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C H A P T E R 29

Approach to the Child with a Suspected Bleeding Disorder

Brian Branchford and Jorge Di Paola

INTRODUCTIONCLINICAL EVALUATIONClinical Presentation of BleedingRelevant Clinical HistoryAge of OnsetFamily Bleeding HistoryMedications

PHYSICAL EXAMINATIONLABORATORY EVALUATIONSample Collection and Technique and Preanalytical

VariablesScreening TestsGlobal Tests for the Evaluation of BleedingBLEEDING IN THE CRITICALLY ILL CHILD

C H A P T E R O U T L I N E

INTRODUCTIONBefore initiating the laboratory workup of any patient with a suspected defect of hemostasis, the hematologist must first verify that the patient has a clinical history, signs, and symptoms compatible with a bleeding disor-der. This is not an easy task because mild bleeding and bruising are common in the general population. Fur-thermore, bleeding, particularly in the outpatient setting, is difficult to quantify because patient reports may be biased; the definition of “excessive” bleeding or bruising is subjective and varies among individuals. Additionally, a critical consideration in children is the fact that many of them have not had specific hemostatic chal-lenges such as surgeries or menarche that might unveil a bleeding disorder. All these factors contribute to the dif-ficulty in the diagnosis of bleeding in the pediatric population.

Therefore, an accurate diagnosis is made primarily by obtaining a thorough personal and family history and then performing a careful physical examination, which will lead to an appropriate set of laboratory tests. Once suspicion for a bleeding disorder is confirmed, the remain-ing workup items are implemented in a focused manner with reference to particular differential diagnoses.

Children with suspected bleeding disorders might present for evaluation in a variety of ways: concerning signs and symptoms, abnormal presurgical screening laboratory results, or a known family history of hemo-stasis defects that requires consultation. The variety in severity of different bleeding disorders also results in

children presenting at different ages. The goal for the consulting hematologist is to approach the child with a broad differential diagnosis in mind, narrow the options by carefully assessing the medical and family history as well as pertinent physical findings, and order the most appropriate laboratory tests to reach a diagnosis and initiate definitive therapy, if indicated.

Although the approach to the bleeding child is often similar in the outpatient and inpatient setting, the practic-ing hematologist is sometimes consulted because of bleed-ing in the critically ill patient. In such cases therapeutic measures will likely be required immediately and an accu-rate diagnosis made later.

CLINICAL EVALUATIONThe initial clinical evaluation of a child with a suspected bleeding disorder starts with a series of questions, usually at a doctor’s office or clinic, that attempt to summarize the most important aspects of the clinical presentation and history of bleeding. Although several standardized bleeding assessment tools have been used recently in research projects, their value in clinical practice is still unproven. Therefore, questions should be designed to establish certain parameters that would prompt an appro-priate laboratory workup. The initial set of questions should establish the following: (1) the most common site and type of bleeding (e.g., mucocutaneous versus articu-lar or deep muscle), (2) bleeding on hemostatic challenge such as surgeries or trauma, and (3) family history of bleeding.

1000 SECTION IX HEMOSTASIS

however, have found an incidence as high as 25%6 to 33%7 for coagulopathy among children referred to pedi-atric hematologists for recurrent epistaxis. Therefore it is important that epistaxis be taken seriously as a presenting symptom, particularly in cases that require emergency medical care, occur in both nostrils, or appear in associa-tion with other bleeding signs or a family history of similar bleeding.

Menorrhagia is also a frequent presenting sign for mild or moderate bleeding disorders (including VWD, platelet function disorders, and other coagulopathies)3 and can quickly lead to severe anemia and decreased quality of life. The classic definition of menorrhagia (i.e., greater than 80 mL of blood loss per cycle) is rarely used clini-cally8 because most women describe limitations of their daily activities as more important than the actual volume of blood lost.9 A more popular working definition is “excessive cyclic uterine bleeding that occurs at regular intervals over several cycles, or prolonged bleeding that lasts for more than 7 days”.10 In fact, the American College of Obstetrics and Gynecology has recommended that testing for VWD be performed in all adolescents with severe menorrhagia,11 although a subsequent meta-analysis determined that there may not be adequate data to support this universal recommendation.12 It is essential for practitioners to be judicious about laboratory testing in adolescents with menorrhagia. All adolescents that present with menorrhagia should be evaluated by a gyne-cologist; testing for a bleeding disorder is not always warranted, particularly in the absence of family and per-sonal history or other bleeding manifestations.

Surgical (e.g., circumcision, tonsillectomy) or dental (e.g., extractions) bleeding also may be associated with disorders of hemostasis. This type usually manifests as uncontrolled bleeding during or after the procedure, bleeding that extends beyond the surgical site, unexpected need for blood transfusion, or delayed bleeding after a procedure.3

Hereditary hemorrhagic telangiectasia may also be manifested as mucosal bleeding, particularly epistaxis. Profuse bleeding into soft tissues or joints suggests defi-ciency of a coagulation factor (such as factors VIII or IX). Umbilical stump bleeding is typically seen with factor XIII deficiency, but it may also occur with deficiencies of prothrombin, factor X, and fibrinogen.13

After establishing the possibility of a true bleeding disorder, the clinician should next consider a broad dif-ferential diagnosis for the bleeding child and approach the history taking and physical examination with the intent to systematically remove options and pare down the list to a certain category or group of potential dis-eases. Briefly, the main categories to be considered should include anatomic abnormalities, quantitative and qualita-tive platelet defects affecting platelet plug formation (primary hemostasis), and quantitative and qualitative defects of clot propagation (secondary hemostasis). Dif-ferentiation also must be made between inherited and acquired disorders. Common diseases should be consid-ered before rare ones, and diagnoses that are either life threatening or easy to treat should be prioritized in the evaluation process.

Clinical Presentation of BleedingSignificant surgical or postoperative hemorrhage, rectal or genitourinary bleeding, and major muscle or joint bleeding are easily identified as abnormal, but they rep-resent a minority of new cases. Most often the clinician’s challenge consists in differentiating mild but common presenting symptoms of bleeding disorders, such as easy bruising and mucosal bleeding (e.g., epistaxis, menor-rhagia, oropharyngeal), from those encountered in healthy children and then determining when additional laboratory evaluation is warranted. Large bruises without previous significant trauma, disseminated petechiae, intramuscular hematomas, hemarthrosis (joint effusion, warmth, and pain with passive movement) usually indi-cate a bleeding disorder. In young children, refusal to walk is often a sign for an extremity-related bleed and could represent the first sign of hemarthrosis in a boy with hemophilia (Table 29-1).

