Parents bringing their children to pediatricians and other primary care providers with concerns of abnormal bleeding or easy bruising is a relatively common occurrence. It can be difficult for physicians to distinguish if the symptoms are truly abnormal or are just part of “being a kid.” Are those areas of ecchymosis truly abnormal in size or quantity, or does the patient have mild hemophilia? Are episodes of epistaxis due to allergic rhinitis or mechanical trauma from nose picking, or does the patient have dysfibrinogenemia? Are menstrual periods abnormally heavy and excessive, or does the patient have von Willebrand disease? It is important for clinicians to recognize abnormal symptoms and to develop a diagnostic approach due to the diverse range of diagnostic possibilities for inherited or acquired bleeding disorders. Specific diagnosis leads to determining optimal hemostatic management. Patients with more severe bleeding disorders may require prophylaxis for optimal hemostatic management, in addition to episodic hemostatic management for times of increased bleeding risk such as with surgical procedures or with trauma, whereas children with mild bleeding disorders may only require episodic treatment. How to develop a clinical approach to evaluate clinical questions like these will be covered in this review.
Bleeding disorders can be inherited or acquired and can be conceptualized as disorders of primary or secondary hemostasis. Primary hemostasis is the process of forming an initial platelet plug at the site of endothelial injury. Primary hemostatic disorders encompass those of platelet or von Willebrand factor (VWF) dysfunction or deficiency. Secondary hemostasis is the process of coagulation activation leading to thrombin generation and ultimately the formation of cross-linked fibrin. Secondary hemostatic disorders include coagulation factor and other rare factor deficiencies (Table 1). In general, disorders of primary hemostasis manifest with clinical symptoms of mucocutaneous bleeding, whereas those disorders of secondary hemostasis, such as hemophilia, may manifest with muscle, joint, or other more severe bleeding.
Obtaining a detailed medical, bleeding, and family history is essential to the initial evaluation of a child with abnormal bleeding. Age is an important consideration, as many inherited severe bleeding disorders will clinically manifest in infancy or as a toddler. Common hemostatic challenges in infancy and early childhood include circumcision, tonsillectomy, adenoidectomy, and epistaxis. Those children with severe bleeding disorders may present with other bleeding symptoms early in life such as prolonged umbilical stump bleeding or intracranial hemorrhage. However, some children with milder underlying inherited bleeding disorders will not present until later in childhood or adolescence, such as with heavy menstrual bleeding or excessive bleeding with trauma or other surgeries. Acquired bleeding disorders such as immune thrombocytopenic purpura (ITP) can occur at any age, and abrupt development of petechiae, purpura, spontaneous ecchymosis, and other bleeding can also occur.1
The child's sex is another important consideration in certain bleeding disorders, such as males primarily affected in hemophilia A (Factor VIII deficiency),2 hemophilia B (Factor IX deficiency),2,3 and X-linked thrombocytopenia and Wiskott-Aldrich syndrome.4 Although other inherited or acquired bleeding disorders can occur in both males and females, some such as von Willebrand disease (VWD), presentation for clinical evaluation in females is more commonly due to heavy menstrual bleeding.5
The child's general medical history is also important, as it may provide additional insights to the etiology of underlying conditions with associated bleeding symptoms. For example, recurrent or persistent fevers, weight loss, night sweats, fatigue, generalized pain, adenopathy, spontaneous ecchymosis, and petechiae may suggest malignancy with associated coagulopathy. Poor growth, malabsorption, and liver disease may signal an underlying inborn error of metabolism, and the child may have bleeding symptoms from a related coagulopathy due to poor liver synthetic function. A critically ill child may have sepsis and secondarily develop a consumptive coagulopathy with thrombocytopenia, and additionally have uremia that further contributes to platelet dysfunction. Various medications and antibiotics may lead to secondary thrombocytopenia or platelet function defects. Poor diet and antibiotic use may contribute to vitamin K deficiency, causing impaired synthesis of vitamin K-dependent coagulant and anticoagulant factors.
