Other ||Congenital ||Acquired |
|Idiopathic thrombocytopenic purpura ||Disseminated intravascular coagulopathy ||Hemolytic-uremic syndrome || |
|Aplastic anemia |
|Infection ||Sepsis ||Thrombotic thrombocytopenic purpura ||Wiskott-Aldrich syndrome ||Leukemia and other malignancies |
|Immunologic diseases || |
Respiratory distress syndrome
Thrombocytopenia with absent radii
Vitamin B12 and folate deficiencies
Severe hemorrhage and bleeding into vital organs are feared complications of ITP. Intracranial hemorrhage is the most serious complication, occurring in less than 1% of affected children. The most important risk factors for hemorrhage are a platelet count less than 10,000/μL and mean platelet volume less than 8 fL.
Observation is recommended for most children in the absence of bleeding regardless of platelet count. Aspirin, other medications (eg, NSAIDs such as Advil, Naproxin, etc) that compromise platelet function should be avoided. Bleeding precautions (eg, restriction from physical contact activities and use of helmets) should be observed. Platelet transfusion should be avoided except in circumstances of life-threatening bleeding, in which case emergent splenectomy may be considered. In this setting, administration of corticosteroids and IVIG is also advisable.
Patients with clinically significant, but non–life-threatening bleeding (ie, epistaxis, hematuria, and hematochezia) and those with a platelet count of less than 10,000/dL may benefit from treatment with corticosteroids. No single dose or dosing regimen has evidence to support its use above another. Prednisone 2 mg/kg/day (maximum of 60 mg/day) for 14–21 days, or alternatively, prednisone 4 mg/kg/day for 7 days, with a taper to day 14–21 are commonly used regimens. An initial higher dose (3–5 mg/kg/day) for 3–7 days may lead to faster count recovery. Long-term use of corticosteroids should be avoided because of toxicity.
C. Intravenous Immunoglobulin
Intravenous immunoglobulin (IVIG) is the treatment of choice for severe, acute bleeding, and may also be used as an alternative or adjunct to corticosteroid treatment in both acute and chronic ITP. IVIG may be effective when the patient is resistant to corticosteroids; responses are prompt and may last for several weeks. A single dose of 0.8–1 g/kg has been recommended. Platelets may be given simultaneously during life-threatening hemorrhage but are rapidly destroyed. Side effects of IVIG are common, including transient neurologic complications in one-third of patients (eg, headache, nausea, and aseptic meningitis) that mimic intracranial hemorrhage and necessitate radiologic evaluation. A transient decrease in neutrophil number may also be seen, and hemolytic anemia is rare.
D. Anti-Rh(D) Immunoglobulin
This polyclonal immunoglobulin binds to the D antigen on RBCs. The splenic clearance of anti-D–coated red cells interferes with removal of antibody-coated platelets, resulting in improvement in platelet count. This approach is effective only in Rh(+) patients with a functional spleen who are DAT negative. At doses of 50–75 mcg/kg, approximately 80% of Rh+ children with acute or chronic ITP respond; however, there is no clear difference between Anti-D and IVIG in the time to reach a platelet count of 20 × 109/L. Significant hemolysis may occur in up to 5% of patients. The FDA has provided specific monitoring requirements because of reports of fatal intravascular hemolysis.
Many children with chronic ITP have platelet counts less than 30,000/μL. Up to 70% of such children recover with a platelet count less than 100,000/μL within 1 year. For the remainder, corticosteroids, IVIG, and anti-D immunoglobulin are typically effective treatment for acute bleeding. Splenectomy produces a complete response in 70% and partial response in 20% of children with ITP, but should be considered only after persistence of significant thrombocytopenia for more than 12 months, and the failure of a preferred or alternative second-line therapy. The risk of overwhelming infection with encapsulated organisms is increased after splenectomy, particularly in the young child. Preoperative vaccination with polyvalent pneumococcal conjugate and polysaccharide vaccines, meningococcal C conjugate, and H. influenza b conjugate is recommended. If possible, the splenectomy should be postponed, until age 5 years. For patients younger than 5 years, daily penicillin prophylaxis should be started postoperatively and continued at least until 5 years of age. Postoperatively, a reactive thrombocytosis mat raise the platelet count to more than 1 million/μL, but is not associated with thrombotic complications in children. However, thrombosis is recognized as a potential post-splenectomy complication in the long term.
F. Rituximab (Anti-CD20 Monoclonal Antibody)
There have been no randomized trials for rituximab in children. The efficacy of treating childhood chronic ITP in several series and case studies has demonstrated response rates between 26% and 60%. Because of significant adverse events, this therapy may be reserved for refractory cases with significant bleeding or as an alternative to splenectomy.
Thrombopoietin receptor agonists are now available for the treatment of ITP for children. One randomized clinical trial in children with romiplostim, showed an 88% response rate and improved quality of life. In addition, as a second-line agent, they may be useful in patients for corticosteroid sparing. One pitfall of this approach is that these agents require long-term administration, and continued study in children are addressing long-term adverse effects, efficacy, and sustained response.
Eighty percent of children with ITP will achieve a remission. Predictors of the development of chronic ITP include female gender, age greater than 10 years at presentation, insidious onset of bruising, and the presence of other autoantibodies. Older child- and adolescent-onset ITP is associated with an increased incidence of chronic autoimmune diseases or immunodeficiency states. Appropriate screening by history and laboratory studies is warranted.
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C: The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011;117:4190
2. Thrombocytopenia in the Newborn
Thrombocytopenia is one of the most common causes of neonatal hemorrhage and should be considered in any newborn with petechiae, purpura, or other significant bleeding. Defined by a platelet count of less than 150,000/μL, thrombocytopenia occurs in approximately 0.9% of unselected neonates; however, up to 80% of neonates in a newborn intensive care unit may experience thrombocytopenia; most of these cases are transient. Several specific entities may be responsible for more severe thrombocytopenia (see Table 30–7). Infection and DIC are the most common causes of thrombocytopenia in ill full-term newborns and in preterm newborns. In the healthy neonate, antibody-mediated thrombocytopenia (alloimmune or maternal autoimmune), viral syndromes, hyperviscosity, and major-vessel thrombosis are frequent causes of thrombocytopenia. Management is directed toward the underlying etiology. Other infants are affected by unknown mechanisms in mothers with preeclampsia. Most of these cases resolve over several days to a few weeks without treatment, but some are severe enough to warrant platelet transfusions.
A. Thrombocytopenia Associated With Platelet Alloantibodies (Neonatal Alloimmune Thrombocytopenia-NAIT)
NAIT is the most common cause of thrombocytopenia in well, term infants, with a prevalence of 0.7 per 1000 pregnancies. Alloimmunization occurs when a platelet antigen of the infant differs from that of the mother, and the mother is sensitized by fetal platelets that cross the placenta into the maternal circulation. In Caucasians, 80% are associated with HPA1a, and 10%-15% HPA5b. Sensitization of a mother homozygous for HPA-1b to paternally acquired fetal HPA-1a antigen results in severe fetal thrombocytopenia in 1 in 1200 fetuses. Only 1 in 20 HPA-1a–positive fetuses of HPA-1a–negative mothers develop alloimmunization. Other platelet-specific alloantigens may be etiologic. Unlike in Rh incompatibility, 30%–40% of affected neonates are first-born. Thrombocytopenia is progressive over the course of gestation and worse with each subsequent pregnancy. The presence of antenatal maternal platelet antibodies on more than one occasion and their persistence into the third trimester is predictive of severe neonatal thrombocytopenia; a weak or undetectable antibody does not exclude thrombocytopenia. Severe intracranial hemorrhage occurs in 10%–30% of affected neonates as early as 20 weeks’ gestation. Petechiae or other bleeding manifestations are usually present shortly after birth. The disease is self-limited, and the platelet count normalizes within 4 weeks.
