CHAPTER 99

Bleeding Disorders

Joseph L. Lasky III, MD, FAAP; Moran Gotesman, MD; and Eduard H. Panosyan, MD

When evaluating a child with bruising or bleeding symptoms, the major challenge for the pediatrician is ascertaining whether the degree of bleeding is appropriate for the hemostatic stress or whether further evaluation for a potential bleeding disorder is warranted. Bruising and bleeding are common childhood occurrences and usually follow minor injury or trauma. In the child with an underlying hemostatic disorder, non-accidental trauma, or both, however, the bruising or bleeding may be more extensive than expected. A thorough medical history and physical examination and an understanding of hemostasis aids in focusing the laboratory evaluation and elucidating the underlying etiology.

Epidemiology

Bleeding disorders may be inherited or acquired. Of the inherited bleeding disorders, von Willebrand disease is the most common, with a reported prevalence of between 1 in 100 and 1 in 1,000. von Willebrand disease is of autosomal inheritance, affecting males and females equally; more females are diagnosed, however, because of the inherent hemostatic challenges that they experience (eg, menses, childbirth). Hemophilia is the most common severe bleeding disorder, affecting approximately 1 in 5,000 males. Approximately 80% of cases are hemophilia A (factor VIII [FVIII] deficiency) and 20% are hemophilia B (factor IX [FIX] deficiency). Hemophilia is inherited in an X-linked fashion, but one-third of newly diagnosed males have no previous family history and represent new mutations. Other inherited coagulation and platelet disorders are rare (Table 99.1).

Acquired abnormalities of coagulation or platelets are much more common than inherited coagulopathies. Acquired abnormalities may be associated with liver disease, renal disease, malignancy, autoimmune or alloimmune disorder, vitamin K deficiency, infection, disseminated intravascular coagulation (DIC), massive transfusion, medication use, and surgery. Immune thrombocytopenic purpura (ITP) is a common acquired childhood bleeding disorder with an incidence of 4 to 8 per 100,000 children per year. Neonatal alloimmune thrombocytopenia occurs in approximately 1 in 1,800 live births. Common acquired bleeding disorders are also listed in Table 99.1.

Clinical Presentation

Bleeding disorders can manifest in various ways depending on the etiology. Inherited bleeding disorders often manifest during infancy or early childhood; mild disorders, however, may go undiagnosed until later in life. In general, disorders of primary hemostasis (eg, von Willebrand disease, platelet disorders, collagen vascular disorders) manifest with superficial, immediate, mucocutaneous bleeding. Characteristic bleeding symptoms include easy bruising, epistaxis, bleeding gums, menorrhagia, postpartum bleeding, and bleeding with dental extractions or surgeries. Disorders of secondary hemostasis, such as hemophilia A or B, often manifest with deep, delayed bleeding, such as hemarthrosis or muscular hematoma.

Acute onset is typical of acquired bleeding disorders, and they often involve abnormalities of primary and secondary hemostasis. Acute onset of bleeding symptoms in a toxic or ill-appearing child is suggestive of a systemic process, such as sepsis, DIC, malignancy, or hepatic or renal dysfunction. A well-appearing child with acute bleeding symptoms is suggestive of ITP, an acquired inhibitor, or a medication-related cause.

Abbreviations: DIC, disseminated intravascular coagulation; F, factor.

Pathophysiology

After vascular injury, hemostasis is initiated by exposure of flowing blood to subendothelial collagen and tissue factor (TF). The primary phase of hemostasis results in the production of a platelet plug. von Willebrand factor (vWF), a multimeric glycoprotein (GP) of varying size, attaches to exposed subendothelial collagen and binds platelets via the platelet GPIb-V-IX receptors. von Willebrand factor also serves as a carrier protein for FVIII, thereby localizing FVIII to areas of endothelial disruption. After platelets adhere to vWF, they become activated and release their granular contents, produce thromboxane A₂, and express the fibrinogen receptor GPIIb/IIIa. The release of thromboxane A₂ and other granular contents results in local vasoconstriction and activation of additional platelets and their respective GPIIb/IIIa receptors, thereby facilitating platelet aggregation. Fibrinogen binds to all the exposed activated GPIIb/IIIa sites, clumping the platelets together to form a platelet plug. The platelet plug stops local bleeding and provides a phospholipid surface on which the coagulation reactions of secondary hemostasis occur to form a definitive fibrin plug.