Susceptibility to increased bruising must first be dif-ferentiated from nonmedical causes such as abuse, a phe-nomenon that is, unfortunately, common enough to warrant its own set of guidelines for evaluation in recent reports from the American Academy of Pediatrics.1,2 Inflicted trauma is most likely to manifest over the head, chest, back, and long bones (and may retain the outlines of the instrument used to inflict harm), whereas bruises associated with primary hemostasis defects are usually located over areas of typical childhood trauma, such as bony protuberances of extremities or spinous processes.3

Epistaxis is a frequent presenting sign in children with hemostatic disorders, but it is also a common complaint among healthy children, usually the result of local aggra-vating factors (dry nasal mucosa, trauma, allergic rhini-tis).4 In a recent study of 248 children referred to the otolaryngology clinic at Children’s Hospital of Philadel-phia for epistaxis, 11% were found to have a bleeding disorder (type 1 von Willebrand disease [VWD], platelet aggregation defect, or mild factor VII deficiency), with clinical predictive factors being younger age or previous emergency medical care for the epistaxis.5 Other studies,

TABLE 29-1 Differences in Clinical Manifestations of Primary Hemostatic Defects and Clotting Factor Deficiencies

Clinical Characteristic

Primary Hemostatic Defect

Clotting Factor Deficiency

Site of bleeding Skin, mucous membranes

Soft tissues, muscles, joints

Bleeding after minor cuts

Yes Rare

Petechiae Present Absent

Ecchymosis Small, superficial Large, deep, palpable

Hemarthrosis Rare Common

Bleeding after trauma/surgery

Immediate Delayed

29 APPROACH TO THE CHILD WITH A SUSPECTED BLEEDInG DISORDER 1001

presentation. A sick child with fever, shock, and muco-cutaneous purpura may have disseminated intravascular coagulation (DIC) associated with bacteremia. Hemo-philia should be considered in a male toddler who has just started crawling and exhibits subcutaneous or joint bleeding, or who bleeds after circumcision. A girl who has had severe menorrhagia since menarche may have VWD. A well-appearing child covered with petechiae likely has immune thrombocytopenia, but if the lesions are localized to the buttocks, ankles, and feet, and they present as palpable bruises, Henoch-Schönlein purpura should be considered.

When applicable, a detailed menstrual history, includ-ing age at menarche, duration of menses, interval between menses, and frequency of pad or tampon replacement necessary to control the bleeding, should be obtained. The prevalence of bleeding disorders in women with men-orrhagia is as high as 20%, and menorrhagia is a common initial symptom in women with VWD (approximately 90% of female patients).22-26

It is also important to note whether the patient has an underlying medical disorder that may affect hemostasis, such as hepatic or renal disease, malabsorption syndrome, or Ehlers-Danlos syndrome (EDS) or another connective tissue disorder.27 Most of the coagulation proteins are synthesized in the liver, and as a result, liver insufficiency is a common cause of prolongation of clotting times and bleeding.28,29 Certain metabolites that accumulate in uremia can interfere with platelet function,30,31 whereas low-molecular-weight coagulation proteins (factors IX and XI) are lost through the kidney in children with nephrotic syndrome.32 In malabsorption syndrome, levels of the vitamin K–dependent coagulation factors (II, VII, IX, and X) may be depleted and lead to excessive bleed-ing.33,34 A child with cyanotic congenital heart disease and polycythemia may have petechiae and excessive bleeding with surgery, in part as a result of thrombocytopenia, hypofibrinogenemia, or both.35

Age of OnsetIt is also important to investigate the age of onset of clini-cal bleeding. Generally, early age of onset correlates with more severe bleeding and may indicate a congenital cause. Bleeding that develops later in childhood may indicate either an acquired problem or a milder congenital bleed-ing disorder. For example, mild hemophilia may not be diagnosed until late childhood or adolescence, when participation in contact sports presents an increased hemostatic challenge.36,37 Postcircumcision hemorrhage, umbilical stump bleeding, cephalohematomas, and sub-galeal hemorrhage are cardinal manifestations of under-lying bleeding disorders and should be evaluated thoroughly. The incidence of neonatal intracranial hem-orrhage among boys with hemophilia is estimated to be as high as 3% and may be as high as 25% in patients with FXIII deficiency.3

The neonatal period (first 4 weeks after delivery) is a time of unique transitional physiology, which includes the coagulation system. The neonate has physiologically decreased levels of most procoagulant and anticoagulant proteins (although levels of acute phase reactants, such

Finally, it is clear that the clinical assessment and the laboratory workup of the bleeding child will vary depend-ing on the emergent nature of the clinical situation. The practicing hematologist is often consulted in the inpatient setting regarding bleeding in the intensive care unit or operating room. The approach in these situations is sometimes limited by the inability to obtain reliable base-line hemostatic laboratory values because of the presence of active disease or the fact that most patients receive hemostatic agents (including blood products) to stop the hemorrhage. Therefore it becomes difficult to distinguish congenital bleeding conditions frin acquired ones. Often the immediate need for treatment supersedes a more thor-ough evaluation. In these cases it is reasonable to treat the patient and then, if a baseline defect of hemostasis is suspected, perform the laboratory evaluation days or even months after the episode, when the acute process is resolved.

Relevant Clinical HistoryInformation about the patient’s previous response to hemostatic challenges (e.g., surgical procedures, invasive dental work, traumatic injuries) is an essential part of the initial evaluation. For example, a congenital hemorrhagic disorder is unlikely in a patient with a history of surgical procedures or tooth extractions without any abnormal bleeding, whereas postoperative transfusion requirements and iron-responsive anemia often signal hemostatic defects. In view of the variability of patients’ perception of bleeding, as well as the lack of a uniform clinical measure of bleeding severity, the history may be most discriminatory when a standardized and validated ques-tionnaire is used and a “bleeding score” is incorporated into the diagnosis.14,15 Several such instruments currently exist, but consensus on a single questionnaire that can quantitate bleeding optimally is still evolving.16-18 The International Society of Thrombosis and Hemostasis (ISTH) Joint Scientific Subcommittee (SSC) on von Wil-lebrand factor (VWF) and Pediatric/Perinatal Bleeding Disorders recently developed a bleeding assessment tool to provide more accurate determination of bleeding phe-notype in individuals with bleeding disorders and com-pared them to healthy subjects.19 The main objective of all the existing bleeding assessment tools is to accurately diagnose bleeding and predict the risk of bleeding in the future. However, owing to their high negative predictive value, it is becoming increasingly clear that these new instruments are more effective at excluding the likelihood of a bleeding disorder than predicting future bleeding risk. Family history is also a key component in establish-ing both the likelihood of an inherited bleeding disorder and its specific nature. However, determination of which family members may have been affected by relying on testimony from one or more relatives can be difficult. Therefore the ISTH SSC on VWF has a specific definition of a positive family history for VWD.20 In summary, a personal history of bleeding triggers clinical and labora-tory evaluation, and a positive family history serves as supportive evidence for a hereditary bleeding disorder.21

