INTRODUCTION — This topic reviews the approach to the 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")

HISTORY — Clinical evaluation of a patient with bleeding symptoms begins with taking a careful history, taking into account the child's age, sex, clinical presentation, past history, and family history.

Bleeding history — In assessing the patient's bleeding history, it is important to ask about prior bleeding episodes and to characterize the type of bleeding (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 oral mucosal bleeding (picture 1A-C).

●Bleeding into soft tissue, muscle, and joints suggests the presence of hemophilia or other disorders of coagulation proteins.

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, symptoms that occur with unusual frequency, duration, or severity should prompt consideration of an underlying bleeding disorder. (See "Causes of epistaxis in children".)

Abnormal post-procedural 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. (See "Tonsillectomy (with or without adenoidectomy) in children: Postoperative care and complications".)

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 [1]. (See "Physical child abuse: Diagnostic evaluation and management".)

In a prospective study that followed 433 young children (58 with severe bleeding disorders, 47 with mild bleeding disorders, and 328 without bleeding disorders) over a period of 12 weeks, children with bleeding disorders had more and larger bruises compared with those without bleeding disorders, especially at premobile stages of development (ie, nonrolling/rolling over/sitting) [2]. Bruising was uncommon among premobile infants without bleeding disorders or with only mild bleeding disorders (noted at 7 percent of assessments in both groups). By contrast, premobile infants with severe bleeding disorders were noted to have bruises at 52 percent of assessments. Among early mobile (crawling/cruising) and ambulatory children, bruising was common in all groups, noted in 50 to 80 percent of those without bleeding disorders and >90 percent of children with severe bleeding disorders.

Clinical features — 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 [3]. 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 boy is a common presentation of hemophilia [4], 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 acute postinfectious immune thrombocytopenia [5-8]. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Clinical features'.)

●An adolescent girl who presents with excessive menstrual bleeding, recurrent nosebleeds, and pallor may have von Willebrand disease (VWD), the most common inherited bleeding disorder [9]. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Clinical features'.)

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 X-linked recessive inheritance, such as that seen in 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 [10]. (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 individuals of both sexes for several generations [11]. Most instances of VWD are also transmitted 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 [12]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)" and "Rare inherited coagulation disorders".)

Medication — A thorough history of medication use, including herbal medicines (eg, ginger, feverfew, ginkgo biloba, large amounts of garlic) [13,14], is crucial. In particular, specific information should be sought about the ingestion of aspirin, aspirin-containing over-the-counter medications, and other nonsteroidal antiinflammatory drugs such as ibuprofen or naproxen. 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.

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)'.)

LABORATORY EVALUATION

Overview — No single test reliably screens the overall process of hemostasis, particularly for abnormalities of platelet function or the fibrinolytic pathway. The evaluation for bleeding disorders in children begins with general screening tests that assess hemostasis (table 2 and algorithm 1 and algorithm 2). Based upon the results of these tests and clinical suspicion, additional, more specific testing is performed to narrow the possibilities or make a definitive diagnosis.

Initial testing — The usual initial screening tests include:

●Complete blood count, including platelet count

●Examination of the peripheral blood smear

●Prothrombin time/international normalized ratio (PT/INR)

●Activated partial thromboplastin time (aPTT)

●At the author's center, we also routinely measure the fibrinogen activity level; however, other centers may not include this in the initial testing

In most cases, we initially obtain all of these screening tests; however, in certain circumstances it may be appropriate to perform only limited screening. 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 3). In particular, normal PTs and aPTTs should be based upon an individual clinical laboratory's reference ranges [15]; 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 [16]. (See "Clinical use of coagulation tests", section on 'Sample collection and handling'.)

Platelet count and the peripheral smear — The platelet count is performed most commonly using automated cell counters. (See "Automated hematology instrumentation".)

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) [17]. 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 [18]. Platelet clumping on the smear of a patient with bleeding symptoms may also suggest type 2B von Willebrand disease (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 suggest an underlying etiology (eg, peripheral blasts (picture 3 and picture 4), schistocytes (picture 5)). In addition, it permits assessment of platelet size, which helps to narrow the diagnostic possibilities in a patient with thrombocytopenia (table 4). (See "Causes of thrombocytopenia in children".)