Secondary hemostasis is also initiated at the time of endothelial disruption with exposure of TF to circulating blood. Tissue factor binds to factor VIIa (FVIIa), and this complex serves as the key initiator of in vivo hemostasis by activating other TF:FVIIa complexes, as well as FIX and factor X (FX). Once Fx is activated (by FIXa or TF:FVIIa), FXa, along with its cofactor, factor Va, activates prothrombin (ie, factor II) to thrombin (ie, factor IIa). Thrombin cleaves circulating fibrinogen to fibrin monomers that self-polymerize. Factor XIII then stabilizes the fibrin clot by forming cross-links within the clump of fibrin polymers. These coagulation reactions occur on the surface of the platelet plug and, with the generation of cross-linked fibrin, the primary platelet plug is converted into a definitive fibrin plug that prevents further bleeding. An overview of hemostasis is depicted in Figures 99.1 and 99.2. Deficiencies or impairments in any of these elements can result in abnormal test results or inadequate hemostasis and excessive hemorrhage.

Figure 99.1. Intrinsic pathway reflected by activated partial thromboplastin time. The roman numerals represent factors.

Figure 99.2. Coagulation pathway. Extrinsic pathway reflected by prothrombin time. The roman numerals represent factors.

The delicate balance of hemostasis and thrombosis is maintained by inhibitors (eg, protein C, protein S, antithrombin, TF pathway inhibitor) at each step of the coagulation pathway. These natural anticoagulants prevent excessive thrombus formation. Fibrinolysis is mediated by plasmin, which cleaves fibrinogen and fibrin within a thrombus, which enables restoration of vessel patency following hemostasis. Plasmin is activated by tissue plasminogen activator and urokinase. Fibrinolysis is kept in check by plasminogen activator inhibitor-1 (PAI-1), which inactivates tissue plasminogen activator, and ₂-antiplasmin, which inactivates plasmin. Any defect in the fibrinolytic system that results in increased fibrinolysis can cause excessive bleeding.

Differential Diagnosis

In developing the differential diagnosis for a child with bleeding symptoms, it is important to obtain a thorough bleeding history and perform a thorough physical examination. The age, bleeding pattern, duration of symptoms, family history, and overall clinical status of the child may help narrow the spectrum of possibilities.

Child With Chronic History of Mucocutaneous Bleeding

In a child who presents with a history of easy bruising, epistaxis, or menorrhagia, the primary differential diagnosis includes von Willebrand disease, platelet disorders, and collagen vascular disorders (ie, disorders of primary hemostasis). von Willebrand disease is caused by a quantitative or qualitative defect of vWF. von Willebrand factor plays an important role in both primary hemostasis, by mediating platelet adhesion at sites of vascular injury and secondary hemostasis, by stabilizing FVIII in plasma. von Willebrand disease is one of autosomal inheritance and has 3 types: partial quantitative deficiency of vWF (type 1); qualitative abnormalities of vWF (types 2A, 2B, 2C, and 2D); and the most severe form—complete deficiency of vWF (type 3)—which is caused by homozygous or compound heterozygous mutation and is inherited in autosomal-recessive fashion. Type 1 is the most common form, accounting for 70% to 80% of cases. Bleeding symptoms tend to be mild and are characterized by easy bruising, epistaxis, menorrhagia, and prolonged oozing after minor or major surgeries. Only the most severely affected patients (ie, with type 3 disease) and with very low FVIII levels experience soft tissue bleeding and hemarthroses similar to that of an individual with moderate or severe hemophilia.

Qualitative platelet disorders also manifest with mucocutaneous bleeding, often during infancy. In Bernard-Soulier syndrome, platelets lack a functional GPIb-V-IX receptor complex on the platelet surface, resulting in defective platelet adhesion to vWF at sites of vascular injury. This autosomal-recessive disorder is usually seen in the presence of consanguinity. The platelets tend to be large on peripheral blood smear, and thrombocytopenia may be present. Glanzmann thrombasthenia is characterized by an absence or defect in the platelet membrane GPIIb/IIIa receptor, the main fibrinogen receptor on the platelet surface that enables platelet aggregation. Inheritance is autosomal-recessive, and the condition is most common in the presence of consanguinity. Other qualitative platelet disorders, such as storage pool disease and platelet release defects, also can manifest in a similar manner.

