Blood and endocrine system diseases in children. Lesson Topics: Hemorrhagic disease in children
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- Hemophilia A. Practice Essentials
- Essential update: FDA approves turoctocog alpha for treating hemophilia A
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Medical Care: The basic principle of management consists of altering the balance between bleeding and clotting. This would consist of replacing the deficient factor and using other measures, such as fibrin glue and antifibrinolytics.
Soft tissue bleeding may not require treatment. When therapy is required, therapeutic products are available to treat patients with factor XI deficiency, including fresh frozen plasma (FFP), solvent-detergent–treated FFP, and factor XI concentrates (available in Europe, but not in the United States). Adjunctive measures include the use of fibrin glue, antifibrinolytic agents, and desmopressin (DDAVP). Fresh frozen plasma -- Product of choice when factor XI concentrates are not available. Dose 15-20 mL/kg IV loading dose, followed by 3-6 mL/kg q12h until hemostasis is achieved Factor XI concentrates. The typical dose of these products is up to 30 U/kg. Prognosis is excellent in patients with partial deficiency who do not have bleeding manifestations. In patients with bleeding tendencies, hemorrhage and bleeding into organs may be life threatening.
Hemophilia A is an X-linked, recessive disorder caused by deficiency of functional plasma clotting factor VIII (FVIII), which may be inherited or arise from spontaneous mutation. The development of inhibitory antibodies to FVIII can result in acquired hemophilia A or can complicate the treatment of genetic cases.
In October 2013, the FDA approved turoctocog alpha (NovoEight, Novo Nordisk), a recombinant coagulation factor VIII, for the treatment of hemophilia A in adults and children. Approval was based on studies demonstrating efficacy and no development of inhibitors in more than 210 patients with severe hemophilia A.
Depending on the level of FVIII activity, patients with hemophilia may present with easy bruising, inadequate clotting of traumatic injury or—in the case of severe hemophilia—spontaneous hemorrhage. Signs of hemorrhage include the following:
General: Weakness, orthostasis, tachycardia, tachypnea
Musculoskeletal (joints): Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children)
CNS: Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes
pain
Genitourinary: Hematuria, renal colic, and post circumcision bleeding
Other: Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction), compartment syndrome symptoms, and contusions; excessive bleeding with routine dental procedures
Laboratory studies for suspected hemophilia include the following:
Coagulation studies
FVIII assay Expected laboratory values are as follows:
Hemoglobin/hematocrit: Normal or low
Platelet count: Normal
Bleeding time and prothrombin time: Normal
Activated partial thromboplastin time (aPTT): Significantly prolonged in severe hemophilia, but may be normal in mild or even moderate hemophilia Normal values for FVIII assays are 50-150%. Values in hemophilia are as follows:
Mild: >5%
Moderate: 1-5%
Severe: < 1% Imaging studies for acute bleeds are chosen on the basis of clinical suspicion and anatomic location of involvement, as follows:
Head computed tomography scans without contrast are used to assess for spontaneous or traumatic intracranial hemorrhage
Magnetic resonance imaging scans of the head and spinal column are used for further assessment of spontaneous or traumatic hemorrhage
MRI is also useful in the evaluation of the cartilage, synovium, and joint space
Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions Testing for inhibitors is indicated when bleeding is not controlled after adequate amounts of factor concentrate are infused during a bleeding episode. Inhibitor concentration is titrated using the Bethesda method, as follows:
Positive result: Over 0.6 Bethesda units (BU)
Low-titer inhibitor: Up to 5 BU
High-titer inhibitor: Over 5 BU Management The treatment of hemophilia may involve the following:
Management of bleeding episodes
Use of factor replacement products and medications
Treatment of patients with factor inhibitors
Treatment and rehabilitation of patients with hemophilia synovitis Disposition of treatment is as follows:
Management ideally should be provided through a comprehensive hemophilia care center
Home administration of treatment and infusions by the family or patient is customary
FVIII treatment may be given prophylactically or on demand
Hospitalization is reserved for severe or life-threatening bleeds For treatment of acute bleeds, target levels by hemorrhage severity are as follows:
an FVIII level of 30%
Major hemorrhages (eg, hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with negative findings on examination): Maintain an FVIII level of at least 50%
