Approach to the child with bleeding symptoms

INTRODUCTION — This topic reviews the approach to evaluating an infant, child, or adolescent presenting with either overt bruising or bleeding or with a history of increased bleeding.

Thrombocytopenia and specific bleeding disorders, including hemophilia and von Willebrand disease (VWD), are discussed in greater detail separately:

●Thrombocytopenia (see "Approach to the child with unexplained thrombocytopenia" and "Causes of thrombocytopenia in children" and "Neonatal thrombocytopenia: Etiology")

●Hemophilia A and B (see "Clinical manifestations and diagnosis of hemophilia" and "Hemophilia A and B: Routine management including prophylaxis" and "Treatment of bleeding and perioperative management in hemophilia A and B")

●VWD (see "Clinical presentation and diagnosis of von Willebrand disease" and "von Willebrand disease (VWD): Treatment of major bleeding and major surgery")

Specific sources of bleeding are also discussed in separate topics:

●Gastrointestinal bleeding (see "Approach to upper gastrointestinal bleeding in children" and "Lower gastrointestinal bleeding in children: Causes and diagnostic approach")

●Epistaxis (see "Evaluation of epistaxis in children" and "Causes of epistaxis in children" and "Management of epistaxis in children")

●Vaginal and/or abnormal uterine bleeding (see "Evaluation of vulvovaginal bleeding in children and adolescents" and "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis" and "Abnormal uterine bleeding in adolescents: Management")

●Bruising that raises concerns for child abuse (see "Physical child abuse: Recognition" and "Physical child abuse: Diagnostic evaluation and management")

HISTORY — Clinical evaluation of a patient with bleeding symptoms begins with taking a careful history, including the child's age, sex, clinical presentation, personal and family medical history, and medications. Careful attention should be paid to the child's bleeding history, including number and severity of bleeding episodes and characterizing the type of bleeding (table 1 and table 2).

Bleeding questionnaires — Validated bleeding assessment tools (BATs) such as the Pediatric Bleeding Questionnaire (PBQ) and the International Society on Thrombosis and Haemostasis (ISTH) BAT allow for more objective quantification of bleeding symptoms in pediatric patients [1-3]. Both tools include a nearly identical panel of questions (table 2). They can be used as screening tools to identify patients who are more likely to have an underlying bleeding disorder (ie, those for whom laboratory evaluation may be appropriate). For pediatric patients, a score ≥3 (using either tool) is considered a positive screen. In patients with inherited platelet function defects, a high baseline BAT score is associated with increased risk of future bleeding [4]. BATs have high negative predictive value in children undergoing investigation for von Willebrand disease (VWD; types 1 to 3) [5]. In other words, a child with a low BAT score is unlikely to have VWD. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Personal bleeding history and bleeding assessment tool (BAT)'.)

A self-administered version of the PBQ is available that uses lay language at a fourth grade reading level rather than medical terminology, making the tool more accessible in clinical practice [6-9]. It has been validated in patients as young as 8 to 12 years of age.

BATs do not perform as well in the preoperative setting (ie, to identify children at increased risk of surgical bleeding) [10-12]. Nevertheless, if the preoperative history raises concerns for a possible bleeding disorder, it is reasonable to use a BAT to objectively quantify the bleeding symptoms and help determine whether preoperative laboratory testing is warranted. Clinicians should be aware however, that a normal BAT score does not necessarily predict low risk of major bleeding during surgery, nor does an abnormal BAT score accurately predict increased risk of major surgical bleeding [11]. This issue is discussed in greater detail separately. (See "Preoperative assessment of bleeding risk", section on 'Determine bleeding risk'.)

Type of bleeding — Bleeding symptoms caused by platelet disorders are quite distinct from those associated with hemophilia or other disorders of coagulation proteins (table 1)

●Bleeding into the skin and mucous membranes is characteristic of disorders of platelets and their interaction with blood vessels and may be manifested as petechiae, ecchymoses, and/or mucosal bleeding (picture 1A-C). (See "Causes of thrombocytopenia in children" and "Inherited platelet function disorders (IPFDs)".)

●Bleeding into soft tissue, muscle, and joints suggests the presence of hemophilia or other disorders of coagulation proteins. (See "Clinical manifestations and diagnosis of hemophilia".)

Pathologic versus normal bleeding — One important goal of the medical history is to distinguish between a pathologic pattern of bleeding versus normal bleeding symptoms that commonly occur in healthy children.

●Pathologic bleeding – The possibility of an underlying bleeding disorder should be considered in children who experience bleeding symptoms that are:

•Unusually frequent

•Long-lasting, or

•Severe

In addition, an inherited bleeding disorder should be strongly considered when the onset of bleeding manifestations occurs in infancy or early childhood, particularly if associated with a positive family history.

The following are examples of typical presentations suggestive of an underlying bleeding disorder:

•A newborn with bleeding from the umbilical stump should be evaluated for coagulation protein defects, including factor XIII deficiency [13]. Intracranial hemorrhage in an infant without other risk factors should also prompt consideration of this diagnosis. (See "Rare inherited coagulation disorders".)