The history of the present illness often provides useful clues to the diagnosis, including several classic types of

1002 SECTION IX HEMOSTASIS

as factor VIII and fibrinogen, are normal), and thus the hemostatic system can be easily overwhelmed, potentially during the significant head trauma associated with labor and vaginal delivery. One study reported intracranial hemorrhage (ICH) after spontaneous vaginal delivery at a rate of 1 per 1900, whereas the rate of ICH in babies delivered by vacuum-assisted delivery was 1 in 860.38 In addition, 15% to 30% of patients with inherited bleeding disorders have bleeding manifestations in the neonatal period,39 and certain disorders, such as neonatal alloim-mune thrombocytopenia (nAIT), are unique to the neo-natal period. Furthermore, the neonate is significantly affected by the state of maternal health and medications used during labor. Because of the small blood volume in a neonate, a relatively small degree of blood loss can have major hemodynamic consequences.

When evaluating bleeding in a neonate, the hematolo-gist must first assess whether the baby is healthy or has medical conditions that may have precipitated hemor-rhage. It is important to inquire about prolonged rupture of membranes, chorioamnionitis, and fetal distress during labor. Additional details about the mother’s state of health, including infections, autoimmune disease, and platelet count, should be obtained. Vitamin K administra-tion to the baby should be confirmed. The neonate should be examined, with particular attention directed to the presence of birth trauma, bruises, and petechiae and evi-dence of flank masses (renal vein thrombosis), which can cause thrombocytopenia. The presence of hepatospleno-megaly may suggest disseminated intrauterine infection. When blood is obtained for various coagulation tests, particular attention should be paid to the patient’s hema-tocrit concentration and the volume of the sample. Addi-tionally, all laboratory results should be compared with normal values for different gestational ages.40,41

Isolated thrombocytopenia in a healthy infant may be seen in nAIT, in maternal autoimmune thrombocytope-nia, or in cases of decreased platelet production such as amegakaryocytic thrombocytopenia or the syndrome of thrombocytopenia with absent radii. Rarely, type 2B VWD may be manifested as thrombocytopenia in a well infant. Thrombocytopenia in sick neonates is often due to the underlying cause, such as infection or DIC. Isolated prolongation of the prothrombin time (PT) or activated partial thromboplastin time (APTT) in a healthy baby may be caused by a specific clotting factor deficiency in the extrinsic or intrinsic pathway, respectively, and pro-longation of both the PT and APTT suggests either a common pathway clotting factor deficiency or vitamin K deficiency (hemorrhagic disease of the newborn). The so-called early vitamin K deficiency–associated bleeding usually presents in the first week of life and is associated with nutritional deficiencies or failure to administer vitamin K at birth, whereas late vitamin K deficiency bleeding occurs between 3 and 8 weeks after birth and may manifest as intracranial hemorrhage or severe gas-trointestinal bleeding.42

Family Bleeding HistoryThe family history is essential for assessing differential diagnoses. The hematologist should inquire about any

known or suspected bleeding problems in other family members, including any specific diagnoses. If the family history is positive for bleeding, the hematologist should note the type and severity of bleeding (e.g., joint bleeding, epistaxis, menorrhagia), age at onset, and the relationship of the affected family member or members to the patient. An X-linked recessive inheritance pattern (maternal cousins, uncles, and grandfather) suggests a diagnosis of hemophilia A or B,43 whereas an autosomal dominant pattern would be more consistent with VWD or heredi-tary hemorrhagic telangiectasia. Most other clinically relevant clotting factor deficiencies are inherited in an autosomal recessive manner, and the family history is frequently negative for bleeding, although consanguinity may be noted.

Approximately one third of infants and young chil-dren with newly diagnosed hemophilia have a negative family history,3 consistent with the Haldane hypothesis for the fraction of new mutations in all lethal X-linked recessive disorders.44,45 For VWD, considerable variation in symptoms may be noted among affected family members because of the incomplete penetrance (i.e., not every person that inherits the mutation will exhibit an abnormal phenotype) and variable expressivity (i.e., family members with the same mutation have a variable phenotype) that are hallmarks of this disease. Bleeding manifestations may be very mild in some and give the misleading impression of a negative family history. Factor XI deficiency, an autosomal trait most often (but not exclusively) seen in persons of Ashkenazi Jewish descent, may be associated with a very mild or moderate tendency for bleeding. The degree of bleeding manifesta-tions does not correlate well with the level of factor XI or the APTT, although the patient’s specific mutation may be predictive.46,47

MedicationsA careful history of medication use should be obtained, including prescribed medications, over-the-counter drugs, recreational drugs, and herbal products.48 A number of drugs are associated with bleeding diatheses, with mechanisms including induction of thrombocytopenia (e.g., quinine or quinidine, rifampin, trimethoprim-sulfamethoxazole, carbamazepine, cimetidine, ranitidine, valproic acid)49-52 and platelet dysfunction (nonsteroidal antiinflammatory drugs [nSAIDs] such as ibuprofen [reversible effect] and aspirin [irreversible]).53,54-57 In the case of medications that cause platelet dysfunction, it is important to note that they primarily exacerbate preexist-ing bleeding disorders rather than cause clinically relevant bleeding by themselves. In addition, prolonged antibiotic use may lead to lower vitamin K levels and induce bleeding secondary to acquired deficiency of vitamin K–dependent factors. Table 29-2 lists medications, com-pounds, and herbal supplements known to be associated with bleeding.

PHYSICAL EXAMINATIONA thorough physical examination must begin with an evaluation of the vital signs, with particular emphasis on

29 APPROACH TO THE CHILD WITH A SUSPECTED BLEEDInG DISORDER 1003

TABLE 29-2 Compounds that Decrease Platelet Number and/or Function

Effect Compound Class Examples Mechanism

Platelet dysfunction

COX-1 inhibitors Aspirin, ibuprofen, naproxen Inhibit conversion of AA to thromboxane A2

Thienopyridines Clopidogrel, prasugrel, ticagrelor, cangrelor Inhibit ADP-induced platelet activation

Phosphodiesterase inhibitors

Dipyridamole, cilostazol Increased cAMP decreases agonist-induced activation

GPIIb/IIIa inhibitors Abciximab, tirofiban, eptifibatide Inhibit integrin activation and conformational change

β-Lactam antibiotics Cephalosporins, penicillins (esp. in high doses) Inhibit epinephrine- and ADP-induced aggregation and granule release. Also, interference with platelet-VWF interaction