Collagen-vascular disorders, such as Marfan syndrome and Ehlers-Danlos syndrome, may manifest with bruising and bleeding symptoms. This increased bleeding diathesis is caused by an easy disruption of the integrity of the vascular endothelium.

Other rare coagulation disorders to consider in a child with recurrent bleeding symptoms include deficiencies of factor XI, factor XIII (FXIII), PAI-1, and ₂-antiplasmin. Factor XI deficiency (ie, hemophilia C) is a rare bleeding disorder with a high prevalence in the Ashkenazi Jewish population. It differs from other types of hemophilia in that inheritance is autosomal and symptoms tend to be milder. Bleeding episodes typically occur in response to trauma or surgery; these episodes do not include the deep tissue or intra-articular bleeds characteristic of FVIII and FIX deficiency. Factor XIII deficiency is characterized by delayed or prolonged bleeding because the clots formed are friable, resulting from the lack of cross-linkage of fibrin monomers by FXIII. The inheritance is autosomal-dominant, and in the homozygous state it usually manifests in infancy with umbilical cord bleeding or delayed separation, as well as intracranial hemorrhage. Heterozygous individuals may present later in life with delayed or prolonged bleeding after trauma or surgery as well as poor wound healing. Disorders of fibrinolysis (eg, deficiency of PAI-1 or ₂-antiplasmin) also may manifest with prolonged bleeding after trauma.

Child With a History of Deep, Delayed Bleeding

Deep tissue and intra-articular bleeding is the hallmark bleeding pattern of hemophilia. Differential diagnosis for a child who presents with this type of bleeding is hemophilia A (ie, FVIII deficiency) or B (ie, FIX deficiency), FVII deficiency, and type 3 von Willebrand disease. Clinically, hemophilia is classified according to the factor level: less than 1% factor activity (severe), 1% to 5% (moderate), and greater than 5% (mild). The factor level correlates with the bleeding tendency. Males with severe hemophilia can have “spontaneous” bleeds or bleeding with minimal trauma. Males with moderate or mild hemophilia bleed with more significant trauma. The bleeding pattern of hemophilia varies as the child grows. Infants may present with a cephalohematoma or intracranial hemorrhage, particularly if the delivery was complicated by the use of forceps or vacuum extraction. Bleeding with circumcision, heel sticks, or blood draws may also occur. As the infant starts crawling, bruises and soft tissue hematomas on the lower extremities become common. As the toddler becomes upright, the first hemarthroses can occur, typically involving the ankle. The older child incurs hemarthroses primarily of the knees and elbows.

Factor VII deficiency is rare; however, it can manifest with a bleeding pattern similar to that of hemophilia A or B. The patient with type 3 von Willebrand disease, which is characterized by an absence of vWF (the carrier protein for FVIII), may have FVIII levels as low as an individual with severe or moderate hemophilia A. In addition to the characteristic mucocutaneous bleeding that occurs with von Willebrand disease, these individuals also experience deep tissue and intra-articular bleeding.

Well-Appearing Child With Acute Onset of Bleeding Symptoms

Acute onset of bleeding symptoms is consistent with an acquired abnormality of hemostasis. Acute ITP is a common acquired bleeding disorder of childhood that is caused by the development of autoantibodies directed against the patient’s platelets. These autoantibodies, which cross-react with platelet surface antigens, are thought to develop in response to infection. Typically, a healthy child (usually between ages 2 and 4 years) presents with abrupt onset of bleeding symptoms, diffuse petechiae and bruising, and occasionally, “wet” bleeding (eg, epistaxis, gum bleeding, gastrointestinal [GI] bleeding). Often a history exists of a viral illness or recent immunization. The complete blood cell count (CBC) reveals isolated thrombocytopenia, and large platelets are seen on peripheral blood smear, which is indicative of active marrow and production of young platelets. In approximately 80% of cases, ITP is an acute, self-limited process that resolves within 6 months of diagnosis with or without therapy. Chronic ITP exists when the thrombocytopenia persists longer than 6 months. Although it is impossible to predict at diagnosis whether a patient will progress to chronic ITP, certain presenting features are associated with increased risk for chronicity. These include older age at presentation (>10 years), female sex, existing autoimmune disease, and insidious onset of symptoms. In most cases of chronic ITP, the platelet count ranges between 40,000 and 80,000/μL, and bleeding symptoms are minimal.