•A male infant who is starting to walk and presents with a painful swollen joint after a fall is presumed to have hemophilia until proven otherwise. Similarly, an unusually prominent forehead hematoma ("goose-egg") in a male infant or young male is a common presentation of hemophilia [14], as is excess bleeding after circumcision. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Initial presentation'.)

•An otherwise healthy child who presents with petechiae and/or mucocutaneous purpura in the wake of a viral infection most likely has postinfectious immune thrombocytopenia [15-18]. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Clinical features'.)

•An adolescent female who presents with excessive menstrual bleeding, recurrent nosebleeds, and pallor may have VWD, the most common inherited bleeding disorder [19]. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Clinical features'.)

Clinicians should be alert to the possibility that bruising or bleeding judged to be abnormal (eg, due to frequency, duration, or severity of episodes or lack of explanation for symptoms or physical findings) may be caused by a bleeding disorder or by nonaccidental injury (ie, child abuse). Furthermore, child abuse and bleeding disorders are not mutually exclusive. Therefore, the history should include complete details as to the type of bleeding, location, degree of symptoms, nature of provoking injuries, and whether such injuries are consistent with the child's development and level of activity [20]. (See "Physical child abuse: Recognition".)

●Bleeding in healthy children – Bleeding symptoms do occur in healthy children and may not necessarily suggest a generalized bleeding disorder. For example:

•Epistaxis may be caused by rhinitis, trauma, superficial vessels, or dry air. However, evaluation for a bleeding disorder may be warranted for children with frequent recurrent nosebleeds, severe nosebleeds that are difficult to control, bilateral nosebleeds, and prior history of bleeding symptoms and/or positive family history [21]. (See "Evaluation of epistaxis in children" and "Causes of epistaxis in children".)

•Abnormal postprocedural bleeding (eg, following tonsillectomy, circumcision, tooth extraction) may occur simply due to surgical trauma; however, it may also suggest the possibility of an underlying bleeding disorder, particularly if the child has had a prior history of bleeding symptoms and/or positive family history. (See "Tonsillectomy (with or without adenoidectomy) in children: Postoperative care and complications", section on 'Hemorrhage'.)

•Bruising, particularly of the lower extremities, is common in active toddlers and young children. However, in children with abnormal bruising patterns the possibility of a bleeding disorder or nonaccidental trauma (child abuse) should be considered. The acronym TEN-4-FACESp is commonly used to screen children <4 years of age with bruising to identify when a bruise is more likely to be caused by abuse than accidental injury. TEN-4-FACESp stands for bruising to the Torso, Ears, or Neck; any bruising in an infant ≤4.9 months old; Frenulum tear, bruising on the Angle of the jaw, fleshy Cheeks, Eyelids, or Subconjunctivae; or patterned bruising (eg, bites, grip marks, outline of an object) [22]. (See "Physical child abuse: Recognition", section on 'Inflicted bruises'.)

In a study that followed 433 young children with and without bleeding disorders over a period of 12 weeks, children with bleeding disorders had more and larger bruises compared with healthy children, especially at premobile stages of development (ie, nonrolling/rolling over/sitting) [23]. Approximately 50 percent of infants with severe bleeding disorders had bruising noted during premobile stages, whereas bruising was uncommon among healthy premobile infants. Among early mobile (crawling/cruising) and ambulatory children, bruising was common in both groups (>90 percent of children with severe bleeding disorders and 50 to 80 percent of healthy children).

•Abnormal uterine bleeding is commonly reported by adolescents and can be due to a variety of causes including immaturity of the hypothalamic-pituitary-ovarian axis, other causes of ovulatory dysfunction (eg, polycystic ovary syndrome, thyroid disease), pregnancy-related problems, medications, and infections. Features of abnormal uterine bleeding that are suggestive of an underlying bleeding disorder include heavy menses starting with menarche, presence of iron deficiency anemia, family history of bleeding, other symptoms of bleeding, or failure to respond to first-line treatment of heavy menses [24]. (See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis".)

Family history — The family history is helpful in supporting a possible diagnosis of an inherited disorder of coagulation. The presence of bleeding manifestations only in male siblings and maternal uncles is suggestive of an X-linked recessive disorder, such as hemophilia A or B. However, a negative family history does not exclude an inherited coagulation disorder, as up to one-third of patients with hemophilia have a negative family history [25]. In addition, females carrying the hemophilia gene may also manifest symptoms (eg, heavy menstrual bleeding) [26]. (See "Genetics of hemophilia A and B", section on 'Transmission'.)

In contrast, in autosomal dominant disorders such as hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease), an accurate pedigree will show affected male and female family members for several generations [27]. Most instances of VWD are also inherited in an autosomal dominant fashion. In autosomal recessive disorders, such as severe forms of the rarer coagulation factor deficiencies (eg, factor VII or factor XI deficiency), the family history may be negative; consanguinity increases the probability of such disorders [28]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)" and "Rare inherited coagulation disorders".)

Medications — It is important to review any medications that the child is taking, particularly nonsteroidal antiinflammatory drugs (NSAIDs; eg, ibuprofen, naproxen), aspirin, or over-the-counter medications that contain NSAIDs or aspirin. Such drugs impair platelet function and may exacerbate an underlying coagulation disorder. It is important to ask about recent use (ie, within one to two weeks) of these agents even if they are not the suspected cause of the bruising or bleeding in the child because they may cause abnormalities in platelet function tests, which may lead to further unnecessary and expensive studies.