The bleeding type, severity, and pattern are vital aspects to determine when gathering a detailed history. Mucocutaneous bleeding such as prolonged bleeding after dental procedures, epistaxis, heavy menstrual bleeding, spontaneous ecchymosis, petechiae, and gastrointestinal bleeding may signal a disorder of primary hemostasis such as VWD or platelet deficiency or dysfunction (Table 1). Alternatively, more severe bleeding manifesting as spontaneous or excessive hemorrhage into joints, muscles, soft tissues, and prolonged or delayed bleeding with surgical procedures, in addition to mucocutaneous bleeding, may suggest a coagulation disorder of secondary hemostasis (Table 1). In infancy, excessive or expanding cephalohematoma, intracranial hemorrhage, prolonged umbilical stump bleeding, or postcircumcision bleeding should prompt urgent hemostatic evaluation. Specifically, congenital afibrinogenemia or factor XIII deficiency may be signaled with prolonged bleeding from the umbilical stump.6
The timing of the patient's symptoms is vital for evaluation. The child's symptoms may occur in a matter of a few hours or days as with ITP1 or in critical illness, or symptoms may manifest over many months or years. Mild bleeding disorders may remain clinically silent until a child has a significant hemostatic challenge with surgery or trauma.
Determining if bleeding symptoms are abnormal or clinically significant can be a challenge. In more recent years, the development of bleeding assessment tools (BATs), which are clinical questionnaires to assess bleeding symptoms, have assisted with recognition of significant clinical bleeding.7 Further evaluation of the International Society on Thrombosis and Haemostasis (ISTH)-BAT determined a normal range of bleeding scores (BSs) for the tool in adult and pediatric patients, with an abnormal BS in adult males being ≥4, in adult females ≥6, and in children ≥3.8 Administration of the ISTH-BAT originally required an expert, but more recently a self-administered BAT has been developed and validated in VWD.9 This validated self-BAT showed comparable BS to the expert-administered ISTHBAT; however, this was investigated in a cohort of VWD patients with female predominance.9
Family history can provide critical clues regarding the inheritance of specific bleeding disorders. For example, hemophilia A or B are inherited in an X-linked recessive inheritance pattern with males being affected and females being carriers.2 Therefore, a maternal history of bleeding in a male relative, such as a maternal grandfather, should prompt consideration of hemophilia A or B in a male child being evaluated for bleeding. Similarly, as some females who are hemophilia carriers experience bleeding symptoms,10 hemophilia carrier status also could be considered in girls. Type 1 VWD is typically inherited in an autosomal dominant manner, although type 2 VWD variants may have autosomal dominant or recessive inheritance.11 Autosomal recessive bleeding disorders, such as factor XIII deficiency, may occur in instances of consanguinity.6 Typically, there is minimal ethnic predisposition to a particular bleeding disorder; however, there are some instances of specific bleeding disorders being more common in certain populations, such as factor XI deficiency among Ashkenazi Jews.12
A comprehensive physical examination is imperative for the evaluation of abnormal bleeding in children. Specific attention should be given to evaluate the skin for ecchymosis, petechiae, and purpura. Abnormal bruising pattern or shapes should raise concern for evaluation of nonaccidental trauma. However, ecchymosis in a premobile infant, such as “fingertip bruising” on an infant's trunk, may occur in severe hemophilia and highlights the importance of obtaining a careful past medical, bleeding, and family history. Mucocutaneous bleeding, such as epistaxis, may signal a primary hemostatic defect including VWD, platelet function defects, or platelet deficiency including acquired disorders such as acute ITP. Large hematomas, intramuscular hemorrhage, hemarthrosis, or evidence of chronic joint disease suggests hemophilia or other disorder of secondary hemostasis.