SSRIs Fluoxetine, olanzapine, citalopram, sertraline, escitalopram

Decrease platelet serotonin

Herbs and foods Ginkgo (Ginkgo biloba)Garlic (Allium sativum)Bilberry (Vaccinium myrtillus)Ginger (Zingiber officinale)Dong quai (Angelica sinensis)Feverfew (Tanacetum parthenium)Asian ginseng (Panax ginseng)American ginseng (Panax quinquefolius)Siberian ginseng/eleuthero (Eleutherococcus senticosus)Turmeric (Curcuma longa)Meadowsweet (Filipendula ulmaria)Willow (Salix alba)Black tree fungus (Auricularia polytricha)

Various

Alcohol Alcohol Decrease P-selectin exposureOther Amitriptyline, imipramine, chlorpromazine, cocaine,

lidocaine, isoproterenol propranolol, penicillin, ampicillin, cephalothin, promethazine, diphenhydramine, carbenicillin

Interfere with platelet membrane

Furosemide, verapamil, hydralazine, cyclosporine, hydrocortisone

Inhibit prostaglandin pathways

Caffeine, dipyridamole, aminophylline, theophylline, vinblastine, vincristine, colchicine, papaverine

Inhibit platelet phosphodiesterase

Thrombocytopenia Antiepileptic drugs Phenytoin, valproate, carbamazepine UnclearGlycoprotein IIB/IIIa

inhibitorsAbciximab Drug-dependent antibody

Anticoagulants Unfractionated heparin (more common) low-molecular-weight heparin (less common)

Drug-dependent antibody

Foods Quinine, white lupin, tahini, jui herbal tea Various

AA, Arachidonic acid; A2, annexin 2; ADP, adenosine diphosphate; cAMP, cyclic adenosine monophosphate; COX, cyclooxygenase-1; GP, glycoprotein; SSRI, selective serotonin reuptake inhibitors; VWF, von Willebrand factor.

potential signs of severe bleeding-related anemia or intra-vascular volume loss, such as tachycardia (early finding) or hypotension (late finding). next, a global overview should be undertaken to observe the pattern of bleeding stigmata. Petechiae are small capillary hemorrhages and characteristically develop in crops in areas of increased venous pressure, such as dependent parts of the body or those compressed by elastic waistbands, sock tops, or straps (e.g., from backpacks, purses, luggage). They are painless, nonpalpable, and nonblanching and must be distinguished from small telangiectases and angiomas. In general, the presence of petechiae indicates a defect in primary hemostasis (platelet number or function or vas-cular integrity). Ecchymoses are palpable purplish lesions induced by subcutaneous bleeding and usually indicate a defect in secondary hemostasis (clot propagation), such as deficiency of a coagulation factor. Additionally, hemarthrosis, associated with severe coagulation factor

deficiency, should be evaluated for joint size, swelling, and range of motion limitations. Identification of hepa-tomegaly and splenic enlargement may point toward coagulopathy associated with systemic disorders such as leukemia or hepatocellular disease.

Knowledge of the bleeding manifestations of certain syndromes can help the hematologist efficiently evaluate children with known syndromes. Conversely, the hema-tologist’s identification of a particular bleeding pattern may pave the way to an important syndrome diagnosis that can guide other system-based evaluation or interven-tions earlier than would otherwise be possible. For example, it is important for the hematologist to know that patients with noonan syndrome can have thrombo-cytopenia, platelet function defects, and prolonged APTTs secondary to abnormalities of the intrinsic pathway (defi-ciencies of FVIII, FIX, FXI).58,59 Another example is the importance of recognizing bleeding related to skin or

1004 SECTION IX HEMOSTASIS

When tubes with various anticoagulant types are used, the citrate tubes should be collected before ethylenedi-aminetetraacetic acid–containing or heparin-containing tubes to avoid the potential for carryover.69

Once the tube is filled, the anticoagulated blood should be gently mixed by inversion three to four times, sent to a special coagulation laboratory without delay, and tested within 2 hours of collection if maintained at room tem-perature or within 4 hours if kept cold. Samples with visible hemolysis or clots should be discarded. Plasma samples must be frozen if they are not tested within this time frame. When they are to be analyzed, frozen samples should be rapidly thawed at 37° C and tested immedi-ately. normal values differ from one laboratory to another and between instruments and reagents. Thus the values obtained should be compared with the age-appropriate normal range for that particular laboratory.

Screening TestsA focused history and physical examination may lead the physician to obtain certain assays immediately, in order to identify common disorders, life-threatening situations, or easily treated conditions. However, if the initial evalu-ation does not suggest a specific disorder, a panel of screening tests should be ordered, including a complete blood count with evaluation of platelet number, size, morphology, PT, APTT, and thrombin time (TT) to help in the process of differential diagnosis. Although screen-ing tests represent a very important part of the initial laboratory evaluation, they are usually neither predictive nor confirmatory of bleeding. Therefore, if a specific bleeding disorder is suspected, the laboratory evaluation should be directed to that specific disorder. These prin-ciples are illustrated in Figure 29-1, which provides an algorithm representing the general approach to working up clinically significant mucocutaneous bleeding.

Prothrombin TimeThe PT is performed by adding a thromboplastin reagent that contains calcium chloride to the citrated plasma sample. The time required for clot formation is recorded with an automated instrument that signals the end point, as defined by optical or electromechanical change. The normal (reference) range varies depending on the labora-tory (its instrumentation and the lot of thromboplastin), but it is generally 10 to 11 seconds. The PT measures the activities of factors I (fibrinogen), II (prothrombin), V, VII, and X. Prolongation of the PT beyond the reference range is not generally seen until the functional level of one of these factors is less than 30% or until fibrinogen is less than 100 mg/dL. Isolated prolongation of the PT may reflect factor VII deficiency. Though rare, the PT can also be prolonged by a circulating inhibitor to one of the involved clotting factors or by the presence of abnormal fibrinogen molecules or fragments in the circulation.

The PT is also quite useful for monitoring the effect of coumarin-type anticoagulants. When the PT is used to monitor a patient taking warfarin, differences in the sensitivities of different thromboplastin preparations in different laboratories need to be taken into account. This consideration has led to the development of a

vascular fragility as a potential manifestation of heritable connective tissue disorders such as EDS.27 The molecular basis for bleeding in these syndromes is not well under-stood, but the clinical association between these syn-dromes and excessive hemorrhage is strong enough to warrant a careful investigation.