Less commonly, easy bruising may be attributable to selective serotonin reuptake inhibitors, stimulant medications used to treat attention deficit disorder (eg, as methylphenidate), and oral or topical corticosteroids. All of these agents can lead to easy bruising. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Bleeding' and "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Stimulant adverse effects' and "Major adverse effects of systemic glucocorticoids", section on 'Other effects'.)

In addition, the clinician should inquire about use of herbal medicines that may contribute to abnormal bleeding (eg, ginger, feverfew, ginkgo biloba, large amounts of garlic) [29-32].

Accidental or intentional ingestion of warfarin or warfarin-containing rodenticides can also cause bleeding symptoms in children. (See "Overview of rodenticide poisoning", section on 'Anticoagulants (superwarfarins and warfarins)'.)

INITIAL LABORATORY EVALUATION

Approach to testing — The evaluation for bleeding disorders in children begins with general screening tests that assess hemostasis (table 3 and algorithm 1 and algorithm 2). Based upon the results of these tests and clinical suspicion, additional and more specific testing is performed to narrow the possibilities or make a definitive diagnosis. (See 'Diagnostic approach' below and 'Additional selective testing' below.)

For children with clinically significant bleeding symptoms (eg, a score ≥3 using a bleeding assessment tool [BAT] (table 2)) in whom the cause is not readily apparent based upon the history and physical examination, we suggest the following initial tests, which are discussed in the sections below:

●Complete blood count, including platelet count

●Examination of the peripheral blood smear

●Prothrombin time (PT)/international normalized ratio

●Activated partial thromboplastin time (aPTT)

At the author's center, we also commonly obtain the following tests as part of the initial evaluation; however, other centers may not include these in the initial testing:

●Fibrinogen activity level (see 'Fibrinogen' below)

●Testing for von Willebrand disease (VWD) (see 'von Willebrand disease testing' below)

In most cases, we initially obtain all of these screening tests; however, in certain circumstances, it may be appropriate to perform only limited testing. For example, in an otherwise well child who presents with mucocutaneous bleeding, a complete blood count with platelet count and examination of the peripheral blood smear are the most informative initial tests (algorithm 2).

Normal values of coagulation tests may vary with age and among different laboratories (table 4). In particular, normal PTs and aPTTs should be based upon an individual clinical laboratory's reference ranges [33]; published ranges should not be used to conclusively ascertain whether an individual result is normal or abnormal.

Proper collection of the blood sample is essential for interpreting the results of coagulation tests. Blood for coagulation tests should not be drawn from an existing heparinized indwelling line. A cleanly drawn venipuncture sample without air bubbles or tissue fluid contamination is the most appropriate sample for coagulation tests. Coagulation tests are performed on blood anticoagulated with a solution of sodium citrate in a ratio of nine parts of blood to one part of citrate. When the hematocrit is high (eg, newborns and children with cyanotic cardiac disease), the amount of citrate must be adjusted (reduced) to provide the proper ratio [34]. (See "Clinical use of coagulation tests", section on 'Sample collection and handling'.)

Platelet count and the peripheral smear — The platelet count is typically performed with an automated cell counter. (See "Automated complete blood count (CBC)".)

Platelets may also be counted directly on the blood smear. Examination of the peripheral blood smear is essential in patients with low platelet counts in order to exclude the presence of pseudothrombocytopenia caused by platelet aggregation after using ethylenediaminetetraacetic acid (EDTA) as an in vitro anticoagulant (picture 2) [35]. Platelet aggregation causes falsely low platelet counts by the automated cell counter, but the platelet clumps are obvious on examination of the smear. Alternative anticoagulants (eg, trisodium citrate or heparin) may circumvent in vitro EDTA-associated platelet aggregation [36]. Platelet clumping on the smear of a patient with bleeding symptoms may also suggest type 2B VWD or pseudo (platelet type)-VWD (algorithm 2). (See "Approach to the child with unexplained thrombocytopenia", section on 'Verification of thrombocytopenia'.)

Examination of the peripheral smear is important as it may reveal findings that point to an underlying etiology (eg, peripheral blasts (picture 3 and picture 4), schistocytes (picture 5)). In addition, it permits assessment of platelet size and granularity, which helps to narrow the diagnostic possibilities in a patient with thrombocytopenia (table 5). (See "Causes of thrombocytopenia in children".)

Prothrombin time (PT) — The production of fibrin via the extrinsic pathway and the final common pathway requires tissue thromboplastin (tissue factor); factors VII, X, and V; prothrombin (factor II); and fibrinogen. The functioning of these pathways is measured by the PT (figure 1). This test bypasses the intrinsic pathway and uses "complete" thromboplastins (ie, tissue factor) capable of activating the extrinsic pathway.

The PT is sensitive to alterations in the vitamin K-dependent coagulation factors, especially factors II, VII, and X. (See "Clinical use of coagulation tests", section on 'Prothrombin time (PT) and INR'.)