If alloimmunization is associated with clinically significant bleeding, transfusion of platelets harvested from the mother is more effective than random donor platelets in increasing the platelet count. Transfusion with HPA-matched platelets from unrelated donors or treatment with IVIG or methylprednisolone to acutely block macrophage uptake of sensitized platelets has also been successful in raising the platelet count and achieving hemostasis. If thrombocytopenia is not severe and bleeding is absent, observation alone is often appropriate.
Intracranial hemorrhage in a previous child secondary to alloimmune thrombocytopenia is the strongest risk factor for severe fetal thrombocytopenia and hemorrhage in a subsequent pregnancy. Amniocentesis or chorionic villus sampling to obtain fetal DNA for platelet antigen typing is sometimes performed if the father is heterozygous for HPA-1a. If alloimmunization has occurred with a previous pregnancy, irrespective of history of intracranial hemorrhage, screening cranial ultrasound for hemorrhage should begin at 20 weeks gestation and be repeated regularly. In addition, cordocentesis should be performed at approximately 20 weeks gestation, with prophylactic transfusion of irradiated, leukoreduced, maternal platelet concentrates. If the fetal platelet count is less than 100,000/μL, the mother should be treated with weekly IVIG. Delivery by elective cesarean section is recommended if the fetal platelet count is less than 50,000/μL to minimize the risk of intracranial hemorrhage associated with birth trauma.
B. Thrombocytopenia Associated With ITP in the Mother (Neonatal Autoimmune Thrombocytopenia)
Infants born to mothers with ITP or other autoimmune diseases (eg, antiphospholipid antibody syndrome or systemic lupus erythematosus) may develop thrombocytopenia as a result of transfer of antiplatelet IgG from the mother to the infant. Unfortunately, maternal and fetal platelet counts and maternal antiplatelet antibody levels are unreliable predictors of bleeding risk. Antenatal corticosteroid administration to the mother is generally instituted once maternal platelet count falls below 50,000/μL, with or without a concomitant course of IVIG.
Most neonates with autoimmune thrombocytopenia do not develop clinically significant bleeding, and treatment is not often required. The risk of intracranial hemorrhage is 0.2%–2%. If diffuse petechiae or minor bleeding are evident, a 1- to 2-week course of oral prednisone, 2 mg/kg/day, may be helpful. If the platelet count remains consistently less than 20,000/μL or if severe hemorrhage develops, IVIG should be given (0.8–1 g/kg daily for 1–2 days). Platelet transfusions are only indicated for life-threatening bleeding, and may only be effective after removal of antibody by exchange transfusion. The platelet nadir is typically between the fourth and sixth day of life and improves significantly by 1 month; full recovery may take 2–4 months. Platelet recovery may be delayed in breast-fed infants because of transfer of IgG to the milk.
C. Neonatal Thrombocytopenia Associated With Infections
Thrombocytopenia is commonly associated with severe generalized infections during the newborn period. Between 50% and 75% of neonates with bacterial sepsis are thrombocytopenic. Intrauterine infections such as rubella, syphilis, toxoplasmosis, HIV, CMV, herpes simplex (acquired intra- or postpartum), enteroviruses, and parvovirus are often associated with thrombocytopenia. In addition to specific treatment for the underlying disease, platelet transfusions may be indicated in severe cases.
D. Thrombocytopenia Associated With Kaposiform Hemangioendotheliomas (Kasabach-Merritt Syndrome)
A rare but important cause of thrombocytopenia in the newborn is kaposiform hemangioendotheliomas, a benign neoplasm with histopathology distinct from that of classic infantile hemangiomas. Intense platelet sequestration in the lesion results in thrombocytopenia and may rarely be associated with a DIC-like picture and hemolytic anemia. The bone marrow typically shows megakaryocytic hyperplasia in response to the thrombocytopenia. Corticosteroids, α-interferon, vincristine, and sirolimus are all useful for reducing the size of the lesion and are indicated if significant coagulopathy is present, the lesion compresses a vital structure, or the lesion is cosmetically unacceptable. If consumptive coagulopathy is present, heparin or an antifibrinolytic agent may be useful. Depending on the site, embolization may be an option. Surgery is often avoided because of the high risk of hemorrhage.
BA: Consensus-derived practice standards plan for complicated kaposiform hemangioendothelioma. J Pediatrics 2013;163(1):285–291
RN: Differential diagnosis and management of thrombocytopenia in childhood. Pediatr Clin North Am 2004;51:1109
3. Disorders of Platelet Function
Individuals with platelet function defects typically develop abnormal bruising and mucosal bleeding similar to that occurring in persons with thrombocytopenia. The PFA-100, which can evaluate platelet dysfunction and vWD, has replaced the template bleeding time in many institutions but is not unanimously endorsed. Although labor-intensive, platelet aggregometry remains important in selected clinical situations. Platelet aggregometry is now used for in vitro assessment of platelet function, and uses agonists, such as adenosine diphosphate, collagen, arachidonic acid, and ristocetin. Unfortunately, none of these screening tests of platelet function uniformly predicts clinical bleeding severity.
Platelet dysfunction may be inherited or acquired, with the latter being more common. Acquired disorders of platelet function may occur secondary to uremia, cirrhosis, sepsis, myeloproliferative disorders, congenital heart disease, and viral infections. Many pharmacologic agents decrease platelet function. The most common offending agents in the pediatric population are aspirin and other NSAIDs, synthetic penicillins, and valproic acid. In acquired platelet dysfunction, the PFA-100 closure time is prolonged with collagen-epinephrine, while normal with collagen-ADP.
The inherited disorders are due to defects in platelet-vessel interaction, platelet-platelet interaction, platelet granule content or release (including defects of signal transduction), thromboxane and arachidonic acid pathway, and platelet-procoagulant protein interaction. Individuals with hereditary platelet dysfunction have a prolonged bleeding time with normal platelet number and morphology by light microscopy. PFA-100 closure time is typically prolonged with both collagen-ADP and collagen-epinephrine.
Congenital causes of defective platelet–vessel wall interaction include Bernard-Soulier syndrome, which is characterized by increased platelet size and decreased platelet number. The molecular defect in this autosomal recessive disorder is a deficiency or dysfunction of glycoprotein Ib-V-IX complex on the platelet surface resulting in impaired von Willebrand factor (vWF) binding, and hence, impaired platelet adhesion to the vascular endothelium.
Glanzmann thrombasthenia is an example of severe platelet-platelet dysfunction. In this autosomal recessive disorder, glycoprotein IIb-IIIa is deficient or dysfunctional. Platelets do not bind fibrinogen effectively and exhibit impaired aggregation. As in Bernard-Soulier syndrome, acute bleeding is treated by platelet transfusion, and more recently with recombinant factor VIIa.
Disorders involving platelet granule content include storage pool disease and Quebec platelet disorder. In individuals with storage pool disease, platelet-dense granules lack adenosine dinucleotide phosphate and adenosine trinucleotide phosphate and are found to be low in number by electron microscopy. These granules are also deficient in Hermansky-Pudlak, Chédiak-Higashi, and Wiskott-Aldrich syndromes. Whereas deficiency of a second granule class, α-granules, results in the gray platelet syndrome, Quebec platelet disorder is characterized by a normal platelet α-granule number, but with abnormal proteolysis of α-granule proteins and deficiency of platelet α-granule multimerin. α-Granule abnormality in this disorder also results in increased serum levels of urokinase-type plasminogen activator. Epinephrine-induced platelet aggregation is markedly impaired.