Prothrombin time — 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, and is used to monitor treatment with vitamin K antagonists. (See "Clinical use of coagulation tests", section on 'Prothrombin time (PT) and INR' and "Biology of warfarin and modulators of INR control", section on 'Mechanism of action' and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Initial dosing'.)

Activated partial thromboplastin time — 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). This aPTT is routinely used to evaluate intrinsic coagulation and the degree of heparin anticoagulation. (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. Although high levels of a single factor (eg, factor VIII) can shorten the aPTT, whether an association exists between a shortened aPTT and a hypercoagulable state remains controversial. (See "Clinical use of coagulation tests", section on 'Shortened PT and/or aPTT'.)

Fibrinogen — Fibrinogen levels are typically measured using immunologic assays, whereas the functional fibrinogen concentration is typically measured using a sensitized modification of the thrombin time (TT). Immunologic and functional assays of fibrinogen may be discordant in patients with an inherited dysfibrinogenemia. (See "Disorders of fibrinogen".)

In most cases of clinically significant fibrinogen disorders, the PT and aPTT are both prolonged. At our institution, we routinely obtain fibrinogen levels as part of the initial screen because this test is more sensitive than the PT/aPTT for detecting fibrinogen disorders. However, some centers do not routinely obtain fibrinogen levels if the PT and aPTT are normal. (See 'Well child' below and "Disorders of fibrinogen".)

Second tier testing — Based upon the results of the initial tests, additional testing is performed to narrow the possibilities or make a definitive diagnosis. The approach to the diagnostic evaluation is reviewed below. (See 'Diagnostic approach' below.)

Thrombin time and reptilase time — The TT is prolonged in the presence of heparin or hypofibrinogenemia (as in disseminated intravascular coagulation [DIC]). (See "Clinical use of coagulation tests", section on 'Thrombin time (TT)'.)

Simultaneous measurement of TT and reptilase time (RT) is useful to assess the possibility of heparin contamination, which prolongs the former but not the latter. These tests measure conversion of fibrinogen to fibrin monomers and the formation of the initial clot by thrombin and reptilase, respectively (figure 1). Reptilase, a thrombin-like enzyme obtained from snake venom, differs from thrombin by generating fibrinopeptide A but not fibrinopeptide B from fibrinogen and by resisting inhibition by heparin via antithrombin III. Fibrin strand cross-linking, mediated by factor XIII, is not measured in these assays (figure 1). (See 'Clot solubility in urea and factor XIII activity testing' below.)

Tests for specific factor deficiencies and inhibitors — An abnormally prolonged PT or 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 inhibitors of coagulation", section on 'Diagnosis'.)

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 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").

Antiphospholipid antibodies — In addition to factor inhibitors, certain antiphospholipid antibodies (lupus anticoagulants) also can result in a prolonged aPTT that is not correctable by the addition of normal plasma. The effect of these antibodies on the aPTT can be partially overcome by adding excess platelet phospholipid (particularly a hexagonal phase phospholipid) or by assessing the diluted Russell viper venom time [19]. (See "Clinical use of coagulation tests", section on 'dRVVT'.)

In otherwise healthy children, the finding of a lupus anticoagulant is of no clinical consequence. However, when a lupus anticoagulant is present with other clinicopathologic features (eg, arthritis, serositis, renal abnormalities), an increased thrombotic risk may exist. (See "Clinical manifestations of antiphospholipid syndrome".)

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 [3]. 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".)

PFA-100 and bleeding time — The platelet function analyzer (PFA-100) is a simple, rapid test that can be performed at the point of care. Because of its simplicity, it has been used as a screening tool for globally assessing platelet function in children [20,21]. However, it is neither sensitive nor specific for any particular disorder, and experts continue to disagree on its clinical utility. The PFA-100 is discussed in greater detail separately. (See "Platelet function testing", section on 'The platelet function analyzer'.)

The bleeding time, which is a measure of platelet interaction with the vessel wall, is not performed routinely as a screening test in children (or adults) because of difficulty in administering the test in a standardized fashion. Moreover, a normal test does not predict the safety of surgical procedures [22]. We do not recommend it as a screening test prior to surgery. (See "Preoperative assessment of hemostasis", section on 'PFA-100 and bleeding time'.)