Activated partial thromboplastin time (aPTT) — The aPTT measures the intrinsic and common pathways of coagulation (figure 1). It is called "partial" because clotting is initiated in vitro with agents that are only partial thromboplastins (ie, they are incapable of activating the extrinsic pathway). (See "Clinical use of coagulation tests", section on 'Activated partial thromboplastin time (aPTT)'.)

The aPTT is sensitive to deficiencies of factors XII, XI, IX, and VIII and to inhibitors such as heparin (figure 1). It is less sensitive than the PT to deficiencies within the common pathway (eg, factors X and V, prothrombin, and fibrinogen) and is unaffected by alterations in factors VII and XIII.

Fibrinogen — We routinely obtain fibrinogen levels in addition to the PT and aPTT because the three tests together are more sensitive than the PT/aPTT alone for detecting fibrinogen disorders. Mild hypofibrinogenemia (fibrinogen levels between 100 to 150 mg/dL) may not cause prolongation in the PT/aPTT. However, in most cases of severe fibrinogen disorders, the PT and aPTT are both prolonged. Thus, some centers do not routinely obtain fibrinogen levels if the PT and aPTT are normal. (See "Disorders of fibrinogen".)

The functional fibrinogen concentration is typically measured using a sensitized modification of the thrombin time (TT), whereas fibrinogen protein levels are measured using immunologic assays. Immunologic and functional assays of fibrinogen may be discordant in patients with an inherited dysfibrinogenemia (generally with a significantly higher protein level than activity level). Fibrinogen levels reported by most clinical coagulation labs represent functional fibrinogen concentrations.

von Willebrand disease testing — Functional assays of VWF binding to platelets or collagen. Though the VWF:RCo assay the quantity and function of von Willebrand factor (VWF). These tests can usually establish whether or not the patient has VWD (algorithm 3):

●VWF antigen – Quantitative measurement of VWF protein level.

●VWF activity – Functional assays of VWF binding to platelets or collagen. Though the VWF:RCo assay is the traditional assay used to measure VWF activity, newer tests such as the VWF:GPIbM are generally more reproducible and are becoming widely used.

●Factor VIII activity.

The rationale for these tests and the details of their interpretation are summarized in the table (table 6) and discussed in greater detail separately. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Laboratory testing'.)

DIAGNOSTIC APPROACH — Results of the initial laboratory testing allow the clinician to narrow the diagnostic possibilities in the child with a bleeding disorder (table 3 and algorithm 1 and algorithm 2).

Abnormal blood count

Pancytopenia — Two important diagnostic considerations in a child with mucocutaneous bleeding and pancytopenia include:

●Leukemia – Other concerning findings that may point to this diagnosis include organomegaly, lymphadenopathy, and/or bone pain. Examination of the peripheral blood smear may reveal the presence of leukemic blasts (picture 3 and picture 4), an observation that should be confirmed with a bone marrow examination. (See "Evaluation of the peripheral blood smear", section on 'Worrisome findings'.)

●Aplastic anemia – Children with aplastic anemia present with varying combinations of symptomatic anemia, bleeding, and infection, depending upon the severity of the pancytopenia. Single or multiple skeletal anomalies may be present in children with the congenital forms of aplastic anemia. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

Thrombocytopenia — Causes of thrombocytopenia in pediatric patients are summarized in the table (table 7). The approach to evaluating children with thrombocytopenia is discussed in detail separately. (See "Approach to the child with unexplained thrombocytopenia" and "Neonatal thrombocytopenia: Etiology" and "Causes of thrombocytopenia in children".)

Abnormal coagulation tests — The results of coagulation studies (prothrombin time [PT], international normalized ratio, activated partial thromboplastin time [aPTT]) may help narrow the diagnostic possibilities (algorithm 1 and table 3).

aPTT prolonged/PT normal — An isolated prolonged aPTT can be seen in the following conditions (algorithm 1):

●Hemophilia A or B – Hemophilia A (factor VIII deficiency) is the most common inherited disorder yielding a significantly prolonged aPTT. The reported incidence is 1 in 5000 males [25]. Hemophilia B (factor IX deficiency) occurs less often: 1 in 20,000 males. Both disorders have an X-linked recessive transmission and demonstrate a range of presentations depending on severity of the phenotype, ranging from prolonged bleeding after surgery or other trauma to spontaneous soft tissue and joint hemorrhages. Mucocutaneous bleeding (eg, excessive bruising, prolonged oozing from oral wounds) can also occur. Hemophilia carriers, even those with normal factor levels, may have symptoms similar to affected males with mild hemophilia and are at increased risk for reproductive bleeding. (See "Clinical manifestations and diagnosis of hemophilia".)

●Factor XI deficiency – Factor XI deficiency is seen more commonly in Ashkenazi Jews and presents with a variable history of bleeding, often mucocutaneous in nature [37]. (See "Factor XI (eleven) deficiency".)