Platelet dysfunction has also been observed in other congenital syndromes, such as Down and Noonan syndromes, without a clear understanding of the molecular defect.
Acute bleeding in many individuals with acquired or selected congenital platelet function defects responds to therapy with desmopressin acetate, likely due to an induced release of vWF from endothelial stores and/or upregulated expression of glycoprotein Ib-V-IX on the platelet surface. If this therapy is ineffective, or if the patient has Bernard-Soulier syndrome or Glanzmann syndrome, the mainstay of treatment for bleeding episodes is platelet transfusion, possibly with HLA type-specific platelets. Recombinant VIIa, which has variable efficacy and may be helpful in platelet transfusion-refractory patients, is FDA-approved for patients with Glanzmann syndrome.
S: Platelet disorders in children: a diagnostic approach. Pediatr Blood Cancer 2011;56:975
INHERITED BLEEDING DISORDERS
Table 30–8 lists normal values for coagulation factors. The more common factor deficiencies are discussed in this section. Individuals with bleeding disorders should avoid exposure to medications that inhibit platelet function. Participation in contact sports should be considered in the context of the severity of the bleeding disorder.
Table 30–8.Physiologic alterations in measurements of the hemostatic system. ||Download (.pdf) Table 30–8. Physiologic alterations in measurements of the hemostatic system.
|Measurement ||Normal Adults ||Fetus (20 wk) ||Preterm (25–32 wk) ||Term Infant ||Infant (6 mo) ||Pregnancy (term) ||Exercise (acute) ||Aging (70–80 y) |
|Count μL/103 ||250 ||107–297 ||293 ||332 ||— ||260 ||↑ 18%–40% ||225 |
|Size (fL) ||9.0 ||8.9 ||8.5 ||9.1 ||— ||9.6 ||↑ ||— |
|Aggregation ADP ||N ||+ ||↓ ||↓ ||— ||↑ ||↓ 15% ||— |
|Collagen ||N ||↓ ||↓ ||↓ ||— ||N ||↓ 60% ||N |
|Ristocetin ||N ||— ||↑ ||↑ ||— ||— ||↓ 10% ||— |
|BT (min) ||2–9 ||— ||3.6 ± 2 ||3.4 ± 1.8 ||— ||9.0 ± 1.4 ||— ||5.6 |
|Procoagulant system |
|PTT* ||1 ||4.0 ||3 ||1.3 ||1.1 ||1.1 ||↓ 15% ||↓ |
|PT* ||1.00 ||2.3 ||1.3 ||1.1 ||1 ||0.95 ||N ||— |
|TCT* ||1 ||2.4 ||1.3 ||1.1 ||1 ||0.92 ||N ||— |
|Fibrinogen mg/dL ||278 (0.61) ||96 (50) ||250 (100) ||240 (150) ||251 (160) ||450 (100) ||↓ 25% ||↑ 15% |
|II, U/mL ||1 (0.7) ||0.16 (0.10) ||0.32 (0.18) ||0.52 (0.25) ||0.88 (0.6) ||1.15 (0.68–1.9) ||— ||N |
|V, U/mL ||1.0 (0.6) ||0.32 (0.21) ||0.80 (0.43) ||1.00 (0.54) ||0.91 (0.55) ||0.85 (0.40–1.9) ||— ||N |
|VII, U/mL ||1.0 (0.6) ||0.27 (0.17) ||0.37 (0.24) ||0.57 (0.35) ||0.87 (0.50) ||1.17 (0.87–3.3) ||↑ 200% ||↑ 25% |
|VIIIc, U/mL ||1.0 (0.6) ||0.50 (0.23) ||0.75 (0.40) ||1.50 (0.55) ||0.90 (0.50) ||2.12 (0.8–6.0) ||↑ 250% ||1.50 |
|vWF, U/mL ||1.0 (0.6) ||0.65 (0.40) ||1.50 (0.90) ||1.60 (0.84) ||1.07 (0.60) ||1.7 ||↑ 75–200% ||↑ |
|IX, U/mL ||1.0 (0.5) ||0.10 (0.05) ||0.22 (0.17) ||0.35 (0.15) ||0.86 (0.36) ||0.81–2.15 ||↑ 25% ||1.0–1.40 |
|X, U/mL ||1.0 (0.6) ||0.19 (0.15) ||0.38 (0.20) ||0.45 (0.3) ||0.78 (0.38) ||1.30 ||— ||N |
|XI, U/mL ||1.0 (0.6) ||0.13 (0.08) ||0.2 (0.12) ||0.42 (0.20) ||0.86 (0.38) ||0.7 ||— ||N |
|XII, U/mL ||1.0 (0.6) ||0.15 (0.08) ||0.22 (0.09) ||0.44 (0.16) ||0.77 (0.39) ||1.3 (0.82) ||— ||↑ 16% |
|XIII, U/mL ||1.04 (0.55) ||0.30 ||0.4 ||0.61 (0.36) ||1.04 (0.50) ||0.96 ||— ||— |
|PreK, U/mL ||1.12 (0.06) ||0.13 (0.08) ||0.26 (0.14) ||0.35 (0.16) ||0.86 (0.56) ||1.18 ||— ||↑ 27% |
|HK, U/mL ||0.92 (0.48) ||0.15 (0.10) ||0.28 (0.20) ||0.64 (0.50) ||0.82 (0.36) ||1.6 ||— ||↑ 32% |
|Anticoagulant system |
|AT, U/mL ||1.0 ||0.23 ||0.35 ||0.56 ||1.04 ||1.02 ||↑ 14% ||N |
|α2-MG, U/mL ||1.05 (0.79) ||0.18 (0.10) ||— ||1.39 (0.95) ||1.91 (1.49) ||1.53 (0.85) ||— ||— |
|C1IN, U/mL ||1.01 ||— ||— ||0.72 ||1.41 ||— ||— ||— |
|PC, U/mL ||1.0 ||0.10 ||0.29 ||0.50 ||0.59 ||0.99 ||N ||N |
|Total PS, U/mL ||1.0 (0.6) ||0.15 (0.11) ||0.17 (0.14) ||0.24 (0.1) ||0.87 (0.55) ||0.89 ||— ||N |
|Free, PS, U/mL ||1.0 (0.5) ||0.22 (0.13) ||0.28 (0.19) ||0.49 (0.33) ||— ||0.25 ||— ||— |
|Heparin ||1.01 ||0.10 (0.06) ||0.25 (0.10) ||0.49 (0.33) ||0.97 (0.59) ||— ||— ||↓15% |
|Cofactor II, U/mL ||(0.73) || || || || || || || |
|TFPI, ng/mL ||73 ||21 ||20.6 ||38 ||— ||— ||— ||— |
|Fibrinolytic system |
|Plasminogen U/mL ||1.0 ||0.20 ||0.35 (0.20) ||0.37 (0.18) ||0.90 ||1.39 ||↓ 10% ||N |
|tPA, ng/mL ||4.9 ||— ||8.48 ||9.6 ||2.8 ||4.9 ||↑ 300% ||N |
|α2-AP, U/mL1.0 ||1.0 ||1.0 ||0.74 (0.5) ||0.83 (0.65) ||1.11 (0.83) ||0.95 ||N ||N |
|PAI-1, U/mL ||1.0 ||— ||1.5 ||1.0 ||1.07 ||4.0 ||↓ 5% ||N |
|Overall fibrinolysis ||N ||↑ ||↑ ||↓ ||— ||↓ ||↑ ||↓ |
1. Factor VIII Deficiency (Hemophilia A)
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Bruising, soft-tissue bleeding, hemarthrosis.
Reduced factor VIII activity.