LABORATORY EVALUATIONSample Collection and Technique and Preanalytical VariablesA properly drawn blood sample is crucial for adequate interpretation of coagulation test results.60,61 Many labo-ratories develop independent ranges, controlling for pre-analytic variables (patient posture, medical condition, lipid levels, hormones, mental and physical stress, activity before blood draw, tourniquet time, proper tube filling, specimen processing, and transport conditions).62 Prefer-ably, subjects should be fasting and should have refrained from smoking, caffeine, or alcohol ingestion, and they should not have taken any medications known to affect platelet function (see Table 29-2) on the day of testing; for some medications, such as aspirin and nSAIDs, the period of abstinence should be at least 2 weeks.63 Herbal remedies, garlic, and alcohol may also cause acquired mild platelet dysfunction.53 Blood for coagulation assays should be obtained by venipuncture performed by an experienced phlebotomist using a 19- to 21-gauge needle.60,61 Drawing samples from an indwelling catheter often results in sample contamination with heparin or intravenous fluids and spuriously abnormal values. Improper sample collection is one of the most common reasons for falsely prolonged clotting times.64-66 The total tourniquet time should be less than 3 minutes.67

The initial 1 to 2 mL of blood should be drawn into a waste tube to prevent activation of the test sample by tissue factor. Then blood is collected into citrated antico-agulant in an evacuated sample tube containing a fixed amount of buffered sodium citrate (3.2% preferred over 3.8% for coagulation assays) as anticoagulant in the ratio of one part citrate to nine parts whole blood.63,68,69 A clinically significant difference between glass and plastic tubes has not been identified.70 If the patient is polycy-themic (hematocrit ≥55%), the amount of plasma in the tube would be reduced in proportion to the citrate, thereby leading to falsely abnormal coagulation test results. In such circumstances the amount of citrated anticoagulant should be reduced proportionate to the high hematocrit.71,72 Conversely, anemia (hematocrit <25%) does not seem to significantly affect the accuracy of coagulation tests,73 but it does have an effect on some global assays of hemostasis such as the Platelet Function Analyzer (PFA-100) in which hemoglobin should be greater than 10 mg/dL (and platelets should be >100,000/µL) to provide proper biorheologic effect to bring platelets in contact with the agonist-coated periph-eral section of the device.63 For infants and children, small 3-mL tubes (2.7 mL blood to 0.3 mL citrate) are avail-able. Tubes of all sizes should be filled to at least 90% of the expected fill volume to prevent false elevation of clot-ting times from a disproportionately high citrate level.

29 APPROACH TO THE CHILD WITH A SUSPECTED BLEEDInG DISORDER 1005

be noted that the sensitivity and reproducibility of the APTT are highly dependent on the specific reagents used (particularly the activator in the partial thromboplastin reagent). With most APTT reagents, the APTT will not be prolonged until the amount of factor VIII is less than 35% (0.35 U/mL). The laboratory should establish a ref-erence range for each new lot of reagent and each new method of clot detection. The reference range will gener-ally be approximately 26 to 35 seconds for children and adults but longer (30 to 54 seconds) in term infants (and often even longer in premature infants).

The APTT is somewhat less sensitive than the PT to deficiency of the vitamin K–dependent factors (so mild deficiencies could be missed), but it is more sensitive to the presence of circulating anticoagulants and heparin. The APTT can detect circulating anticoagulants (e.g., lupus anticoagulants) and is routinely used to monitor standard heparin therapy.75 Among hospitalized infants or children, unintentional contamination of patient samples with heparin is a common cause of an unex-pected prolongation of the APTT that does not correct on mixing.

standardized method of expressing the prolongation as an international normalized ratio.

Activated Partial Thromboplastin TimeThe APTT is performed by adding a “partial thrombo-plastin” reagent, which is a source of phospholipids without tissue factor, to the patient’s citrated plasma sample, plus introducing controlled activation of the contact factors (factors XI and XII, prekallikrein, and high-molecular-weight kininogen) by preincubation with a surface-activating reagent (e.g., Celite, kaolin, silica, or ellagic acid).74 This mixture is incubated for 2 to 5 minutes before calcium chloride is added, and the time required for clot formation is recorded. As for the PT, automated instruments are generally used. The APTT measures factors I (fibrinogen), II (prothrombin), V, VIII, IX, X, XI, and XII; prekallikrein; and high-molecular-weight kininogen. Deficiency of any of the latter three factors can result in a markedly prolonged APTT in the absence of clinically significant bleeding. Isolated prolongation of the APTT in a patient with clinical bleeding is likely to result from a deficiency of factor VIII, IX, or XI. It should

Figure 29-1 A provider’s guide to the staged workup of clinically significant mucocutaneous bleeding. ADP, Adenosine diphosphate; aPTT, acti-vated partial thromboplastin time; ATP, adenosine triphosphate; CAMT, congenital amegakaryocytic thrombocytopenia; CBC, complete blood count; FDP/AML, familial platelet disorder with predisposition to acute myelogenous leukemia; ITP, immune thrombocytopenia; MPV, mean platelet volume; PT, prothrombin time; Rco, ristocetin cofactor test; TAR, thrombocytopenia with absent radii syndrome; TXA2, thromboxane A2; VWD, von Willebrand disease; VWF, von Willebrand factor.

Low Platelet Count

Low MPV

High MPV Normal MPV

Platelet Aggregation

Mixing studies correct, consider studying other

coagulation factor deficiencies (Factor XI

deficiency can present with mucocutaneous bleeding)

Type 3 VWDVWF:Ag absent VWF:Rco absent FVIII:C very low (� 5%) Multimers: absent VWF:Rco/VWF:Ag ratioN/A

ITPBernard-SoulierOther GP1b-IX-VSyndromesGiant Platelet SyndromesGATA1Platelet type VWDIf VWF low, Type2BVWD

Wiskott AldrichSyndromeX-linkedthrombocytopenia

Drug Induced, Malignancy/MetabolicFDP/AMLCAMTParis TrousseauTARTHC2

Normal Platelet Count (and no other abnormal labs including normal

VWF levels)

CBC with differential Blood smear

aPTT, PT, Fibrinogen

If PT, aPTTprolonged perform

mixing study

Type 1 VWDVWF:Ag lowVWF:Rco lowFVIII:C low or normal Multimers: Normaldistribution VWF:Rco/VWF:Ag ratio � 1

Type 2 VWDVWF:Ag lowVWF:Rco very lowFVIII:C low or normalMultimers: Loss of HMWM (or normal)VWF:Rco/VWF:Ag ratio normal to low

If normal labs and high clinical suspicion of VWD

order VWF levels

Abnormally low levels of VWF

Second wave Absent/ secretion

Hermansky-Pudlak Chediak-HigashiStorage Pool DefectSignal Transduction Defect R/O Aspirin Effect

Glanzmann’sThrombasthenia

Scott syndromeOther causes of bleeding

ADP receptor P2Y12TXA2 receptorADP/ATP receptor P2X1

Absent(except ristocetin)

Abnormal toADP & TXA2

VWDNormal

Normal

Clinically Significant Mucocutaneous Bleeding

1006 SECTION IX HEMOSTASIS

collagen/epinephrine (CEPI)-coated membranes with a small aperture (150 µm). Citrated blood is aspirated under high shear (5000 to 6000/sec) from the sample reservoir through a capillary tube onto the membrane, and blood flow is monitored through the aperture. Plate-lets begin to adhere and aggregate primarily through interactions with collagen under high shear, thereby resulting in closure of the aperture. The instrument moni-tors the drop in flow rate with time as the aperture gradu-ally occludes and records the final closure time (CT) with either cartridge. Although the test is reproducible between cartridge lots and instruments, each laboratory should establish normal control times. Citrate samples have been shown to be stable for up to 4 hours after sample collec-tion, but transport through a pneumatic vacuum trans-port or “tube” system is not recommended.