●Lupus anticoagulants – Lupus anticoagulants are acquired inhibitors (autoantibodies) directed against phospholipid-protein complexes that produce a prolonged aPTT. They are commonly seen in children, frequently associated with recent infections (particularly viral infections), and usually transient. Lupus anticoagulants are not associated with bleeding symptoms but rather an increased risk of thrombosis. However, children with transient viral-triggered lupus anticoagulants are generally not at risk for thrombotic complications. (See 'Antiphospholipid antibodies' below.)

●Deficiencies of factor XII, high molecular weight kininogen, and prekallikrein – These disorders are typically asymptomatic and not associated with clinical bleeding. Patients with these deficiencies are often discovered when an asymptomatic child demonstrates a significantly prolonged aPTT on routine preoperative screening. Although such a deficiency may hold little clinical consequence, it can be important to identify since it provides an explanation for an otherwise puzzling prolonged aPTT.

●Heparin contamination – Blood drawn from heparin-containing intravascular lines is another cause of isolated aPTT prolongation. This possibility can generally be excluded by obtaining a fresh blood sample from a venipuncture stick. Heparin contamination can also be confirmed by measuring the thrombin time (TT) and reptilase time (RT; the former will be prolonged, while the latter will be normal); however, this is not commonly done in clinical practice. (See 'Thrombin time and reptilase time' below.)

PT prolonged/aPTT normal — An isolated prolonged PT is characteristic of (figure 1 and algorithm 1):

●Inherited factor VII deficiency, which displays phenotypic and molecular heterogeneity (see "Rare inherited coagulation disorders")

●Acquired factor VII inhibitors, which are very rare occurrences during childhood [38] (see "Acquired hemophilia A (and other acquired coagulation factor inhibitors)", section on 'Factor VII inhibitors')

PT and aPTT both prolonged

Well child — Prolongation of both PT and aPTT in a child with bleeding symptoms but who is otherwise well indicates an inherited disorder within the common pathway or an acquired disorder involving multiple pathways (figure 1 and algorithm 1).

Inherited deficiencies in this category include deficiency of factors X, V, and II; (prothrombin); or fibrinogen. These deficiencies are rare. (See "Rare inherited coagulation disorders".)

Inherited disorders of fibrinogen (hypo- or afibrinogenemia) are autosomal recessive disorders, and bleeding associated with these disorders is treatable with cryoprecipitate or fibrinogen concentrates. Dysfibrinogenemia, an autosomal dominant disorder, may be associated with either bleeding or excessive clotting. (See "Disorders of fibrinogen".)

Sick child — In a sick child with prolongation of both PT and aPTT, disorders to consider are disseminated intravascular coagulation (DIC; eg, due to sepsis or other systemic illness), severe liver disease, or severe vitamin K deficiency (algorithm 1). The factor V level can be used to distinguish between vitamin K deficiency and liver disease or DIC (it is normal in the former and decreased in the latter two conditions). (See "Disseminated intravascular coagulation in infants and children".)

Other rare causes of prolonged PT and aPTT in an ill-appearing child include major vessel thrombosis, as well as consumption coagulopathy in certain vascular lesions.

Accidental or intentional ingestion of warfarin or warfarin-containing rodenticides sufficient to cause bleeding usually results in a prolongation of the PT and aPTT because the vitamin K-dependent factors that are inhibited by warfarin are present in the extrinsic (factor VII), intrinsic (factor IX), and common pathways (factors II and X) (figure 1) [39]. Hemorrhage under such circumstances may be life-threatening and requires immediate treatment with combinations of intravenous vitamin K, fresh frozen plasma, and/or prothrombin complex concentrates (which contain all of the vitamin K-dependent coagulation factors). (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Treatment of bleeding' and "Overview of rodenticide poisoning", section on 'Anticoagulants (superwarfarins and warfarins)'.)

There have been rare case reports of acquired inhibitors to prothrombin, factor V, and factor X. (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)".)

Abnormal von Willebrand disease testing — von Willebrand disease (VWD) is the most common inherited bleeding disorder. There are three major types of VWD. Types 1 and 3 are quantitative deficiencies of von Willebrand factor (VWF), whereas type 2 is a qualitative disorder. (See "Clinical presentation and diagnosis of von Willebrand disease".)

Laboratory tests for VWD include VWF antigen, VWF activity, and factor VIII activity (algorithm 3). The platelet count may be low in some patients with type 2B VWD. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Laboratory testing'.)

The laboratory diagnosis of VWD in pediatric patients is complicated by VWF assay variability and stress-induced elevations in VWF levels. Patients with a high suspicion of VWD who have borderline initial laboratory results should undergo repeat testing. In a retrospective cohort of 811 patients undergoing evaluation for a suspected bleeding disorder, 22 percent were ultimately diagnosed with VWD, of whom approximately 30 percent required repeat testing to make the diagnosis [40]. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Repeat testing in individuals with borderline or discordant clinical and laboratory findings'.)

Normal initial testing — In children with bleeding symptoms and a normal initial laboratory screen, possible diagnoses include some cases of hemophilia, factor XIII deficiency, platelet function disorders, vascular anomalies, connective tissue disorders, and fibrinolytic disorders. In addition, some patients with VWD may have equivocal or borderline results on initial testing, as discussed above. (See 'Abnormal von Willebrand disease testing' above.)