Factor VIII activity is reported in units per milliliter, with 1 U/mL equal to 100% of the factor activity found in 1 mL of normal plasma. The normal range for factor VIII activity is 0.50–1.50 U/mL (50%–150%). Hemophilia A occurs predominantly in males as an X-linked disorder. One-third of cases are due to a spontaneous mutation. The incidence of factor VIII deficiency is 1:5000 male births.
Persons with hemophilia who have less than 1% factor VIII activity have severe hemophilia A, and have frequent spontaneous bleeding episodes involving skin, mucous membranes, joints, muscles, and viscera. In contrast, patients with mild hemophilia A (5%–40% factor VIII activity) mainly bleed at times of trauma or surgery. Those with moderate hemophilia A (1% to <5% factor VIII activity) typically have intermediate bleeding manifestations. The most crippling aspect of factor VIII deficiency is the tendency to develop recurrent hemarthroses that incite joint destruction.
Individuals with hemophilia A have a prolonged aPTT, except in some cases of mild deficiency. The PT is normal. The diagnosis is confirmed by finding decreased factor VIII activity with normal vWF activity. In two-thirds of families of hemophilic patients, the females are carriers and some manifest symptomatic bleeding. Carriers of hemophilia can be diagnosed by DNA sequencing, and their bleeding severity by factor activity. In a male fetus or newborn with a family history of hemophilia A, cord blood sampling for factor VIII activity is accurate and important for subsequent care.
Intracranial hemorrhage is the leading disease-related cause of death among persons with hemophilia. Most intracranial hemorrhages in moderate to severe deficiency are spontaneous and not associated with trauma. Hemarthroses begin early in childhood and, particularly when recurrent, can result in joint destruction (ie, hemophilic arthropathy). Large intramuscular hematomas can lead to a compartment syndrome with resultant neurologic compromise, or pseudotumors. Although these complications are most common in severe hemophilia A, they may be experienced by individuals with moderate or mild disease. Acquired neutralizing antibodies to factor VIII is a potential serious complication after treatment with factor VIII concentrate. These antibodies develop in up to 30% of patients with severe hemophilia A, and especially in patients with large deletions in the factor VIII gene. Inhibitors may be amenable to desensitization with regular factor VIII infusion (immune tolerance therapy). Bypassing agent therapy with recombinant factor VIIa and/or FEIBA has become standard treatment of acute hemorrhage in patients with hemophilia A and a high-titer inhibitor, and may also be used for prophylaxis.
In prior decades, therapy-related complications in hemophilia A have included factor-related infection with HIV, hepatitis B virus, and hepatitis C virus. Through stringent donor selection, the implementation of sensitive screening assays, the use of heat or chemical methods for viral inactivation, and the development of recombinant products, the risk of these infections is effectively eliminated. Inactivation methods do not eradicate viruses lacking a lipid envelope; however, so that transmission of parvovirus and hepatitis A remains a concern with the use of plasma-derived products. Immunization with hepatitis A and hepatitis B vaccines is recommended for all hemophilia patients.
The general aim of management is to raise the factor VIII activity to prevent or stop bleeding. Some patients with mild factor VIII deficiency may respond to desmopressin via release of endothelial stores of factor VIII and vWF into plasma; however, most patients require administration of exogenous factor VIII to achieve hemostasis. The in vivo half-life of infused factor VIII is 6–14 hours but varies among individuals. Non–life-threatening, non–limb-threatening hemorrhage is treated with 20–30 U/kg of factor VIII, to achieve a rise in plasma factor VIII activity to 40%–60%. Joint hemarthrosis and life- or limb-threatening hemorrhage is treated with 50 U/kg of factor VIII, targeting a rise to 100% factor VIII activity. Subsequent doses are determined according to the site and extent of bleeding, and clinical response to FVIII infusion. In circumstances of poor clinical response, recent change in bleeding frequency, or comorbid illness, monitoring the plasma factor VIII activity response is recommended. For most instances of non–life-threatening hemorrhage in experienced patients with moderate or severe hemophilia A, treatment can be administered at home, provided adequate intravenous access and management with the hemophilia treatment center.
Prophylactic factor VIII infusions prevent the development of arthropathy in severe and moderate hemophilia, and is the standard of care in pediatric hemophilia. Extended half-life factor VIII concentrates have been approved by the FDA with the hope of decreasing infusions and improving clinical outcomes. In addition, multiple non-factor replacement strategies (eg, emicizumab, fitusiran, concizumab) are emerging that may replace factor VIII for prophylaxis and are disruptive technologies. Along with gene therapy, they look to reshape the lives and outcomes of PWH.
The development of innovative, safe and, effective therapies for hemophilia A has resulted in improved long-term survival in recent decades. In addition, comprehensive care managed through hemophilia treatment centers have greatly improved quality of life and level of function.
2. Factor IX Deficiency (Hemophilia B, Christmas Disease)
The mode of inheritance and clinical manifestations of factor IX deficiency are the same as those of factor VIII deficiency. Hemophilia B is 15%–20% as prevalent as hemophilia A. Factor IX deficiency is associated with a prolonged aPTT, but normal PT and thrombin time. However, the aPTT is slightly less sensitive to factor IX deficiency than factor VIII deficiency. Diagnosis of hemophilia B is made by assaying factor IX activity, and severity is determined similar to hemophilia A.
The mainstay of treatment in hemophilia B is exogenous factor IX. Unlike factor VIII, about 50% of the administered dose of factor IX diffuses into the extravascular space. Therefore, 1 U/kg of plasma-derived factor IX concentrate or recombinant factor IX is expected to increase plasma factor IX activity by approximately 1%. Factor IX typically has a half-life of 18–22 hours in vivo. In contrast to severe factor VIII deficiency, only 1%–3% of persons with factor IX deficiency develop a factor IX inhibitor, but patients may be at risk for anaphylaxis when receiving exogenous factor IX. The prognosis for persons with factor IX deficiency is comparable to that of patients with factor VIII deficiency. Extended half-life factor concentrates have changed treatment of severe and moderate hemophilia B. Gene therapy and non-factor replacement technologies are in clinical trial.
F: The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet 2016 Jul 9;388(10040):187–197
3. Factor XI Deficiency (Hemophilia C)
Factor XI deficiency is a genetic, autosomally transmitted coagulopathy, typically of mild to moderate clinical severity. Cases of factor XI deficiency account for less than 5% of all persons living with hemophilia. Homozygotes generally bleed at surgery or following severe trauma and at hyperfibrinolytic sites, but do not commonly have spontaneous hemarthroses. In contrast to factor VIII and IX deficiencies, factor XI activity is least predictive of bleeding risk. Pathologic bleeding may be seen in heterozygous individuals with factor XI activity as high as 60%. The aPTT is often considerably prolonged. In individuals with deficiency of both plasma and platelet-associated factor XI, the PFA-100 may also be prolonged. Management typically consists of perioperative prophylaxis and episodic therapy for acute hemorrhage. Treatment includes infusion of fresh frozen plasma (FFP); platelet transfusion may also be useful for acute hemorrhage in patients with deficiency of platelet-associated factor XI. Desmopressin has been used in some cases, and antifibrinolytic therapy is common. The prognosis for an average life span in patients with factor XI deficiency is excellent.
4. Other Inherited Bleeding Disorders
Other hereditary single clotting factor deficiencies are rare. Transmission is generally autosomal. Homozygous individuals with a deficiency or structural abnormality of prothrombin, factor V, factor VII, or factor X may have excessive bleeding.
Persons with dysfibrinogenemia (ie, structurally or functionally abnormal fibrinogen) may develop recurrent venous thromboembolic episodes or bleeding. Immunologic assay of fibrinogen is normal, but clotting assay may be low and the thrombin time prolonged. The PT and aPTT may be prolonged. Fibrinogen concentrates are now widely available.