A secondary acquired bleeding disorder may be present in the context of other illnesses. Physical examination findings such as lymphadenopathy, hepatosplenomegaly, and pallor raise suspicion of malignancy. Right upper quadrant tenderness and jaundice may signal liver disease and associated coagulopathy. Nonhematologic physical examination findings such as oculocutaneous albinism may occur in Hermansky-Pudlak syndrome or Chediak-Higashi syndrome,13 skeletal defects may occur in thrombocytopenia with absent radii syndrome,4 and eczema and immunodeficiency may occur in Wiskott-Aldrich syndrome.4
Developing a stepwise approach for laboratory evaluation of hemostatic disorders is imperative to ensure an accurate and timely diagnosis is accomplished. Conceptualizing an initial hemostatic screen with evaluation of primary and secondary hemostasis assists in evaluating most common bleeding disorders (Table 2). Additionally, it is important to recognize that some hemostatic disorders may be missed with initial screening tests; therefore, having a strategy for advanced hemostatic testing is also beneficial, especially in instances where one has a high clinical suspicion of a bleeding disorder (Table 2).
Hemostatic Laboratory Evaluation
Evaluation of Primary Hemostasis
Initial evaluation of a bleeding disorder should begin with obtaining a complete blood count to exclude thrombocytopenia, as well as evaluate for other white blood cell (WBC) or red blood cell (RBC) abnormalities. The peripheral blood smear should be reviewed to determine additional information about platelet size, number, granularity, and clumping. It is important to note that automated cell counters commonly in use may underestimate platelet counts and report an inaccurate mean platelet volume when outside reference intervals. Pseudothrombocytopenia may occur as a result of platelets clumping in ethylenediaminetetraacetic acid (EDTA) collection tubes. In this scenario, repeating blood sample collection in citrate anticoagulant and comparing to EDTA can confirm pseudothrombocytopenia. Evaluation of the peripheral blood smear can reveal WBC abnormalities, such as malignant blasts suggestive of leukemia, and RBC abnormalities, such as schistocytes, which may signal microangiopathy with associated thrombocytopenia.
An initial screen of platelet function can be determined by the platelet function analyzer (PFA)-100, which is a whole blood platelet function screening assay.14 The PFA-100 can be conceptualized as replacing the archaic “bleeding time” measure. It consists of a blood sample being passed through a capillary with a microscopic aperture coated with collagen and epinephrine or adenosine 5′-diphosphate (ADP), and measuring the time needed for platelet adhesion, aggregation, and ultimate closure of the aperture.14 Prolongation of the collagen-epinephrine cartridge closure time is typically more sensitive to medication effects, such as aspirin,14 whereas prolongation of the collagen-ADP cartridge closure time is typically more sensitive to endogenous platelet function defects. It is important to note that more common mild platelet function defects may be missed on the PFA-100, thus necessitating more extensive evaluation with tests such as platelet aggregometry (Table 2).
VWD is the most common inherited bleeding disorder, affecting up to 0.1% to 1% of the general population.11 It is caused by deficiency or dysfunction of VWF, which mediates platelet and collagen binding at the site of vascular injury, as well as stabilization of factor VIII (FVIII) in circulation.11 A diagnostic approach to VWD is imperative, as although it is the most common inherited bleeding disorder, it is one of the most challenging to accurately diagnose.15 An initial VWF screen involves assessment of VWF antigen (VWF:Ag), VWF platelet-binding activity (VWF:ristocetin cofactor [RCo] or VWF:glycoprotein 1bM [GP1bM]), VWF collagen-binding activity (VWF:CB), as well as FVIII activity due to VWF being the chaperone for FVIII, stabilizing it in circulation (Table 2).11,15,16 Additional VWF activity assays can be done to evaluate for less common variant VWD (Table 2); however, a recent VWF multiplex activity assay was developed to perform multiple VWF activity assays on a single testing platform17 with further evaluation of the assay ongoing.