Some cases of hemophilia — Mild cases of hemophilia B, in which factor IX activity is in the 6 to 40 percent range, may not reliably result in prolongation of the aPTT on initial hemostatic screening, due to relative insensitivity of aPTT reagents to mild factor IX deficiency. In addition, there exist uncommon forms of hemophilia A in which factor VIII deficiency may be undetectable on the typical, one-stage, aPTT-based assay used in the majority of laboratories worldwide [41]. In such cases, a mild "discrepant" form of hemophilia A may only be recognized with use of special two-stage or chromogenic assays of factor VIII activity [42]. When there is a high clinical suspicion for an underlying bleeding disorder but the initial coagulation tests are normal, these diagnoses can be ruled out by specific testing of factor IX activity and a two-stage or chromogenic assay of factor VIII activity, respectively. Carriers of the hemophilia gene may also experience bleeding symptoms in the setting of normal factor levels and normal aPTT. (See 'Specific factor deficiencies and inhibitors' below.)

Factor XIII deficiency and other fibrinolytic disorders — Activated factor XIII is responsible for clot stabilization and crosslinking of fibrin polymer (figure 1). Factor XIII deficiency is not detected by prolongation of either PT or aPTT since neither assay measures the mechanical strength or stability of the fibrin clot.

Inherited factor XIII deficiency is an autosomal recessive disorder characterized by reduced clot stability and abnormal bleeding. One of the characteristic abnormalities of factor XIII deficiency is delayed separation of the umbilical cord and delayed bleeding from the umbilical stump. In the neonatal period, intracranial hemorrhage with little or no trauma and poor wound healing also are associated with the deficiency. Evaluation and management of factor XIII deficiency are discussed in detail separately. (See "Rare inherited coagulation disorders", section on 'Factor XIII deficiency (F13D)'.)

If factor XIII deficiency is suspected, the quantitative assay should be performed [13]. (See 'Clot solubility in urea and factor XIII activity testing' below.)

Deficiencies of alpha-2-antiplasmin and plasminogen activator inhibitor have also been associated with an increased bleeding tendency. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'Alpha-2-antiplasmin deficiency' and "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'PAI-1 deficiency' and "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'Alpha-2-antiplasmin'.)

Platelet function disorders — Studies to confirm the presence of qualitative disorders of platelet function include evaluation of platelet morphology on the peripheral blood smear, tests of platelet aggregation, and other tests of platelet function [43,44]. (See "Platelet function testing".)

Acquired causes of abnormal platelet function are much more common than inherited causes and include use of certain medications (eg, aspirin, nonsteroidal antiinflammatory drugs [NSAIDS]), uremia, and the myeloproliferative and myelodysplastic syndromes. As noted above, it is critical to ascertain a history of ingestion of NSAIDs or other platelet inhibitors in any patient with a bleeding disorder. In addition, if platelet function tests are to be performed (eg, platelet function analyzer [PFA]-100, platelet aggregation studies), the subject must refrain from taking these drugs prior to testing. (See "Platelet function testing", section on 'Caveats with testing'.)

Classic inherited disorders of platelet function are relatively rare and include (table 8) (see "Inherited platelet function disorders (IPFDs)"):

●Glanzmann thrombasthenia – Characterized by a defect in the platelet glycoprotein IIb/IIIa complex that normally upon platelet activation functions as the fibrinogen receptor, mediating platelet aggregation by enabling crosslinking between platelets and fibrinogen. Affected children present with significant mucocutaneous bleeding and a normal platelet count but highly abnormal platelet aggregation (absent or decreased aggregation to adenosine phosphate, epinephrine, collagen, and thrombin but normal aggregation to ristocetin) [45]. (See "Inherited platelet function disorders (IPFDs)", section on 'Glanzmann thrombasthenia'.)

●Bernard-Soulier syndrome – Characterized by a defect in one of the components of the platelet glycoprotein Ib-IX-V complex, giant platelets, and bleeding that is greater than expected for the degree of thrombocytopenia [46]. (See "Inherited platelet function disorders (IPFDs)", section on 'Bernard-Soulier syndrome'.)

●Storage pool diseases – Hermansky-Pudlak syndrome and Chediak-Higashi syndrome are characterized by deficiency of delta-granule platelet storage pools. Milder and less specific forms of platelet storage pool disorders, such as alpha-granule deficiency (gray platelet syndrome), are more common than these two rare syndromes [47]. These are readily identifiable by specific platelet morphologic changes on the peripheral blood smear. (See "Hermansky-Pudlak syndrome" and "Chediak-Higashi syndrome" and "Inherited platelet function disorders (IPFDs)", section on 'Chediak-Higashi syndrome'.)

●Other platelet function disorders – Platelet function testing in patients undergoing evaluation of mucocutaneous bleeding frequently identifies abnormalities that are less well characterized than for the classic disorders described above. These nonspecific platelet function defects are quite common and should be tested for concurrent with or soon after testing for VWD [43,44].

Vascular purpuras — Screening tests usually are normal in patients with bleeding disorders related to vascular abnormalities. (See "Purpuric skin lesions (petechiae, purpura, and ecchymoses) in children: Causes", section on 'Disruptions in vascular integrity'.)