Afibrinogenemia resembles hemophilia clinically but has an autosomal recessive inheritance. Affected patients can experience a variety of bleeding manifestations, including mucosal bleeding, ecchymoses, hematomas, hemarthroses, and intracranial hemorrhage, especially following trauma. Fatal umbilical cord hemorrhage has been reported in neonates. The PT, aPTT, and thrombin time are all prolonged. A severely reduced fibrinogen concentration in an otherwise well child is confirmatory of the diagnosis. As in dysfibrinogenemia, fibrinogen concentrates are used for surgical prophylaxis and for acute hemorrhage.
P: Rare bleeding disorders—bleeding assessment tools, laboratory aspects and phenotype and therapy of FXI deficiency. Haemophilia 2014 May;20 Suppl 4:71–75
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Easy bruising and epistaxis from early childhood.
Prolonged PFA-100 (or bleeding time), normal platelet count, absence of acquired platelet dysfunction.
Reduced amount or abnormal activity of von Williebrand factor (vWf).
von Willebrand disease (vWD) is the most common inherited bleeding disorder among Caucasians, with a prevalence as high as 1%. vWF is a multimeric plasma protein that binds factor VIII and is a cofactor for platelet adhesion to the endothelium. An estimated 70%–80% of all patients with vWD have classic vWD (type 1), caused by a partial quantitative deficiency of vWF. vWD type 2 involves a qualitative deficiency of (ie, dysfunctional) vWF, and vWD type 3 is characterized by a nearly complete deficiency of vWF. vWD is most often transmitted as an autosomal dominant trait, but it can be autosomal recessive. The disease can also be acquired, developing in association with hypothyroidism, Wilms tumor, cardiac disease, renal disease, or systemic lupus erythematosus, and in individuals receiving valproic acid. Acquired vWD is most often caused by the development of an antibody to vWF or increased turnover of vWF.
A history of increased bruising and excessive epistaxis is often present. Prolonged bleeding also occurs with trauma or at surgery. Menorrhagia is often a presenting finding in females.
PT is normal, and aPTT is prolonged if factor VIII is decreased. Prolongation of the PFA-100 or bleeding time is usually present since vWF plays a role in platelet adherence to endothelium. Platelet number may be decreased in type 2b vWD. Factor VIII and vWF antigen are decreased in types 1 and 3, but may be normal in type 2 vWD. vWF activity (eg, ristocetin cofactor or collagen binding) is decreased in all types. Since normal vWF antigen levels vary by blood type (type O normally has lower levels), blood type must be determined. Complete laboratory classification also requires vWF multimer assay. The diagnosis requires confirmatory laboratory testing.
Desmopressin acetate can be given intravenously or subcutaneously to prevent or halt bleeding for many patients with vWD types 1 and 2, by releasing vWF from endothelial stores. In responding patients, the increase in vWF and factor VIII in the plasma can be two- to fivefold. A high-concentration desmopressin nasal spray (150 mcg/spray), different from the preparation used for enuresis, may also be used. Because response to vWF is variable among patients, factor VIII and vWF activities are typically measured before, 30–60 minutes post, and 4 hours after desmopressin administration to document response. Desmopressin causes fluid retention which can result in hyponatremia; therefore, fluid restriction should be discussed, especially in children younger than 2 years. Because release of stored vWF is limited, tachyphylaxis often occurs after 2–3 administered doses of desmopressin.
If further therapy is indicated, vWF-replacement therapy (plasma derived or recombinant VWF) is recommended; such therapy is also used in patients with type 1 or 2a vWD who exhibit suboptimal laboratory response to desmopressin, and for all individuals with type 2b or 3 vWD. Antifibrinolytic agents (eg, ε-aminocaproic acid and tranexamic acid) are useful for control of mucosal bleeding. Estrogen-containing contraceptive therapy may be helpful for menorrhagia as they may limit menstrual bleeding and increase vWF levels.
With the availability of effective treatment and prophylaxis for bleeding, life expectancy in vWD is normal.
AH: State of the art: von Willebrand disease. Haemophilia 2016 Jul;22(Suppl 5):54–59
WL: von Willibrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008;14(2):171–232
ACQUIRED BLEEDING DISORDERS
1. Disseminated Intravascular Coagulation
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Presence of a disorder known to trigger DIC.
Evidence for consumptive coagulopathy (prolonged aPTT, PT, or thrombin time; increase in FSPs [fibrin-fibrinogen split products]; decreased fibrinogen or platelets).
Disseminated intravascular coagulation (DIC) is an acquired pathologic process characterized by tissue factor–mediated coagulation activation in the host. DIC involves dysregulated, excessive thrombin generation, with consequent intravascular fibrin deposition and consumption of platelets and procoagulant factors. Microthrombi, composed of fibrin and platelets, may produce tissue ischemia and end-organ damage. The fibrinolytic system is frequently activated in DIC, leading to plasmin-mediated destruction of fibrin and fibrinogen; this results in fibrin-fibrinogen degradation products (FDPs) which exhibit anticoagulant and platelet-inhibitory functions. DIC commonly accompanies severe infection and other critical illnesses in infants and children. Conditions known to trigger DIC include endothelial damage (eg, endotoxin, virus), tissue necrosis (eg, burns), diffuse ischemic injury (eg, shock, hypoxia acidosis), and systemic release of tissue procoagulants (eg, certain cancers, placental disorders).
Signs of DIC may include (1) complications of shock, often including end-organ dysfunction, (2) diffuse bleeding tendency (eg, hematuria, melena, purpura, petechiae, persistent oozing from needle punctures or other invasive procedures), and (3) evidence of thrombotic lesions (eg, small and major vessel thrombosis, purpura fulminans).
Tests that are sensitive, easiest to perform, useful for monitoring, and reflect the hemostatic capacity of the patient are the PT, aPTT, platelet count, fibrinogen, and FDPs (including D-dimer). The PT and aPTT are typically prolonged and the platelet count and fibrinogen concentration may be decreased. However, in children, the fibrinogen level may be normal until late in the course. Levels of FSPs are increased, and elevated levels of D-dimer, a cross-linked fibrin degradation byproduct, may be helpful in monitoring the degree of activation of both coagulation and fibrinolysis. However, D-dimer is nonspecific and may be elevated in the context of a triggering event (eg, severe infection) without concomitant DIC. Often, physiologic inhibitors of coagulation, especially antithrombin III, protein C, and protein S are consumed, predisposing to thrombosis. The specific laboratory abnormalities in DIC may vary with the triggering event and the course of illness.
DIC can be difficult to distinguish from coagulopathy of liver disease (ie, hepatic synthetic dysfunction), especially when the latter is associated with thrombocytopenia secondary to portal hypertension and hypersplenism. Generally, factor VII activity is decreased markedly in liver disease (due to deficient synthesis of this protein, which has the shortest half-life among the procoagulant factors), but only mildly to moderately decreased in DIC (due to consumption). Factor VIII activity is often normal or even increased in liver disease, but decreased in DIC.
A. Therapy for Underlying Disorder
The most important aspect of therapy in DIC is the identification and treatment of the triggering event. If the pathogenic process underlying DIC is reversed, often no other therapy is needed for the coagulopathy.
B. Replacement Therapy for Consumptive Coagulopathy
Replacement of consumed procoagulant factors with FFP, cryoprecipitate, unactivated prothrombin complex concentrates (PCCs), and platelets is warranted in the setting of DIC with hemorrhagic complications, or as periprocedural bleeding prophylaxis. Infusion of 10–15 mL/kg FFP typically raises procoagulant factor activities by approximately 10%–15%. Cryoprecipitate can also be given as a rich source of fibrinogen; one bag of cryoprecipitate per 3 kg in infants or one bag of cryoprecipitate per 6 kg in older children typically raises plasma fibrinogen concentration by 75–100 mg/dL.