recurrent hemarthrosis): Maintain an FVIII level of 80-100% To find the number of units of factor VIII needed to correct the factor VIII activity level, use the following formula: Units factor VIII = (weight in kg)(50 mL plasma/kg)(1 U factor VIII/mL plasma)(desired factor VIII level minus the native factor VIII level) FVIII regimens are as follows:
half the initial calculated dose
Minor hemorrhage requires 1-3 doses of FVIII
Major hemorrhage requires many doses and continued FVIII activity monitoring with the goal of keeping the trough activity level at least 50%
The following types of FVIII concentrates are available:
Plasma-based products: Undergo purification to inactivate viruses
First-generation recombinant products: Produced in mammalian cell lines and have a small amount of human serum albumin added for stability
Third-generation products: Have no exposure to animal proteins Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP), has the following attributes:
Not effective in the treatment of severe hemophilia
Can be intravenously administered at a dose of 0.3 mcg/kg of body weight in the inpatient setting
Peak effect is observed in 30-60 minutes
A concentrated DDAVP intranasal spray is available for outpatient use The following antifibrinolytics are used in addition to FVIII replacement for oral mucosal hemorrhage and prophylaxis:
Tranexamic acid (Cyklokapron) Treatments used in patients with inhibitors of FVIII are as follows:
High doses of FVIII for low-titer inhibitors
Anti-inhibitor coagulant complex (FEIBA VH)
Porcine FVIII, which has low cross-reactivity with human FVIII antibody
Activated prothrombin complex concentrate (PCC)
Activated FVII
Desensitization
Immune tolerance induction (ITI) Background Hemophilia A is an inherited, X-linked, recessive disorder caused by deficiency of functional plasma clotting factor VIII (FVIII). Significant rates of spontaneous mutation and acquired immunologic processes can result in this disorder as well. Morbidity and death are primarily the result of hemorrhage, although infectious diseases (eg, HIV, hepatitis) became prominent, particularly in patients who received blood products prior to 1985. Laboratory studies for suspected hemophilia include a complete blood cell count, coagulation studies, and a factor VIII (FVIII) assay (see Workup). The treatment of hemophilia may involve management of hemostasis, management of bleeding episodes, use of factor replacement products and medications, treatment of patients with factor inhibitors, and treatment and rehabilitation of patients with hemophilia synovitis. Treatment of patients with hemophilia ideally should be provided through a comprehensive hemophilia care center (see Treatment). Please see the following for more information:
Hemophilia B
Hemophilia C Classification The classification of the severity of hemophilia has been based on either clinical bleeding symptoms or on plasma procoagulant levels; the latter are the most widely used criteria. Persons with less than 1% normal factor (< 0.01 IU/mL) are considered to have severe hemophilia. Persons with 1-5% normal factor (0.01-0.05 IU/mL) are considered to have moderately severe hemophilia. Persons with more than 5% but less than 40% normal factor (>0.05 to < 0.40 IU/mL) are considered to have mild hemophilia. Severe disease presents in children younger than 1 year and accounts for 43-70% of those with hemophilia A. Moderate disease presents in children aged 1-2 years and accounts for 15-26% of cases. Mild disease presents in children older than 2 years and accounts for 15-31% of cases. Clinical bleeding symptom criteria have been used because patients with FVIII levels of less than 1% occasionally have little or no spontaneous bleeding and appear to have clinically moderate or mild hemophilia. Furthermore, the reverse is true for patients with procoagulant activities of 1-5%, who may present with symptoms of clinically severe disease. For discussion of factor IX deficiency, see Hemophilia B. Historical background Hemophilia is one of the oldest described genetic diseases. An inherited bleeding disorder in males was recognized in Talmudic records of the second century. The modern history of hemophilia began in 1803 with the description of hemophilic kindred by John Otto, followed by the first review of hemophilia by Nasse in 1820. Wright demonstrated evidence of laboratory defects in blood clotting in 1893; however, FVIII was not identified until 1937 when Patek and Taylor isolated a clotting factor from the blood, which they called antihemophilia factor (AHF). A bioassay of FVIII was introduced in 1950. Although the intimate relationship between FVIII and von Willebrand factor (vWF) is now known, it was not