The test is sensitive to the platelet count, hematocrit concentration, platelet function, and VWF level and func-tion. Generally, a platelet count of less than 80 to 100 × 9/L or a hematocrit concentration of less than 30% leads to a prolonged CT.76 The PFA-100 CT is inversely pro-portional to the VWF levels and has been used by some as a screening test for VWD.77 In congenital platelet dis-orders, PFA-100 CT depends on the severity of the dis-order. Severe platelet function defects in glycoprotein Ib/V/IX (Bernard-Soulier syndrome or platelet-type VWD) and glycoprotein IIb/IIIa (Glanzmann thrombas-thenia) result in a markedly prolonged CT. In platelet-dense granule deficiency or secretion defects, the prolongation in CT is variable and is often seen in the CEPI cartridge. Thus, although the PFA-100 CT is abnor-mal in some forms of platelet disorders, the test does not have sufficient sensitivity or specificity to be used as a screening tool for platelet disorders in general.78 It is most consistently abnormal in severe platelet function disor-ders, in which clinical symptoms alone are significant enough to suggest the diagnosis. Additionally, PFA-100 CT may be altered by drugs that affect platelet function. Aspirin and other nSAIDs prolong the CEPI CT. The role of the PFA-100 in therapeutic monitoring is currently being investigated.78 Despite its wide use, the PFA-100 has not demonstrated great overall efficacy as a screening tool for mild to moderate bleeding disorders.

Specific TestsSpecific Coagulation Factors. Each of the coagulation factors of the intrinsic pathway (prekallikrein, high-molecular-weight kininogen, and factors VIII, IX, XI, and XII) can be measured by one-stage, APTT-based methods. A specific factor assay measures the clotting time of a mixture of diluted test plasma and a specific factor-deficient substrate plasma that supplies all factors except the one being measured.79 Though seldom per-formed in U.S. clinical laboratories, a chromogenic sub-strate assay kit for factor VIII (as well as chromogenic kits for certain other clotting factors) that is based on measuring the generation of factor Xa is also commer-cially available.

Each of the extrinsic and common pathway coagula-tion factors (V, VII, and X) can be measured by specific one-stage assays based on the PT. The patient’s diluted

Thrombin TimeThe TT measures the thrombin-induced conversion of fibrinogen to fibrin and is performed by adding bovine thrombin to the patient’s citrated plasma and recording the clotting time. The TT measures the amount and the clotting function of fibrinogen and is also prolonged in the presence of heparin or circulating fibrin degradation products (FDPs). An extremely prolonged TT usually indicates a heparin effect. Reptilase, a snake venom pro-tease, clots fibrinogen in the presence of heparin and thus can be used to identify heparin as the cause of a pro-longed TT. Thus in the presence of heparin the TT is prolonged, whereas the reptilase time is normal. Alterna-tively, it is possible to test for heparin activity by its anti–factor Xa activity or with the use of commercial heparinase. The sensitivity of the TT can be increased by dilution of the thrombin to give a control TT of 16 to 18 seconds.

Platelet CountThe normal platelet count (for all ages) ranges from 150,000 to 450,000 per microliter. Review of the plate-lets on a well-prepared stained blood smear should give a visual estimate that matches the laboratory’s printed value. A spuriously low automated platelet count (pseu-dothrombocytopenia) may result from ethylenediamine-tetraacetic acid anticoagulant plus an IgG or IgM platelet antibody, platelet cold agglutinins, unexpectedly large platelet size (e.g., as seen in idiopathic thrombo-cytopenia purpura) in which the cell counter is unable to distinguish the platelets from other cell types, or platelet clumping from a partially clotted sample. Elec-tric particle counters also often provide a mean platelet volume and platelet volume (size) distribution. In the setting of thrombocytopenia, increased platelet size may suggest increased platelet turnover. Large platelets are also seen in many hereditary platelet syndromes, and very small platelets are characteristic of Wiskott-Aldrich syndrome.

Bleeding TimeThe bleeding time (BT), a measurement of length of time that bleeding continues after a standardized wound is made on the forearm or ear lobe, is no longer in clinical use in the United States or United Kingdom, primarily because of its poor reliability and parental perception of the test as overly invasive. It is, however, inexpensive and uses moderately accessible materials, and therefore it is still used in developing countries as a global hemostasis assay.

PFA-100Current platelet function tests are often viewed as inac-curate and unreliable (BT) or labor intensive and time consuming (platelet aggregation studies). Recently, a range of new instruments have been developed that attempt to simulate in vivo platelet adhesion and aggrega-tion. The PFA-100 (Dade Behring, Marburg, Germany) is a commercially available instrument that uses test car-tridges containing collagen/adenosine diphosphate- or

29 APPROACH TO THE CHILD WITH A SUSPECTED BLEEDInG DISORDER 1007

Euglobulin Clot Lysis Time. The euglobulin clot lysis time (ECLT) is a screening test for excessive fibrinolysis. It is performed by using the plasma euglobulin fraction prepared from fresh, citrated, platelet-poor plasma. After clot formation, lysis is measured. The normal ECLT is 60 to 300 minutes. It is shortened in conditions character-ized by increased fibrinolysis (e.g. α2-antiplasmin defi-ciency, plasminogen activator inhibitor 1 deficiency, or systemic fibrinolysis).

Platelet Function Tests. When ordering tests of platelet function, the physician must be aware that a wide variety of drugs can affect the platelet count and alter test results. Drugs such as aspirin irreversibly affect platelet function for the entire life span of the platelet (10 to 11 days). Thus tests of platelet function should be scheduled at a time when the individual has not taken any relevant drugs for at least 10 days.