C. Anticoagulant Therapy for Coagulation Activation
Continuous intravenous infusion of unfractionated heparin is sometimes given in order to attenuate coagulation activation and consequent consumptive coagulopathy. The rationale for heparin therapy is to maximize the efficacy of, and minimize the need for, replacement of procoagulants and platelets; however, clinical evidence demonstrating benefit of heparin in DIC is lacking. Prophylactic doses of unfractionated heparin or low-molecular-weight heparin (LMWH) in critically ill and nonbleeding patients with DIC may be considered for prevention of venous thromboembolism. Unfractionated heparin dosing and monitoring is listed on page 946.
D. Specific Factor Concentrates
A nonrandomized pilot study of antithrombin concentrate in children with DIC and associated acquired antithrombin deficiency demonstrated favorable outcomes, suggesting that replacement of this consumed procoagulant may be beneficial. Protein C concentrate has also shown promise in two small pilot studies of meningococci-associated DIC with purpura fulminans. The potential of Activated protein C needs more study.
The liver is the major synthetic site of prothrombin, fibrinogen, high-molecular-weight kininogen, and factors V, VII, IX, X, XI, XII, and XIII. Plasminogen and the physiologic anticoagulants (antithrombin III, protein C, and protein S) are synthesized in the liver, as is α2-antiplasmin, a regulator of fibrinolysis. Deficiency of factor V and the vitamin K–dependent factors (II, VII, IX, and X) is most often a result of decreased hepatic synthesis, and is manifested by a prolonged PT and often a prolonged aPTT. Extravascular loss and increased consumption of clotting factors may contribute to PT and aPTT prolongation. Fibrinogen production is often decreased, or an abnormal fibrinogen (dysfibrinogen) containing excess sialic acid residues may be synthesized, or both. Hypofibrinogenemia or dysfibrinogenemia is associated with prolongation of thrombin time and reptilase time. FSPs and D-dimers may be present because of increased fibrinolysis, particularly in the setting of chronic hepatitis or cirrhosis. Thrombocytopenia secondary to hypersplenism may occur. DIC and the coagulopathy of liver disease also mimic vitamin K deficiency; however, vitamin K deficiency has normal factor V activity. Treatment of acute bleeding in the setting of coagulopathy of liver disease consists of replacement with FFP or PCCs and platelets. Desmopressin may shorten the bleeding time and aPTT in patients with chronic liver disease, but its safety is not well established. Recombinant VIIa also is efficacious for life-threatening refractory hemorrhage.
The newborn period is characterized by physiologically depressed activity of the vitamin K–dependent factors (II, VII, IX, and X). If vitamin K is not administered at birth, a bleeding diathesis previously called hemorrhagic disease of the newborn, now termed vitamin K deficiency bleeding (VKDB), may develop. Outside of the newborn period, vitamin K deficiency may occur as a consequence of inadequate intake, excess loss, inadequate formation of active metabolites, or competitive antagonism.
One of three patterns is seen in the neonatal period:
Early VKDB of the newborn occurs within 24 hours of birth, most often manifested by cephalohematoma, intracranial hemorrhage, or intra-abdominal bleeding. Although occasionally idiopathic, it is most often associated with maternal ingestion of drugs that interfere with vitamin K metabolism (eg, warfarin, phenytoin, isoniazid, and rifampin). Early VKDB occurs in 6%–12% of neonates born to mothers who take these medications without receiving vitamin K supplementation. The disorder is often life threatening.
Classic VKDB occurs at 24 hours to 7 days of age and usually is manifested as gastrointestinal, skin, or mucosal bleeding. Bleeding after circumcision may occur. Although occasionally associated with maternal drug usage, it most often occurs in well infants who do not receive vitamin K at birth and are solely breast-fed.
Late neonatal VKDB occurs on or after day 8. Manifestations include intracranial, gastrointestinal, or skin bleeding. This disorder is often associated with fat malabsorption (eg, in chronic diarrhea) or alterations in intestinal flora (eg, with prolonged antibiotic therapy). Like classic VKDB, late VKDB occurs almost exclusively in breast-fed infants.
The diagnosis of vitamin K deficiency is suspected based on the history, physical examination, and laboratory results. The PT is prolonged out of proportion to the aPTT (also prolonged). The thrombin time becomes prolonged late in the course. The platelet count is normal. This laboratory profile is similar to the coagulopathy of acute liver disease, but with normal fibrinogen level and absence of hepatic transaminase elevation. The diagnosis of vitamin K deficiency is confirmed by a demonstration of non-carboxylation of specific clotting factors in the absence of vitamin K in the plasma and by clinical and laboratory responses to vitamin K. Intravenous or subcutaneous treatment with vitamin K should be given immediately and not withheld while awaiting test results. In the setting of severe bleeding, additional acute treatment with FFP or PCCs may be indicated.
Uremia is frequently associated with acquired platelet dysfunction. Bleeding occurs in approximately 50% of patients with chronic renal failure. The bleeding risk conferred by platelet dysfunction associated with metabolic imbalance may be compounded by decreased vWF activity and procoagulant deficiencies (eg, factor II, XII, XI, and IX) due to increased urinary losses of these proteins in some settings of renal insufficiency. In accordance with platelet dysfunction, uremic bleeding is typically characterized by purpura, epistaxis, menorrhagia, or gastrointestinal hemorrhage. Acute bleeding may be managed with infusion of desmopressin acetate, factor VIII concentrates containing vWF, or cryoprecipitate with or without coadministration of FFP. Red cell transfusion may be required. Prophylactic administration of erythropoietin before the development of severe anemia which increases the potential for bleeding. Recombinant VIIa may be useful in refractory bleeding.
MJ: Vitamin K deficiency bleeding (VKDB) in early infancy. Blood Rev 2009;23:49–59
H: Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost 2013 Feb 4. doi: 10.1111/jth.12155
VASCULAR ABNORMALITIES ASSOCIATED WITH BLEEDING
1. Henoch-Schönlein Purpura (Anaphylactoid Purpura)
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Henoch-Schönlein purpura (HSP), the most common type of small vessel vasculitis in children, primarily affects boys 2–7 years of age. Occurrence is highest in the spring and fall, and upper respiratory infection precedes the diagnosis in two-thirds of children.
Leukocytoclastic vasculitis in HSP principally involves the small vessels of the skin, gastrointestinal tract, and kidneys, with deposition of IgA immune complexes. The most common and earliest symptom is palpable purpura, which results from extravasation of erythrocytes into the tissue surrounding the involved venules. Antigens from group A β-hemolytic streptococci and other bacteria, viruses, drugs, foods, and insect bites have been proposed as inciting agents.
Skin involvement may be urticarial initially, progresses to a maculopapules, and coalesces to a symmetrical, palpable purpuric rash distributed on the legs, buttocks, and elbows. New lesions may continue to appear for 2–4 weeks, and may extend to involve the entire body. Two-thirds of patients develop migratory polyarthralgias or polyarthritis, primarily of the ankles and knees. Intermittent, sharp abdominal pain occurs in approximately 50% of patients, and hemorrhage and edema of the small intestine can often be demonstrated. Intussusception may develop. Approximately 25%–50% develop renal involvement in the second or third week of illness with either a nephritic or, less commonly, nephrotic picture. Hypertension may accompany the renal involvement. In males, testicular torsion may also occur, and neurologic symptoms are possible due to small vessel vasculitis.