appreciated at the time. In 1953, decreased factor FVIII in patients with vWF deficiency was first described. Further research by Nilson and coworkers indicated the interaction between these 2 clotting factors. In 1952, Christmas disease was described and named after the surname of the first patient who was examined in detail. This disease was distinct from hemophilia because mixing plasma from a patient with "true hemophilia" and with plasma from a patient with Christmas disease corrected the clotting time; thus, hemophilia A and B were differentiated. Hemophilia A makes up approximately 80% of hemophilia cases. In the early 1960s, cryoprecipitate was the first concentrate available for the treatment of patients with hemophilia. In the 1970s, lyophilized intermediate-purity concentrates were obtained from a large pool of blood donors. The introduction of concentrated lyophilized products that are easy to store and transport has dramatically improved the quality of life of patients with hemophilia and facilitated their preparation for surgery and home care. Unfortunately, the large size of the donor pool—as many as 20,000 donors may contribute to a single lot of plasma-derived FVIII concentrate—heightened the risk of viral contamination of commercial FVIII concentrates. By the mid 1980s, most patients with severe hemophilia had been exposed to hepatitis A, hepatitis B, and hepatitis C viruses and human immunodeficiency virus (HIV). Viricidal treatment of plasma-derived FVIII concentrates have been effective in eliminating new HIV transmissions and virtually eliminating hepatitis B and hepatitis C exposures. The introduction of recombinant FVIII concentrate, and the gradual elimination of albumin from the production process used for these products, has virtually eliminated the risk of viral exposure.
Factor VIII deficiency, dysfunctional factor VIII, or factor VIII inhibitors lead to the disruption of the normal intrinsic coagulation cascade, resulting in spontaneous hemorrhage and/or excessive hemorrhage in response to trauma. Hemorrhage sites include joints (eg, knee, elbow), muscles, CNS, GI system, genitourinary system,
pulmonary system, and cardiovascular system. Intracranial hemorrhage is most common in patients younger than 18 years and can be fatal. The clotting cascade The role of the coagulation system, as depicted in the image below, is to produce a stable fibrin clot at sites of injury. The clotting mechanism has 2 pathways: intrinsic and extrinsic.
Fig. Coagulation system. The intrinsic system is initiated when factor XII is activated by contact with damaged endothelium. The activation of factor XII can also initiate the extrinsic pathway, fibrinolysis, kinin generation, and complement activation. In conjunction with high-molecular-weight kininogen (HMWK), factor XIIa converts prekallikrein (PK) to kallikrein and activates factor XI. Activated factor XI, in turn, activates factor IX in a calcium-dependent reaction. Factor IXa can bind phospholipids. Then, factor X is activated on the cell surface; activation of factor X involves a complex (tenase complex) of factor IXa, thrombin-activated FVIII, calcium ions, and phospholipid. In the extrinsic system, the conversion of factor X to factor Xa involves tissue factor (TF), or thromboplastin; factor VII; and calcium ions. TF is released from the damaged cells. It is thought to be a lipoprotein complex that acts as a cell surface receptor for FVII, with its resultant activation. It also adsorbs factor X to enhance the reaction between factor VIIa, factor X, and calcium ions. Factor IXa and factor XII fragments can also activate factor VII. In the common pathway, factor Xa (generated through the intrinsic or extrinsic pathways) forms a prothrombinase complex with phospholipids, calcium ions, and thrombin-activated factor Va. The complex cleaves prothrombin into thrombin and prothrombin fragments 1 and 2. Thrombin converts fibrinogen into fibrin and activates FVIII, factor V, and factor XIII. Fibrinopeptides A and B, the results of the cleavage of peptides A and B by thrombin, cause fibrin monomers to form and then polymerize into a meshwork of fibrin; the resultant clot is stabilized by factor XIIIa and the cross-linking of adjacent fibrin strands. Because of the complex interactions of the intrinsic and extrinsic pathways (factor IXa activates factor VII), the existence of only one in vivo pathway with different mechanisms of activation has been suggested. FVIII and FIX circulate in an inactive form. When activated, these 2 factors cooperate to cleave and activate factor X, a key enzyme that controls the conversion of fibrinogen to fibrin. Therefore, the lack of FVIII may significantly alter clot formation and, as a consequence, result in clinical bleeding. Genetics The gene for FVIII (ie, hemophilia A) is located on the long arm of chromosome X, within the Xq28 region. The gene (F8C) is unusually large, representing 186 kb of the X chromosome. It comprises 26 exons and 25 introns. Mature FVIII contains 2332 amino acids. Approximately 40% of cases of severe FVIII deficiency arise from a large inversion that disrupts the FVIII gene. Deletions, insertions, and point mutations account for the remaining 50-60% of hemophilia A defects. Low FVIII levels may arise from defects outside the FVIII gene, as in type IIN von Willebrand disease, in which the molecular defect resides in the FVIII-binding domain of von Willebrand factor.