The most common test of platelet function is platelet aggregometry. Platelet aggregation can be performed in whole blood by impedance technique or in platelet- rich plasma (PRP) by the turbidimetric technique. Whole blood platelet aggregation can be combined with release of adenosine triphosphate by using a lumi-aggregometer. A variety of platelet agonists (ristocetin, epinephrine, collagen, adenosine diphosphate (ADP), and arachidonic acid) can be added to an aliquot of the patient’s sample. The rapidity and extent of platelet agglutination are detected by changes in optical density (PRP) or impedance (whole blood) and are graphically recorded for each agonist used.83 In Glanzmann throm-basthenia, the patient’s platelets will agglutinate nor-mally with ristocetin but not at all with the addition of ADP, epinephrine, collagen, or arachidonic acid. In Bernard-Soulier syndrome, platelet agglutination will occur normally on addition of each of these agonists except ristocetin.83

Global Tests for the Evaluation of BleedingOver the last two decades, investigators and clinicians have attempted to develop global assays of hemostasis that would eventually be able to predict risk of bleeding as well as measure therapeutic efficacy of blood products and clotting factor replacement therapy. As knowledge of the coagulation system developed in the 1950s, specific assays were devised to measure the individual clotting factors. However, it soon became apparent that individ-ual clotting factor assays were inadequate to assess the true nature of the hemostatic system. It was obvious that static end point laboratory tests such as the PT or APTT also did not accurately reflect the patient’s overall hemo-static status and could not assess the dynamic clotting cascade. The common clinical observation that patients with hemophilia have great phenotypic variation in bleed-ing despite identical factor levels stresses this point. This has led to a revival of interest in global clotting assays. In addition, the development of technical innovations and computer-assisted methods of analysis has improved the reliability and reproducibility of global assays. Two such techniques are described here: thromboelastography (TEG) and thrombin generation assays (TGAs). TEG is

test plasma is incubated with commercially available plasma that is deficient in either factor V, VII, or X; a mixture of tissue factor and calcium chloride is added, and the clotting time is determined.79

For each clotting factor assay based on the APTT or PT, the clotting times of serial dilutions of a plasma sample representing a pool obtained from a large number of normal individuals is used to construct a standard curve. The concentration of the specific factor in each of the several dilutions of patient plasma is determined from the standard curve and is used to calculate the level of that clotting factor in the patient’s undiluted plasma.79 In most laboratories, automated instruments are used to perform the assays, and many of these instruments are preprogrammed with a statistical package for plotting the data. The reference pooled normal plasma should be calibrated with a commercial or national standard that has been assayed against an international standard when available.80

Covalent stabilization of fibrin by factor XIIIa is essen-tial for normal hemostasis (see Chapter 27). Factor XIIIa catalyzes the formation of covalent cross-links between the α and γ chains of fibrin, which results in increased mechanical stability of the fibrin clot and resistance to its degradation by plasmin. none of the routine screening tests (PT, APTT, or BT) detect factor XIII deficiency.81 Screening for factor XIII deficiency can be performed with the clot solubility test: solubility of the patient’s recalcified plasma clot in 5 mol/L urea or monochloro-acetic acid is assessed after 30 minutes and periodically at 1, 2, 4, and 24 hours. Clots from patients with less than 1% factor XIII activity are soluble. Quantitation of factor XIII can be done with specific amine incorporation assays, although these tests are generally performed only in specialized research laboratories.81

Recommended tests for VWD include APTT, factor VIII assay, ristocetin cofactor assay to measure VWF activity, VWF antigen assay, and ABO blood group typing. If these tests suggest VWD, VWF multimer analy-sis should be performed. Treatment of VWD depends on accurate subtype diagnosis (see Chapter 31).

Fibrinogen. The concentration of fibrinogen in plasma can be measured immunologically (fibrinogen antigen) or by a chemical method in which the ability of fibrinogen to clot does not influence the assay. normal fibrinogen antigen levels are between 200 to 400 mg/dL. Fibrinogen is an acute phase reactant, and elevated levels are com-monly seen in stress or acute illness.

The level of functional fibrinogen or fibrinogen activity can also be measured. The von Clauss kinetic assay uses a dilute solution of patient plasma and an excess of thrombin, which makes fibrinogen the rate-limiting step in the clotting reaction.82 The resulting clotting time in seconds is compared with a standard dilution curve to determine the concentration of clottable fibrinogen. Fibrinogen is decreased in congenital afibrinogenemia, hypofibrinogenemia, and consumptive states such as DIC. The assay is also sensitive to abnormalities in fibrin-ogen function (dysfibrinogenemia) or the presence of inhibitors of fibrin formation such as FDPs.

1008 SECTION IX HEMOSTASIS

developed test, calibrated automated thrombography (CAT), may be applicable to the routine clinical labora-tory. CAT measures the concentration of thrombin in clotting plasma by monitoring the splitting of a fluoro-genic substrate and comparing the results with known constant thrombin activity in a parallel nonclotting sample (control).91 Application of TGAs is currently being investigated for monitoring of hemophilia treat-ment and anticoagulation therapy and as a means to better understand the differing clinical patterns in bleed-ing disorders.92

Overall, although significant advances have been made in the development of global assays of hemostasis, and some of them are widely used in the clinical and surgical setting, the evidence for making critical diagnostic and therapeutic decisions based on results obtained from these assays is still largely premature; caution should be exercised.

BLEEDING IN THE CRITICALLY ILL CHILDIt is not uncommon for the general pediatric hematologist to be consulted in the critical care setting for acute bleed-ing in the presence of abnormally prolonged clotting tests, thrombocytopenia, or suspected platelet dysfunc-tion. Several clinical situations may lead to the presence of acquired bleeding in the inpatient setting; when the underlying cause is resolved, bleeding typically stops (Table 29-3). Perhaps the most common consult for excessive bleeding in this setting concerns consumption of clotting factors and platelets in the presence of DIC.

usually performed on whole blood and quantitatively measures the dynamics of fibrin formation. TGAs are generally performed on plasma and measure thrombin formation.

ThromboelastographyHartert first described TEG as a global test for blood coagulation more than 50 years ago.84 TEG monitors the whole dynamic process of hemostasis from clot forma-tion to its dissolution and also provides information about platelet function. TEG produces a continuous profile of the overall rheologic changes occurring during coagulation while using a small amount of whole blood. By processing the data, the viscoelastic changes occurring during whole blood clot formation can be transformed into a dynamic velocity profile that is then recorded as a tracing. Currently, reagent-modified TEG with various activators (tissue factor, kaolin) and inhibitors is used with the aim of accelerating the coagulation cascade and obtaining differential diagnostic information.85 The two commonly used instruments are the TEG (Haemoscope Corp, Skokie, Illinois) and the rotating thromboelastom-eter ROTEM (Pentapharm, Munich, Germany).86 Cur-rently used primarily as tools to decrease transfusion requirements during cardiac87 and hepatic surgery, these instruments are also being investigated as screening tools for bleeding disorders.88,89

Thrombin Generation AssaysTGAs have been used extensively in research laboratories but are cumbersome to perform.90 A more recently