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

Abnormal initial testing

Pancytopenia — If the child has pancytopenia with or without organomegaly or lymphadenopathy, 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'.)

Another diagnosis to consider in a child with mucocutaneous bleeding and pancytopenia is aplastic anemia. Subjects 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 "Treatment of acquired aplastic anemia in children and adolescents" and "Inherited aplastic anemia in children and adolescents".)

Thrombocytopenia — Causes of thrombocytopenia in pediatric patients are summarized in the table (table 5). 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".)

Normal PT and prolonged aPTT — An isolated prolongation of activated partial prothrombin time (aPTT) may be due to deficiency in an intrinsic pathway coagulation factor (factors VIII, IX, XI, and XII), high molecular weight kininogen (HMWK), or prekallikrein (algorithm 1). In addition, aPTT may be prolonged with an acquired inhibitor, such as the lupus anticoagulant. Because von Willebrand factor (VWF) protects factor VIII from proteolysis, decreased plasma vWF or a mutation in the factor VIII binding site in type 2N von Willebrand disease (VWD) can also lead to decreased plasma factor VIII concentrations and a prolonged aPTT. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Laboratory testing'.)

The following conditions are characterized by isolated prolonged aPTT:

●Hemophilia – Hemophilia A (factor VIII deficiency) is the most common inherited disorder yielding a significantly prolonged aPTT. The reported incidence is 1 in 5000 males [10]. 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. (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 [23]. (See "Factor XI (eleven) deficiency".)

●Lupus anticoagulants – Lupus anticoagulants are acquired inhibitors that may produce a prolonged aPTT. They are commonly seen in children, frequently associated with recent infections, particularly viral infections, and usually are transient. Lupus anticoagulants seen in these clinical settings are neither a risk for bleeding nor for thrombosis. (See 'Antiphospholipid antibodies' above.)

●Deficiencies of factor XII, HMWK, and prekallikrein – These usually are asymptomatic and not associated with clinical bleeding. Subjects 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 intravenous lines may be one of the reasons for isolated aPTT prolongation. Heparin contamination is likely if the thrombin time (TT) is prolonged, but the reptilase time (RT) is not. (See 'Thrombin time and reptilase time' above.)

Prolonged PT and normal aPTT — An isolated prolongation of the prothrombin time (PT) is characteristic of inherited or acquired factor VII deficiency (figure 1 and algorithm 1). Inherited factor VII deficiency displays phenotypic and molecular heterogeneity, whereas acquired factor VII inhibitors are very rare occurrences during childhood [24]. (See "Acquired inhibitors of coagulation", section on 'Factor VII inhibitors' and "Rare inherited coagulation disorders".)

Prolonged PT and aPTT

Well child — Prolongation of both PT and aPTT in a bleeding child 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 yielding this laboratory result include deficiency of factor X, V, 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), fulminant sepsis with DIC, severe hepatocellular dysfunction, and severe vitamin K deficiency (algorithm 1). Because the production of factor V is independent of the status of vitamin K, the factor V level can be used to distinguish between vitamin K deficiency (in which factor V is normal) and liver disease or DIC (in which factor V is decreased). (See "Disseminated intravascular coagulation in infants and children".)

Major vessel thrombosis, consumption coagulopathy in certain vascular lesions, and acute respiratory distress syndrome are other rare causes of prolonged PT and aPTT in a sick child.

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 which are inhibited by warfarin are present in the extrinsic (factor VII), intrinsic (factor IX), and common pathways (factors II and X) (figure 1) [25]. 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 inhibitors of coagulation".)

Normal initial testing — In children with bleeding symptoms and a normal initial laboratory screen, possible diagnoses include VWD, some cases of hemophilia, factor XIII deficiency, platelet function disorder, vascular abnormality, and a fibrinolytic disorder.

von Willebrand disease — VWD is the most common inherited bleeding disorder, with an estimated prevalence as high as 1 percent. There are three major types of VWD. Types 1 and 3 are quantitative deficiencies of VWF, whereas type 2 is a qualitative disorder. (See "Clinical presentation and diagnosis of von Willebrand disease" and "Classification and pathophysiology of von Willebrand disease", section on 'Mutations in von Willebrand disease and implications for classification'.)