Acquired coagulation inhibitors are rare in children who do not have an underlying coagulation disorder; however, they can occur in the setting of malignancy or infection or postoperatively. Acquired FVIII deficiency resulting from FVIII inhibitor occurs primarily in the adult population but has been reported in children. Acute onset of severe bleeding symptoms is the common presentation. Antiphospholipid antibodies can cause prolonged partial thromboplastin time (PTT) or prothrombin time (PT); however, these antibodies are not associated with bleeding and are typically transient after a viral illness. If the antiphospholipid antibody is specifically directed against prothrombin, prothrombin levels will be low and the prothrombin time elevated. In this situation, if bleeding occurs it is usually mild and intervention is unnecessary.

Acquired abnormalities of coagulation or platelet function also can occur in association with certain medications. Aspirin and nonsteroidal anti-inflammatory drugs are common medications that affect platelet function. Warfarin, a vitamin K antagonist, is commonly used as an anticoagulant. One percent to 3% of patients on therapeutic warfarin experience bleeding complications. Chronic antibiotic use can result in vitamin K deficiency and depletion of the vitamin K-dependent factors (ie, II, VII, IX, X).

Ill-Appearing Child With Acute Onset of Bleeding Symptoms

Acute onset of bleeding in an ill-appearing child is suggestive of an acquired systemic process. Disseminated intravascular coagulation is a consumptive coagulopathy that can occur secondary to several disorders, including sepsis, trauma, and malignancy. Disseminated intravascular coagulation occurs as a result of endothelial disruption and initiation of abnormal coagulation (ie, fibrin deposition along with depletion of multiple clotting factors, inhibitor proteins, and platelets).

Because the liver is the primary site of synthesis for most of the coagulation factors, liver dysfunction caused by any illness can result in an imbalance in the hemostatic system. Additionally, thrombocytopenia may be present in the patient with chronic liver disease because of portal hypertension and associated splenomegaly with sequestration. Causes of the depletion of vitamin K–dependent factors, such as obstructive jaundice, malabsorptive states (eg, cystic fibrosis), parenchymal liver disease, and chronic antibiotic use, can also predispose the patient to bleeding.

Renal disease with uremia impairs platelet function and may manifest with bleeding symptoms as well. A malignancy that infiltrates the bone marrow, such as leukemia, lymphoma, or neuroblastoma, can cause thrombocytopenia and resultant platelet bleeding. Acquired von Willebrand disease can occur in the patient with Wilms tumor and manifest with mucocutaneous bleeding. Bone marrow failure syndromes, such as aplastic anemia and Fanconi syndrome, also may manifest with thrombocytopenia and associated bleeding.

The Newborn or Infant With Bleeding Symptoms

The newborn or infant who presents with bleeding symptoms may have a congenital bleeding disorder or an acquired condition. Inherited coagulation factor deficiencies (FVII, FVIII, FIX, FXI, FXIII, type 3 von Willebrand disease) and qualitative platelet disorders may manifest in the newborn period with intracranial hemorrhage or cephalohematoma, bleeding with heel sticks or blood draws, umbilical cord bleeding, and bleeding with circumcision. Congenital thrombocytopenia usually manifests within the first year after birth and is associated with other syndromic features. Thrombocytopenia-absent radius syndrome is an autosomal-recessive condition that typically is recognized in the newborn period and is characterized by thrombocytopenia, skeletal anomalies (most commonly radial agenesis), and renal and cardiac abnormalities. Other types of congenital thrombocytopenia include amegakaryocytic thrombocytopenia; Fanconi syndrome (with associated skeletal anomalies); and Wiskott-Aldrich syndrome, which is characterized by eczema, frequent infections, and small platelets.