TABLE 29-3 Acquired Bleeding Disorders

Underlying Bleeding Disorder Hemostatic Defect Cause

Overwhelming sepsis Acute DIC Initiation of coagulation, damage to the endothelium; decrease in clotting and anticlotting factors

Liver disease Multiple coagulation factor deficiency Decreased hepatic synthesisIncreased fibrinolysisDecreased clearance of plasminogen activatorsHypercoagulable stateDecreased production of natural anticoagulantsThrombocytopeniaHypersplenism

Malabsorption syndrome Decreased production of factors II, VII, IX, and X and proteins C and S

Vitamin K deficiency

Cyanotic congenital heart disease

Mild to moderate thrombocytopenia Shortened platelet survivalAbnormal platelet functionAcquired defects in platelet aggregation

Acyanotic congenital heart disease (e.g., ASD, PDA)

Decreased high-molecular-weight VWF multimers

Consumption

ECMO and CPB platelet dysfunction

Platelet activation in the oxygenator and physical damage to the platelet membrane

Coagulation factor deficiencyConsumption of coagulation factors in the circuitHyperfibrinolysisIncrease in tPA and decrease in α2-antiplasmin

Acute promyelocytic leukemia

ThrombocytopeniaDecreased production in bone marrow

and increased consumption

Disseminated intravascular coagulationRelease of procoagulant material from the leukemic cellsHyperfibrinolysisIncreased synthesis of plasminogen activators

ASD, Atrial septal defect; CPB, cardiopulmonary bypass; ECMO, extracorporeal membrane oxygenation; PDA, patent ductus arteriosus; tPA, tissue plasminogen activator; VWF, von Willebrand factor.

29 APPROACH TO THE CHILD WITH A SUSPECTED BLEEDInG DISORDER 1009

21. Branchford BR, Di Paola J: Making a diagnosis of VWD. Hematol-ogy Am Soc Hematol Educ Program 2012:161–167, 2012.

This review briefly describes the impact on clinical classification of the life cycle and molecular interactions of VWF. It also includes a brief discussion of the differential diagnosis and general workup of mucocutaneous bleeding, a review of the various VWD subtypes, and pertinent laboratory assays for each, including genetic tests. Finally, common testing pitfalls and diagnostic dilemmas are covered, including the challenge created by the overlap of border-line low VWF levels and mild bleeding.

31. Hassan AA, Kroll MH: Acquired disorders of platelet function. Hematology Am Soc Hematol Educ Program 2005:403–408, 2005.

This article is a comprehensive review of acquired disorders of platelet function, including common etiologies, laboratory workup, and suggested treatment options.

37. Hayward CP: Diagnosis and management of mild bleeding disor-ders. Hematology Am Soc Hematol Educ Program 2005:423–428, 2005.

This review addresses symptoms suggesting mild bleeding disor-ders and appropriate diagnostic investigations, including a stepwise approach to allow detection of common and rare coagulation and fibrinolytic defects, and adequate assessments of potential VWF and platelet problems. Finally, an approach is proposed for transla-tion of knowledge to patients challenged by mild bleeding problems.

39. Kulkarni R, Ponder KP, James AH, et al: Unresolved issues in diagnosis and management of inherited bleeding disorders in the perinatal period: a White Paper of the Perinatal Task Force of the Medical and Scientific Advisory Council of the national Hemo-philia Foundation, USA. Haemophilia 12(3):205–211, 2006.

This document outlines the needs for further research and educa-tion, summarizes the state-of-the-art background information, and provides guidance regarding research, education, and access-to-care issues in the perinatal period.

49. George Jn, Aster RH: Drug-induced thrombocytopenia: pathogen-esis, evaluation, and management. Hematology Am Soc Hematol Educ Program 2009;153–158, 2009.

This article is a comprehensive review of drug-induced thrombo-cytopenia and provides a comprehensive database of the causal relationship between specific drugs and thrombocytopenia.

53. George Jn, Shattil SJ: The clinical importance of acquired abnor-malities of platelet function. N Engl J Med 324(1):27–39, 1991.

This review assesses data on the evaluation and clinical impor-tance of disorders of platelet function.

54. Konkle BA: Acquired disorders of platelet function. Hematology Am Soc Hematol Educ Program 2011:391–396, 2011.

This article is another comprehensive review of acquired disor-ders of platelet function.

62. Blomback M, Konkle BA, Manco-Johnson MJ, et al: Preanalytical conditions that affect coagulation testing, including hormonal status and therapy. J Thromb Haemost 5(4):855–858, 2007.

This summary from the International Society of Thrombosis and Hemostasis Scientific Subcommittee on Women’s Health Issues emphasizes the importance of controlling preanalytical variables that may alter coagulation tests.

63. Harrison P, Mackie I, Mumford A, et al: Guidelines for the labora-tory investigation of heritable disorders of platelet function. Br J Haematol 155(1):30–44, 2011.

This review from the British Committee for Standards in Hae-matology provides guidance on platelet function testing in patients with suspected bleeding disorders.

DIC is an acquired systemic disorder characterized by widespread activation of coagulation and deposition of fibrin leading to the formation of thrombi in the micro-circulation accompanied by secondary activation of fibri-nolyis.72 DIC can be acute or chronic, compensated or decompensated, and caused by a wide variety of condi-tions (Box 29-1). DIC should be suspected in children with shock and bleeding manifestations. In DIC the PT and APTT are usually both prolonged, with decreased fibrinogen, factor VIII, and factor V. A concomitant decrease in natural anticoagulants (protein C, protein S, and antithrombin III) may also be seen. Examination of the peripheral smear usually reveals the presence of schis-tocytes and thrombocytopenia.93 There is also an increase in d-dimer and FDPs secondary to the formation of plasmin. As discussed earlier in the chapter, in most cases the diagnosis of the cause of bleeding becomes compli-cated by the need for immediate therapeutic intervention, which usually requires replacement products.

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K E Y R E F E R E N C E S3. Sharathkumar AA, Pipe SW: Bleeding disorders. Pediatr Rev

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and the clinical features suggesting underlying bleeding disorders, as well as the inheritance and clinical management of commonly encountered bleeding disorders.

Sepsis (particularly gram-negative bacteremia)Trauma

Massive tissue injuryHead injury

Fat embolismMalignancy

Acute promyelocytic leukemiaMyeloproliferative disorders

Obstetric accidentsVascular disorders

Giant hemangiomas (Kasabach-Merritt syndrome)Aortic aneurysm

ToxinsSnake venomDrug overdose

Immunologic reactionsSevere anaphylaxisAcute hemolysisAcute transplant rejection

Box 29-1 Conditions Associated with Disseminated Intravascular Coagulation

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