Laboratory tests for VWD include factor VIII assay, VWF activity (eg, ristocetin cofactor assay or other measure of glycoprotein Ib binding activity), and VWF antigen. 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'.)

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 using the typical, one-stage, aPTT-based assay used in the majority of laboratories worldwide [26]. 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 [27]. 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.

Factor XIII deficiency and other fibrinolytic disorders — Activated factor XIII is responsible for clot stabilization and crosslinking of fibrin polymer (figure 1). Deficiency of this factor is an autosomal recessive disorder resulting in 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. If factor XIII deficiency is suspected, the quantitative assay should be performed [3]. Evaluation and management of factor XIII deficiency are discussed in detail separately. (See "Rare inherited coagulation disorders", section on 'Factor XIII deficiency (F13D)'.)

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 [28,29]. (See "Platelet function testing".)

Acquired causes of abnormal platelet function are much more common than inherited causes and include use of aspirin and nonsteroidal antiinflammatory drugs (NSAIDS), beta-lactam antibiotics, serotonin-specific reuptake inhibitors, uremia, and the myeloproliferative and myelodysplastic syndromes. As noted above, a history of ingestion of NSAIDs or other platelet inhibitors is critical to ascertain in any patient with a bleeding disorder. In addition, if platelet function tests are to be performed (eg, PFA-100, platelet aggregation studies), the subject must refrain from taking these products for at least one to two weeks before testing. (See "Congenital and acquired disorders of platelet function", section on 'Acquired platelet functional disorders'.)

Classic inherited disorders of platelet function are relatively rare and include:

●Glanzmann thrombasthenia – Characterized by a defect in the platelet glycoprotein IIb/IIIa complex. 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) (table 6) [30]. (See "Congenital and acquired disorders of platelet function", 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 [31]. (See "Causes of thrombocytopenia in children", section on 'Large or giant platelets'.)

●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 are likely more common than these two rare syndromes [32]. (See "Congenital and acquired disorders of platelet function", section on 'Storage pool disorders' and "Hermansky-Pudlak syndrome" and "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 observations lead some experts to conclude that platelet function defects are actually quite common and should be tested for concurrent with or soon after testing for VWD [28,29].

Vascular purpuras — Screening tests usually are normal in patients with bleeding disorders related to vascular abnormalities. (See "Evaluation of purpura in children", 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 side 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

Undetermined etiologies — Patients with a significant bleeding history for which no explanation exists are occasionally encountered. Physical abuse of the child should be considered in such cases (see "Physical child abuse: Diagnostic evaluation and management"). However, some disorders of hemostasis may escape detection with the available methods.

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

●The evaluation of a bleeding child begins with a careful history, taking into account the child's age, sex, clinical presentation, past history, and family history. Bleeding into the skin and mucous membranes is characteristic of disorders of platelets or their interactions with blood vessels, while coagulation disorders classically feature musculoskeletal (ie, muscle and joint) and soft tissue bleeding. The nature and extent of the injuries producing bleeding symptoms should be noted. (See 'History' above.)

●A reasonable initial screening evaluation includes complete blood count (including platelet count), examination of the peripheral blood smear, prothrombin time (PT), and activated partial thromboplastin time (aPTT). At the author's center, we also measure a fibrinogen level. Normal values may vary with age and among different laboratories (table 3). The results of the initial testing help differentiate among the different diagnostic possibilities in the child with bleeding symptoms (table 2 and algorithm 1 and algorithm 2). (See 'Initial testing' above and 'Diagnostic approach' above.)

●Further testing of specific coagulation factors depends upon the history and initial laboratory testing. These tests often are performed in order to confirm a specific diagnosis of an inherited or acquired factor deficiency. (See 'Second tier testing' above.)

●If the initial screening evaluation is normal and suspicion remains high for a bleeding disorder, diagnostic possibilities include von Willebrand disease (VWD), some forms of mild hemophilia, platelet function disorders and fibrinolytic disorders (including factor XIII deficiency), and additional testing (or consultation with a hematologist) should be pursued. Vascular abnormalities (eg, Ehlers-Danlos syndrome or hereditary hemorrhagic telangiectasia) and physical abuse should also be considered. (See 'Normal initial testing' above.)

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