Evaluation of Secondary Hemostasis
The prothrombin time (PT) evaluates the extrinsic and common coagulation pathways (factors II [prothrombin], VII, V, X, fibrinogen). Time for platelet-poor plasma (PPP) mixed with tissue factor (tissue thromboplastin) containing phospholipid at 37°C and excess calcium chloride is measured and compared to age-specific laboratory reference intervals.18 The international normalized ratio (INR) is calculated from a ratio of the patient's PT to a normal control calibrated against an international sensitivity index depending on the type of thromboplastin used.19 A prolonged PT/INR suggests deficiency in factors II, VII, V, X, or fibrinogen. In clinical practice, mild factor VII deficiency may be the culprit for a prolonged PT/INR due to the short half-life of factor VII.6 and thus its sensitivity to variations in vita-min K intake. If this scenario is clinically suspected, one might consider an oral vitamin K challenge and subsequently repeat the PT/INR in a few days.
The activated partial thromboplastin time (aPTT) evaluates the intrinsic and common coagulation pathways (factors VIII, IX, XI, XII, V, X, II, fibrinogen).20 The aPTT is less sensitive to deficiencies of common factor pathways than the PT, and, therefore, an isolated prolonged aPTT with a normal PT suggests deficiencies in factors VIII, IX, XI, and XII. For the aPTT, time for PPP incubated at 37°C with the addition of phospholipid, a contact activator, and calcium is measured and compared to age-specific laboratory reference intervals. A prolonged aPTT is the most common screening test to signal a male patient may have hemophilia A or B. It is important to note that mild factor VIII, IX, or XI deficiency may be missed with an aPTT in the normal reference range; therefore, respective factor assays should be performed if there is a strong clinical suspicion for hemophilia in a given patient. Factor XII deficiency may cause the laboratory phenomenon of a prolonged aPTT, but it is not associated with a clinical bleeding phenotype.21
Prolonged aPTT may also occur in the presence of inhibitors, which are antibodies affecting the assay or specific clotting factor, such as a lupus anticoagulant.22 A lupus anticoagulant or lupus-like inhibitor is commonly encountered from immune dysfunction corresponding to a recent infectious process. The inhibitor is typically self-limited and resolves in weeks to months. Additionally, a common cause of an isolated prolonged aPTT is heparin contamination from blood samples obtained from a central venous or arterial catheter. Therefore, obtaining a proper sample and ensuring the test was completed properly should be part of the initial considerations.
If PT or aPTT is truly prolonged, prior to completing the corresponding specific factor activity assays, one should perform a 1:1 mixing study of the PT or aPTT. In this laboratory test, the patient's plasma is mixed with normal control plasma in a 1:1 ratio. If the PT or aPTT normalizes, it suggests there is a specific factor deficiency (Table 2). If the mixing does not correct, it signifies the presence of an inhibitor. Specialized testing is available to identify and quantify specific factor inhibitors.
A thrombin time, which involves the addition of thrombin to PPP, may be completed to evaluate the conversion of fibrinogen to fibrin; however, this may also be accomplished through measuring the fibrinogen activity.23 Measuring fibrinogen activity is an acceptable strategy as this test will show deficiency in afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemia.23
Evaluation of Rare Disorders of Hemostasis
Factor XIII deficiency is a rare bleeding disorder that can be associated with severe bleeding including intracranial hemorrhage and prolonged umbilical stump bleeding in neonates, defective wound healing, and recurrent miscarriages.6,24 Factor XIII deficiency will not be detected on the aforementioned coagulation assays. Therefore, additional tests such as the urea clot lysis test or specific factor XIII activity test must performed for evaluation.6 Additional tests such as the euglobulin lysis time,25 testing for plasminogen activator inhibitor type 1 (PAI-1),26 and alpha 2-anti-plasmin deficiency,27 can evaluate for disorders of fibrinolysis.
Other less conventional test of hemostasis, such as thromboelastography, are also finding their way into clinical practice.28 Evaluation of prekallikerin and high-molecular-weight kininogen are additional tests that can cause aPTT prolongation but are not typically associated with a clinical bleeding phenotype. Additionally, genetic testing is sometimes performed in evaluation of hemostatic disorders but is usually done after corresponding hemostatic activity tests results are abnormal and is used to refine the diagnosis.