These include:

●Structural vascular abnormalities (eg, hereditary hemorrhagic telangiectasia) (see "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)")

●Hereditary disorders of connective tissue (eg, Ehlers-Danlos disease and osteogenesis imperfecta) (see "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes" and "Osteogenesis imperfecta: An overview")

●Acquired connective tissue disorders (eg, scurvy, steroid-induced purpura) (see "Major adverse effects of systemic glucocorticoids", section on 'Dermatologic effects and appearance')

●Small vessel vasculitis (eosinophilic granulomatosis with polyangiitis [Churg-Strauss], immunoglobulin A vasculitis [Henoch-Schönlein purpura], microscopic polyangiitis, or granulomatosis with polyangiitis) (see "Vasculitis in children: Incidence and classification")

●Psychogenic purpura (see "Psychogenic purpura (Gardner-Diamond syndrome)")

●Purpura associated with the presence of paraproteins

Bleeding of unknown cause — A subset of patients with mild to moderate bleeding tendencies have no abnormalities in clinically available laboratory assays [48]. The term "bleeding of unknown cause" is often used as a diagnosis for such patients. Studies in which extensive specialized testing was performed for patients in this category have demonstrated impairments in thrombin-generating potential, clot formation, and fibrinolysis [48-50].

Physical abuse of the child should be considered in such cases. (See "Physical child abuse: Diagnostic evaluation and management".)

ADDITIONAL SELECTIVE TESTING — Based upon the results of the initial tests, additional testing may be performed to narrow the possibilities or make a definitive diagnosis. The approach to the diagnostic evaluation is reviewed above. (See 'Diagnostic approach' above.)

Specific factor deficiencies and inhibitors — An abnormally prolonged prothrombin time (PT) or activated partial thromboplastin time (aPTT) can be due to the absence or reduced concentration of a coagulation factor or the presence of an inhibitor to one of the coagulation factors:

●A factor deficiency should be correctable by the addition of normal plasma ("mixing study"). This normally is performed by repeating the abnormal PT or aPTT with a 1:1 mixture of patient and normal plasma. If the 1:1 mixture corrects the abnormal test, a deficiency of a coagulation factor is likely to be present. (See "Clinical use of coagulation tests", section on 'Evaluation of abnormal results'.)

●The presence of a factor inhibitor is suspected when the abnormal test does not correct, or only partially corrects, after immediate assay of a 1:1 mixture of patient and normal plasma. (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)", section on 'Laboratory testing'.)

Deficiencies of specific factors may be determined by assessing the PT or aPTT in mixtures of patient plasma with commercially available plasma deficient in known factors. Factor levels can be assessed functionally by comparing test results with standard curves generated by mixtures of serially diluted normal plasma and factor-deficient plasma. Immunologic assays also can be used to measure factor protein levels. Immunologic and functional assays should give equivalent results when a quantitative factor deficiency is present (generally referred to as "type 1 deficiency"). Reduction in a functional assay with a normal immunologic assay suggests the presence of a functionally abnormal factor ("type 2 deficiency").

Platelet function testing — In addition to the evaluation of platelet count and morphology by examination of the peripheral blood smear, different tests are available that evaluate platelet function (table 9). Testing is challenging because some tests are highly operator-dependent, many tests are poorly standardized and poorly reproducible, and no test assesses all aspects of platelet function. When platelet function testing is performed, it generally should be carried out in consultation with a hematologist. Platelet aggregation testing should be performed in specialized laboratories with expertise in their methods and interpretation.

The following sections briefly summarize a few of the available platelet function tests. These and other platelet function tests are discussed in greater detail separately (see "Platelet function testing"):

●Platelet function analyzer (PFA-100) – The PFA-100 is a simple, rapid test that can be performed at the point of care to measure global platelet function. Because of its simplicity, it is sometimes used as a screening tool for platelet function defects and von Willebrand disease (VWD) in children [51,52]. However, it is neither sensitive nor specific for any particular disorder and its optimal use in clinical practice remains uncertain. The PFA-100 is discussed in greater detail separately. (See "Platelet function testing", section on 'PFA-100'.)

●Platelet aggregation – Traditional platelet aggregation assays measure platelet activation and aggregation in vitro in response to various known platelet agonists (eg, adenosine diphosphate [ADP], arachidonic acid, collagen, epinephrine, thrombin, and ristocetin). Either whole blood or platelet-rich plasma is used depending on the technique. Since many common medications can affect platelet function, care must be taken to avoid their use in patients prior to testing. Expected aggregation results with specific platelet disorders are summarized in the table (table 8). (See "Platelet function testing", section on 'Platelet aggregometry'.)

●Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) – TEG and ROTEM assess platelet-mediated thrombin formation. These tests are uncommonly used in the evaluation of children with bleeding symptoms. They are discussed separately. (See "Platelet function testing", section on 'Viscoelastic testing (TEG and ROTEM)'.)

●Bleeding time – The bleeding time is not performed routinely as a screening test in children (or adults), because it is poorly reproducible, invasive, insensitive, and time consuming. A normal bleeding time does not predict the safety of surgical procedures, nor does an abnormal bleeding time predict for excessive surgical bleeding. It is not recommended as a preoperative screening test. (See "Platelet function testing", section on 'Tests not commonly used'.)