The platelet count is normal or elevated, and other screening tests of hemostasis and platelet function are typically normal. Urinalysis frequently reveals hematuria, and sometimes proteinuria. Stool may be positive for occult blood. The antistreptolysin O (ASO) titer is often elevated and the throat culture positive for group A β-hemolytic streptococci. Serum IgA may be elevated.
The rash of septicemia (especially meningococcemia) may be similar to skin involvement in HSP, although the distribution tends to be more generalized. The possibility of trauma should be considered in any child presenting with purpura. Other vasculitides should also be considered. The lesions of thrombotic thrombocytopenic purpura (TTP) are not palpable.
Generally, treatment is supportive. NSAIDs may be useful for the arthritis. Corticosteroid therapy may provide symptomatic relief for severe gastrointestinal or joint manifestations but does not alter skin or renal manifestations. If culture for group A β-hemolytic streptococci is positive or if the ASO titer is elevated, a therapeutic course of penicillin is warranted.
The prognosis for recovery is generally good, although symptoms frequently (25%–50%) recur over a period of several months. In patients who develop renal manifestations, microscopic hematuria may persist for years. Progressive renal failure occurs in fewer than 5% of patients with HSP, with an overall fatality rate of 3%.
HJ: Clinical practice: diagnosis and management of Henoch-Schönlein purpura. Eur J Pediatr 2010;169:643–650
Mild to life-threatening bleeding occurs with some types of Ehlers-Danlos syndrome, the most common inherited collagen disorder. Ehlers-Danlos syndrome is characterized by joint hypermobility, skin extensibility, and easy bruising. Coagulation abnormalities may sometimes be present, including platelet dysfunction and deficiencies of coagulation factors VIII, IX, XI, and XIII. However, bleeding and easy bruising, in most instances, relates to fragility of capillaries and compromised vascular integrity. Ehlers-Danlos syndrome types 4 and 6 are associated with at risk for aortic dissection and spontaneous rupture of aortic aneurysms. Surgery should be avoided for patients with Ehlers-Danlos syndrome, as should medications that induce platelet dysfunction.
Although uncommon in children, thrombotic disorders are recognized with increasing frequency, particularly with heightened physician awareness and improved survival in pediatric intensive care settings. Several clinical conditions have a potential association with thrombotic events in childhood.
Initial evaluation of the child who has thrombosis includes an assessment for potential provoking factors, as well as a family history of thrombosis and early cardiovascular or cerebrovascular disease.
Clinical risk factors are present in more than 90% of children with acute venous thromboembolism (VTE). These conditions include the presence of an indwelling vascular catheter, cardiac disease, infection, trauma, surgery, immobilization, collagen-vascular or chronic inflammatory disease, renal disease, sickle cell anemia, and malignancy. Prospective findings employing serial radiologic evaluation as screening indicate that the risk of VTE is nearly 30% for short-term central venous catheters placed in the internal jugular veins. Retrospective data suggest that approximately 8% of children with cancer develop symptomatic VTE.
1. Inherited Thrombophilia (Hypercoagulable) States
a. Protein c deficiency—Protein C is a vitamin K–dependent protein that is activated by thrombin bound to thrombomodulin and inactivates activated factors V and VIII. In addition, activated protein C promotes fibrinolysis. Two phenotypes of hereditary protein C deficiency exist. Heterozygous individuals with autosomal dominant protein C deficiency often present with VTE as young adults, but the disorder may manifest during childhood or in later adulthood. In mild protein C deficiency, anticoagulant prophylaxis is typically limited to periods of increased prothrombotic risk. Homozygous or compound heterozygous protein C deficiency is rare but phenotypically severe. Affected children generally present within the first 12 hours of life with purpura fulminans (Figure 30–6) and/or VTE. Prompt protein C replacement by infusion of protein C concentrate (if unavailable) or FFP every 6–12 hours, along with therapeutic heparin administration, is recommended. Subsequent management requires chronic therapeutic anticoagulation, sometimes along with routine protein C concentrate infusion. Recurrent VTE is common, especially during periods of subtherapeutic anticoagulation or in the presence of conditions associated with increased prothrombotic risk.
Purpura fulminans in an infant with severe protein C deficiency.
b. Protein s deficiency—Protein S is a cofactor for protein C. Neonates with homozygous protein S deficiency have a course similar to those with homozygous or compound heterozygous protein C deficiency. Lifelong anticoagulation therapy is indicated in homozygous/severe deficiency, or in heterozygous individuals who have experienced recurrent VTE. Efforts must be made to distinguish these conditions from acquired deficiency, which can be antibody-mediated or secondary to an increase in C4b-binding protein induced by inflammation.
c. Antithrombin deficiency—Antithrombin, which is the most important physiologic inhibitor of thrombin, also inhibits activated factors IX, X, XI, and XII. Antithrombin deficiency is transmitted in an autosomal dominant pattern and associated with VTE, typically with onset in adolescence or young adulthood. Therapy for acute VTE involves replacement with antithrombin concentrate and therapeutic anticoagulation. The efficiency of heparin may be significantly diminished in the setting of severe antithrombin deficiency and it often requires supplementation of antithrombin via concentrate. Patients with homozygous/severe deficiency or recurrent VTE are maintained on lifelong anticoagulation.
d. Factor v leiden mutation—An amino acid substitution in the gene coding for factor V results in factor V Leiden, a factor V polymorphism that is resistant to inactivation by activated protein C. The most common cause of activated protein C resistance in Caucasians, factor V Leiden is present in approximately 5% of the Caucasian population, 20% of Caucasian adults with deep vein thrombosis, and 40%–60% of those with a family history of VTE. VTE occurs in both heterozygous and homozygous individuals. In the former case, thrombosis is typically triggered by a clinical risk factor (or else develops in association with additional thrombophilia traits), whereas in the latter case, it is often spontaneous. Population studies suggest that the risk of incident VTE is increased two- to sevenfold in the setting of heterozygous factor V Leiden, 35-fold among heterozygous individuals taking the oral contraceptives, and 80-fold in those homozygous for factor V Leiden.
e. Prothrombin mutation—The 20210 glutamine to alanine mutation in the prothrombin gene is a relatively common polymorphism in Caucasians that enhances its activation to thrombin. In heterozygous form, this mutation is associated with a two- to threefold increased risk for incident VTE. This mutation also appears to modestly increase the risk for recurrent VTE.
f. Other inherited disorders—Qualitative abnormalities of fibrinogen (dysfibrinogenemias) are usually inherited in an autosomal dominant manner. Most individuals with dysfibrinogenemia are asymptomatic. Some patients experience bleeding, while others develop venous or arterial thrombosis. The diagnosis is suggested by a prolonged thrombin time with a normal fibrinogen concentration. Hyperhomocysteinemia can be an inherited or an acquired condition and is associated with an increased risk for both arterial and venous thromboses. In children, it may also serve as a risk factor for ischemic arterial stroke. Hyperhomocysteinemia is quite uncommon in the setting of dietary folate supplementation (as in the United States) and is observed almost uniquely in cases of renal insufficiency or metabolic disease (eg, homocystinuria). Methylene tetrahydrofolate reductase receptor mutations do not appear to constitute a risk factor for thrombosis in US children unless homocysteine is elevated.
Lipoprotein(a) is a lipoprotein with homology to plasminogen. In vitro studies suggest that lipoprotein(a) may both promote atherosclerosis and inhibit fibrinolysis. Some evidence to date suggests that elevated plasma concentrations of lipoprotein(a) are associated with an increased risk of VTEs and recurrent ischemic arterial stroke in children.