Neonatal alloimmune thrombocytopenia (NAIT) is a rare condition in which a newborn inherits platelet antigens from the father that are different from those of the mother. The mother becomes alloimmunized to the fetal platelet antigens during pregnancy, similar to the process of erythrocyte alloimmunization resulting from Rh incompatibility. The maternal immunoglobulin G alloantibodies cross the placenta and destroy fetal and newborn platelets, resulting in transient but severe thrombocytopenia in the newborn. Antibodies against the human platelet antigen-1a are responsible for 80% of cases of NAIT among whites. Thrombocytopenia in the newborn or infant can last several weeks, until the maternal antibody is cleared. Unlike Rh alloimmunization, NAIT can occur in the first pregnancy. The risk of intracranial hemorrhage is significant, with a reported incidence of up to 20% in some studies, and it can occur in utero. Neonatal thrombocytopenia also can occur as a result of maternal ITP, with maternal transfer of antibody. Bleeding tends to be mild in this setting, and intracranial hemorrhage is rare. The thrombocytopenia resolves after several weeks. Acquired thrombocytopenia most often occurs in the setting of an ill newborn or infant with sepsis, congenital infection (eg, Toxoplasma, rubella, cytomegalovirus, HIV), necrotizing enterocolitis, respiratory distress syndrome, asphyxia, or congenital heart disease. Drug-associated thrombocytopenia also may occur in the hospitalized newborn or infant.

Vitamin K deficiency in the neonate has 3 different presentations. Classic hemorrhagic disease of the newborn manifests between days 2 and 7 of age and is the result of immature neonatal liver and impaired clotting factor synthesis, inadequate vitamin K intake, and sterile neonatal gut. With the advent of vitamin K prophylaxis at birth, this form of vitamin K deficiency is rare. Early hemorrhagic disease of the newborn manifests in the first 24 hours after birth and is caused by maternal medications that affect vitamin K metabolism (eg, anticonvulsants). Late vitamin K deficiency occurs after 1 week of age and is associated with several conditions in which vitamin K stores may be low, such as inadequate intake in breastfed neonates and infants, impaired absorption in neonates and infants with chronic diarrhea, antibiotic use, cystic fibrosis, and other GI disorders. Bleeding symptoms associated with vitamin K deficiency can be severe, with a significant incidence of GI, deep tissue, and intracranial hemorrhage.

Exposures to the superwarfarin vitamin K antagonists found in rat poisons are relatively common in children but are usually asymptomatic, because it is necessary to ingest a large quantity of rat poison to induce significant coagulopathy. However, this intoxication should be considered in patients presenting with extreme coagulopathy and unexplained elevation of PT and activated PTT (aPTT) secondary to depletion of vitamin K–dependent factors.

Evaluation

History

A thorough bleeding history and physical examination should enable the pediatrician to determine the likelihood of an underlying bleeding disorder. The pattern of bleeding, timing of the symptoms (acute or chronic), overall health of the child, and family history are important in helping determine the underlying etiology. Box 99.1 lists the pertinent questions to ask when obtaining a bleeding history.

Bruises are common in childhood. Normal bruising that occurs in an active child must be differentiated from pathologic bruising resulting from a possible bleeding disorder or non-accidental trauma. Bruises over exposed bony prominences, such as the anterior tibia or the knee, are common. Bruises of a size inconsistent with the degree of reported trauma, and bruises in unexposed or unusual areas (ie, back, chest, shoulders, upper arms), should alert the pediatrician to a possible bleeding disorder or non-accidental trauma. Linear or geometric bruises are concerning for non- accidental trauma. Epistaxis, another common occurrence, typically is caused by digital trauma or allergic rhinitis. However, epistaxis that is unrelieved by 15 minutes of appropriately applied pressure or epistaxis requiring packing, cautery, or transfusion is highly suggestive of a bleeding disorder. Menorrhagia, that is, menstrual flow longer than 7 days, and a history of frequently blood-stained clothes or iron deficiency anemia in the adolescent female are concerning. Persistent or recurrent bleeding with dental extractions (beyond the day of the procedure) or with surgeries also merits a closer evaluation. However, if a child has undergone previous dental extractions or surgeries without bleeding complications, an underlying bleeding disorder is unlikely. A history of deep muscle bleeding or unexplained hemarthroses is suggestive of an inherited factor deficiency.

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