Antiphospholipid antibodies — Antiphospholipid antibodies (aPL) are not typically associated with bleeding symptoms (to the contrary, they are associated with increased thrombotic risk). However, they can be associated with prolongation of the aPTT that is not correctable by the addition of normal plasma. Thus, testing for aPL can be helpful in patients with a prolonged aPTT that is not otherwise explained. The effect of aPL on the aPTT can be partially overcome by adding excess platelet phospholipid or by assessing the diluted Russell viper venom time [53]. (See "Clinical use of coagulation tests", section on 'dRVVT' and "Diagnosis of antiphospholipid syndrome", section on 'Antiphospholipid antibody testing'.)

Thrombin time and reptilase time — The thrombin time (TT) and reptilase time (RT) measure the final step of coagulation: the conversion of fibrinogen to fibrin (figure 1). The TT is performed by incubating citrated plasma in the presence of dilute thrombin, measuring the time to clot formation. Reptilase, a thrombin-like enzyme obtained from snake venom, differs from thrombin in that it resists inhibition by heparin via antithrombin III.

These tests may be used in the following settings (see "Clinical use of coagulation tests", section on 'Thrombin time (TT)'):

●To evaluate patients with otherwise unexplained prolonged PT and aPTT. (See 'PT and aPTT both prolonged' above.)

●To detect heparin in a sample – Simultaneous measurement of TT and RT is useful in this setting since heparin prolongs the former but not the latter.

●To evaluate for an inherited fibrinogen disorder. (See "Disorders of fibrinogen", section on 'Heritable (genetic) disorders'.)

Clot solubility in urea and factor XIII activity testing — The initial immature fibrin clot, held together by noncovalent bonds, is soluble in urea. Subsequent transglutamination within the clot by activated factor XIIIa covalently crosslinks overlapping fibrin strands, which then are resistant to solubilization by urea (figure 1). The ability of urea to solubilize the mature clot reflects a severe deficiency of factor XIII [13]. However, the clot solubility assay is sensitive only at very low levels (factor XIII 1 to 3 percent) and may miss the diagnosis in less severe cases. Therefore, if factor XIII deficiency is suspected, specific quantitative assays are recommended. (See "Rare inherited coagulation disorders", section on 'Diagnostic evaluation'.)

Tests for fibrinolysis — Fibrin and fibrinogen degradation products are protein fragments resulting from the action of plasmin on fibrin or fibrinogen, respectively (figure 2). Elevated levels are seen in states of fibrinolysis such as DIC. (See "Overview of hemostasis", section on 'Clot dissolution and fibrinolysis' and "Disseminated intravascular coagulation in infants and children".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hemophilia A and B" and "Society guideline links: von Willebrand disease" and "Society guideline links: Rare inherited bleeding disorders" and "Society guideline links: Acquired bleeding disorders".)

SUMMARY AND RECOMMENDATIONS

●History – The evaluation of a child with abnormal bleeding begins with a focused history, including the clinical presentation, medical history, family history, and medications. (See 'History' above.)

•Bleeding questionnaires (eg, the International Society on Thrombosis and Haemostasis bleeding assessment tool [ISTH BAT]) can be useful for assessing the bleeding history (table 2). (See 'Bleeding questionnaires' above.)

•Mucocutaneous bleeding into the skin and mucous membranes is characteristic of platelet disorders, while muscle, joint, and soft tissue bleeding is characteristic of coagulation disorders (table 1). (See 'Type of bleeding' above.)

•The nature and extent of the injuries producing bleeding symptoms should be noted. Clinicians should be alert to the possibility of child abuse as a potential cause of abnormal bruising or bleeding. (See "Physical child abuse: Recognition".)

●Initial laboratory evaluation – We suggest the following initial laboratory evaluation for children with clinically significant bleeding symptoms (eg, a score of ≥3 on the ISTH BAT (table 2)) when the cause is not readily apparent based upon the history and physical examination (see 'Initial laboratory evaluation' above):

•Complete blood count (including platelet count)

•Examination of the peripheral blood smear

•Prothrombin time (PT)

•Activated partial thromboplastin time (aPTT)

•Fibrinogen level

•Screening tests for von Willebrand disease (VWD), including von Willebrand factor (VWF) antigen, VWF activity, and factor VIII activity (algorithm 3)

Normal values for coagulation assays may vary with age and among different laboratories (table 4).

●Diagnostic approach – The results of the initial testing help differentiate among the different diagnostic possibilities, as summarized in the table and algorithms (table 3 and algorithm 1 and algorithm 2) and discussed in detail above. (See 'Diagnostic approach' above.)

●Additional testing – Based upon the results of the initial tests, additional testing may be performed to narrow the possibilities or make a definitive diagnosis. Depending on the clinical circumstances, such testing may include tests for specific factor deficiencies, platelet function tests, testing for antiphospholipid antibodies (aPL), thrombin time (TT), factor XIII activity, and tests for fibrinolysis. (See 'Additional selective testing' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Donald Yee, MD, who contributed to an earlier version of this topic review.