Increased factor VIII activity is a risk factor for incident VTE and is common among children with acute VTE. Most Elevation in factor VIII is acquired and may persist in the long-term, but it may also be inherited.
a. Antiphospholipid antibodies—The development of antiphospholipid antibodies is the most common form of acquired thrombophilia in children. Antiphospholipid antibodies, which include the lupus anticoagulant, anticardiolipin antibodies, and β2-glycoprotein-1 antibodies (among others) are common in acute childhood VTE. The lupus anticoagulant is demonstrated in vitro by its inhibition of phospholipid-dependent coagulation assays (eg, aPTT, dilute Russell viper venom time, hexagonal phase phospholipid neutralization assay), whereas immunologic techniques (eg, enzyme-linked immunosorbent assays) are often used to detect anticardiolipin and β2-glycoprotein-1 antibodies. Although common in persons with autoimmune diseases such as systemic lupus erythematosus, antiphospholipid antibodies may also develop following certain drug exposures, infection, acute inflammation, and lymphoproliferative diseases. Sometimes VTE and antiphospholipid antibodies may predate other signs of lupus. Viral illness is a common precipitant in children, and in many cases, the inciting infection may be asymptomatic.
When an antiphospholipid antibody persists for 12 weeks following the acute thrombotic event, the diagnosis of antiphospholipid syndrome (APS) is confirmed. Optimal duration of anticoagulation in this setting is unclear, such that current pediatric treatment guidelines recommend a 3-month to lifelong course.
b. Deficiencies of intrinsic anticoagulants—Acquired deficiencies of proteins C and S and antithrombin may occur in the clinical context of antibodies (eg, protein S antibodies in acute varicella) or in excessive consumption, including sepsis, DIC, major-vessel or extensive VTE, and post–bone marrow transplant sinusoidal obstruction syndrome (formerly termed hepatic veno-occlusive disease). Pilot studies in children have suggested a possible therapeutic role for antithrombin or protein C concentrates in sepsis-associated DIC (eg, meningococcemia) and severe posttransplant sinusoidal obstruction syndrome.
c. Acute phase reactants—As part of the acute phase response, elevations in plasma fibrinogen concentration, plasma factor VIII, and platelet count may occur, all of which may contribute to an acquired prothrombotic state. Reactive thrombocytosis is rarely associated with VTEs in children when the platelet count is less than 1 million/μL.
Presenting features of thrombosis vary with the anatomic site, extent of vascular involvement, degree of vaso-occlusion, and presence of end-organ dysfunction. The classic presentation of deep venous thrombosis of an upper or lower extremity is pain and acute or subacute extremity swelling, while that for pulmonary embolism commonly involves dyspnea and pleuritic chest pain, and in cerebral sinovenous thrombosis (CSVT) often includes severe or persistent headache, with or without neurologic deficit in otherwise well children. Arterial thrombosis of the lower extremity (eg, neonatal umbilical artery catheter–associated) as well as vasospasm without identified thrombosis, often manifests with diminished distal pulses and dusky discoloration of the limb.
A comprehensive laboratory investigation for thrombophilia (ie, hypercoagulability) was recommended in 2002 by the International Society on Thrombosis and Haemostasis in order to disclose possible underlying congenital or acquired abnormalities that may affect acute or long-term management; however, there remains controversy and wide variation of practice. Recent trends favor thrombophilia testing in infants, children and adolescents with unprovoked thrombosis, and in neonates/children with non–catheter-related thrombosis and stroke. There is insufficient data to recommend routine thrombophilia testing in neonates or children with catheter-related thrombosis. When indicated, thrombophilia testing includes evaluation for intrinsic anticoagulant deficiency (proteins C and S and antithrombin), procoagulant factor excess (eg, factor VIII), proteins and genetic mutations mediating enhanced procoagulant activity or reduced sensitivity to inactivation (antiphospholipid antibodies; factor V Leiden and prothrombin 20210 polymorphisms), biochemical mediators of endothelial damage (homocysteine), and markers or regulators of fibrinolysis (eg, D-dimer, plasminogen activator inhibitor-1, and lipoprotein[a]). Interpretation of procoagulant factor and intrinsic anticoagulant levels should take into account the age dependence of normal values for these proteins. Among these VTE risk factors, antiphospholipid antibodies and elevated levels of homocysteine and lipoprotein(a) have also been demonstrated as risk factors for arterial thrombotic ischemic events.
Appropriate radiologic imaging is essential for objective documentation of thrombosis and to delineate the type (venous vs arterial), degree of occlusion, and extent (proximal and distal termini) of thrombosis. Depending on site, typical imaging modalities include compression ultrasound with Doppler, computed tomographic (CT) venography, magnetic resonance venography, and conventional angiography.
Current guidelines for the treatment of first-episode VTE in children have been largely based on adult experience and include therapeutic anticoagulation for at least 3 months. During the period of anticoagulation, bleeding precautions should be followed, as previously described (see Treatment under Idiopathic Thrombocytopenic Purpura, earlier). Initial therapy for acute VTE employs continuous intravenous unfractionated heparin or subcutaneous injections of LMWH) for at least 7 days, monitored by anti-Xa activity level to maintain anticoagulant levels of 0.3–0.7 or 0.5–1.0 IU/mL, respectively. Subsequent extended anticoagulant therapy is given with LMWH or daily oral warfarin, the latter agent monitored by the PT to maintain an international normalized ratio (INR) of 2.0–3.0. During warfarin treatment, the INR optimally should be within the therapeutic range for two consecutive days before discontinuation of heparin. Warfarin pharmacokinetics are affected by acute illness, numerous medications, and changes in diet, and can necessitate frequent monitoring. In children, warfarin dose is determined by age and weight. LMWH offers the advantage of infrequent need for monitoring but is far more expensive than warfarin. Anatomic contributions to venous stasis (eg, mastoiditis or depressed skull fracture as risk factors for CVST; congenital left iliac vein stenosis in DVT of proximal left lower extremity with May-Thurner anomaly) should be addressed to optimize response to anticoagulation. In cases of limb- or life-threatening VTEs, including major proximal pulmonary embolus, and in cases of progressive VTE despite therapeutic anticoagulation, thrombolytic therapy (eg, tissue-type plasminogen activator) may be considered. Whether thrombolytic therapy may also reduce the risk of the postthrombotic syndrome (PTS) in children with veno-occlusive deep venous thrombosis of the proximal limbs in whom adverse prognostic biomarkers (ie, elevated factor VIII and D-dimer levels) are present at diagnosis needs prospective evaluation. In adolescent females, estrogen-containing contraceptives are relatively contraindicated in those with prior VTE if not using anticoagulation, particularly if an additional genetic cause for impairment of protein C pathway is disclosed.
Oral anticoagulants are now first-line therapy for adult acute VTE, and for extended anticoagulation. Phase 3 clinical trials in infants and children are ongoing.
Registries and cohort studies have suggested that recurrent VTE occurs in approximately 10% of children within 2 years. Persistent thrombosis is evident following completion of a standard therapeutic course of anticoagulation in up to 30% of children, with unclear clinical importance. Approximately one in four children with deep venous thrombosis involving the extremities develop post thrombotic syndrome, a condition of venous insufficiency of varying severity characterized by chronic skin changes, edema, and dilated collateral superficial venous formation, and often accompanied by functional limitation (pain with activities or at rest). Complete veno-occlusion and elevated levels of factor VIII and d-dimer at VTE diagnosis have been identified as prognostic factors for PTS among children with deep venous thrombosis affecting the limbs. The presence of homozygous anticoagulant deficiencies, multiple thrombophilia traits, or persistent antiphospholipid antibodies following VTE diagnosis has been associated with increased risk of recurrent VTE, leading to consideration of extended anticoagulation in these instances. In CSVT, failure to provide antithrombotic therapy has been associated with adverse neurologic outcome.
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