The hallmark of hemophilia is hemorrhage into the joints. This bleeding is painful and leads to long-term inflammation and deterioration of the joint, resulting in permanent deformities, misalignment, loss of mobility, and extremities of unequal lengths.
Human synovial cells synthesize high levels of tissue factor pathway inhibitor, resulting in a higher degree of factor Xa (FXa) inhibition, which predisposes hemophilic joints to bleed. This effect may also account for the dramatic response of FVIIa infusions in patients with acute hemarthroses and FVIII inhibitors. Synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage progress, with subchondral bone-cyst formation. Bleeding into a joint may lead to synovial inflammation, which predisposes the joint to further bleeds. A joint that has had repeated bleeds (by one definition, at least 4 bleeds within a 6-month period) is termed a target joint. Commonly, this occurs in knees.
Inhibitors Approximately 30% of patients with severe hemophilia A develop alloantibody inhibitors that can neutralize FVIII. These inhibitors are typically immunoglobulin G (IgG), predominantly of the IgG4 subclass, that do not fix complement and do not result in the end-organ damage observed with circulating immune complexes. They neutralize the coagulant effects of replacement therapy. Inhibitors occur at a young age (about 50% by age 10 y), principally in patients with less than 1% FVIII. Both genetic and environmental factors determine the frequency of inhibitor development. Specific molecular abnormalities (eg, gene deletions, stop codon mutations, frameshift mutations) are associated with a higher incidence of inhibitor development (FVIII and FIX). In addition, inhibitors are more likely to develop in black children. In addition, purified products (some no longer marketed) have been associated with increased inhibitor development. As for recombinant FVIII products, no new inhibitors have been known to develop in previously treated patients, and inhibitors develop in as many as 30% of previously untreated patients (PUPs). In PUPs, the titer of the inhibitors is low in half and transient in one third. In the United States, levels of FVIII inhibitors are most often measured by the Bethesda method. In this method, 1 Bethesda unit (BU) equals the amount of antibody that destroys one half of the FVIII in an equal mixture of normal and patient plasma in 2 hours at 37°C.
Acquired hemophilia is the development of FVIII inhibitors (autoantibodies) in persons without a history of FVIII deficiency. This condition can be idiopathic (occurring in people >50 y), it can be associated with collagen vascular disease or the peripartum period, or it may represent a drug reaction (eg, to penicillin). High titers of FVIII autoantibodies may be associated with lymphoproliferative malignancies.
Hemophilia A is caused by an inherited or acquired genetic mutation or an acquired factor VIII inhibitor. The defect results in the insufficient generation of thrombin by the FIXa and FVIIIa complex by means of the intrinsic pathway of the coagulation cascade. This mechanism, in combination with the effect of the tissue- factor pathway inhibitor, creates an extraordinary tendency for spontaneous bleeding. This disorder is inherited in an X-linked recessive pattern. The gene for FVIII is located on the long arm of the X chromosome in band q28. The factor VIII gene is one of the largest genes; it is 186 kilobases (kb) long and has a 9-kb coding region that contains 26 exons. The mature protein contains 2332 amino acids and has a molecular weight of 300 kd. It includes 3 A domains, 1 B domain, and 2 C domains. Numerous mutations in the gene structure have been described. Genetic abnormalities include genetic deletions of variable size, abnormalities with stop codons, and frame-shift defects. Data suggest that 45% of severe hemophilia A cases result from an inversion mutation. Epidemiology Hemophilia A is the most common X-linked genetic disease and the second most common factor deficiency after von Willebrand disease (vWD). The worldwide incidence of hemophilia A is approximately 1 case per 5000 male individuals, with approximately one third of affected individuals not having a family history. The prevalence of hemophilia A varies with the reporting country, with a range of 5.4- 14.5 cases per 100,000 male individuals. In the United States, the prevalence of hemophilia A is 20.6 cases per 100,000 male individuals, with 60% of those having severe disease. An estimated 17,000 people were affected with hemophilia A in the United States in 2003. History For patients in whom hemophilia is suspected, ascertain the history of hemorrhage disproportionate to trauma, spontaneous hemorrhage, bleeding disorders in the family, concomitant illness (eg, chronic inflammatory disorders, autoimmune diseases, hematologic malignancies [acquired form], allergic drug reactions), and pregnancy. For individuals with documented hemophilia, ascertain the type of deficiency (eg, VIII, IX, von Willebrand), percent factor deficiency, known presence of inhibitors, and HIV/hepatitis status. For patients with mild-to-moderate disease, determine responsiveness to desmopressin acetate (DDAVP). Signs of hemorrhage include the following:
General - Weakness and orthostasis
Musculoskeletal (joints) - Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children)
CNS - Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes
GI - Hematemesis, melena, frank red blood per rectum, and abdominal pain
Genitourinary - Hematuria, renal colic, and post circumcision bleeding
Other - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction), compartment syndrome symptoms, and contusions; excessive bleeding with routine dental procedures Signs of infectious disease include the following:
Hepatitis-related symptoms Male patients with severe hemophilia present at circumcision. Easy bruising may occur at the start of ambulation or primary dentition. The patient may have a history of hemarthroses and prolonged bleeding with surgical procedures, trauma, dental extraction, and he or she may have spontaneous bleeding in soft tissues. A traumatic challenge relatively late in life may have to occur before mild or moderate hemophilia is diagnosed. Factors that elevate factor VIII (FVIII) levels (eg, age, ABO blood type, stress, exercise) may mask mild hemophilia. The principal sites of bleeding in patients with hemophilia are as follows. Bleeds affect weight-bearing joints and other joints. The muscles most commonly affected are the flexor groups of the arms and gastrocnemius of the legs. Iliopsoas bleeding is dangerous because of the large volumes of blood loss and because of compression of the femoral nerve. In the genitourinary tract, gross hematuria may occur in as many as 90% of patients. In the GI tract, bleeding may complicate common GI disorders. Bleeding in the CNS is the leading cause of hemorrhagic death among patients with hemophilia. Physical Examination Signs of hemorrhage include the following:
Tachypnea
Hypotension
Orthostasis Organ system–specific signs of hemorrhage include the following:
Musculoskeletal (joints) - Tenderness, pain with movement, decreased range of motion, effusion, and warmth
meningismus
GI - Can be painless; hepatic/splenic tenderness, and peritoneal signs
Genitourinary - Bladder spasm/distension/pain and costovertebral angle pain
Other - Hematoma leading to location-specific signs (eg, airway obstruction, compartment syndrome) Signs of infectious disease include the following:
HIV/AIDS-related signs
Hepatitis-related signs Approximately 30-50% of patients with severe hemophilia present with manifestations of neonatal bleeding (eg, after circumcision). Approximately 1-2% of neonates have intracranial hemorrhage. Other neonates may present with severe hematoma and prolonged bleeding from the cord or umbilical area. After the immediate neonatal period, bleeding is uncommon in infants until they become toddlers, when trauma-related soft-tissue hemorrhage occurs. Young children may also have oral bleeding when their teeth are erupting. Bleeding from gum and tongue lacerations is often troublesome because the oozing of blood may continue for a long time despite local measures. As physical activity increases in children, hemarthrosis and hematomas occur. Chronic arthropathy is a late complication of recurrent hemarthrosis in a target joint. Traumatic intracranial hemorrhage is a serious life-threatening complication that requires urgent diagnosis and intervention. Petechiae usually do not occur in patients with hemophilia because they are manifestations of capillary blood leaking, which is typically the result of vasculitis or abnormalities in the number or function of platelets.
Hemophilia is classified according to the clinical severity as mild, moderate, or severe (see Table 1, below). Patients with severe disease usually have less than 1% factor activity. It is characterized by spontaneous hemarthrosis and soft tissue bleeding in the absence of precipitating trauma. Patients with moderate disease have 1-5% factor activity and bleed with minimal trauma. Patients with mild hemophilia have more than 5% factor VIII (FVIII) activity and bleed only after significant trauma or surgery. Table 1. Severity, Factor Activity, and Hemorrhage Type Yüklə 1,02 Mb. Dostları ilə paylaş:
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