Clinical Pediatrics

http://cpj.sagepub.com Diagnosis and Management of Bleeding Disorder in a Child

Amit Sarnaik, Deepak Kamat and Nirupama Kannikeswaran Clin Pediatr (Phila) 2010; 49; 422 originally published online Jan 28, 2010; DOI: 10.1177/0009922809351090 The online version of this article can be found at: http://cpj.sagepub.com/cgi/content/abstract/49/5/422

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Diagnosis and Management of Bleeding Disorder in a Child

Amit Sarnaik,1 Deepak Kamat,1 and Nirupama Kannikeswaran1

Clinical Pediatrics 49(5) 422431 The Author(s) 2010 Reprints and permission: http://www. sagepub.com/journalsPermissions.nav DOI: 10.1177/0009922809351090 http://clp.sagepub.com

Abstract Children with symptoms of bleeding and bruising are commonly seen in clinical practice. Primary care providers should be able to decide when and whether evaluation for bleeding disorder is warranted. This decision depends on ones index of suspicion for bleeding disorder based on history, physical examination, and screening laboratory investigations. Knowledge of the hemostatic physiology is essential to be able to order appropriate laboratory investigations and their accurate interpretation. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and blood platelet concentration constitute the initial diagnostic work up of any bleeding disorder.Abnormality in any of these parameters in a child with excessive bleeding should lead to presumptive diagnosis of bleeding disorder and trigger referral to a hematologist for confirmation and definitive treatment. Awareness of basic treatment principles for management of bleeding/clotting disorders may prepare the provider to develop appropriate management plans, especially in a life threatening situation. Keywords children, hemostasis, bleeding disorder, diagnosis, treatment

Introduction
Children with history of recurrent bleeding and easy bruising often pose a diagnostic challenge to health care professionals. They have to determine, depending on the history and physical examination, if the child needs evaluation for an underlying bleeding/clotting disorder. This requires an understanding of the physiology of hemostasis and coagulation so that one can recognize the red flags for hematology consultation. In this review, we will discuss the physiology of hemostasis and coa gulation, and the salient features of history, physical examination, and screening laboratory tests that may aid in deciding if referral to specialty hematological con sultation is required to evaluate and manage a clinically significant and potentially serious bleeding disorder.

Physiology of Hemostasis and Coagulation

Hemostasis is a protective response of the body to limit and reverse loss of vascular integrity and prevent exces sive blood loss. The primary stage of hemostasis is characterized by the formation of a platelet plug, which is a complex interaction between the circulating platelets

and the exposed subendothelial layer. This process involves platelet adhesion, mediated by the interaction between platelet surface glycoprotein Ib and von Wille brand factor (vWF), followed by platelet activation, which causes the release of platelet contents and is medi ated by platelet surface glycoprotein (IIb/IIIa). This glycoprotein further interacts with fibrinogen and vWF,1 which leads to platelet aggregation and enlargement of the platelet plug. Thus, the platelet plug is the first line of defense against hemorrhage and also lays the foundation for the eventual formation of the fibrin clot, which is the secondary stage of hemostasis, represented by activation of coagulation cascades and pathways. The coagulation cascade is a complex series of activa tion reactions that result in the conversion of a precursor protein into its activated form in the presence of calcium, phospholipid surface, and catalytic mediators. This sec ondary stage is characterized, initially, by exposure of tissue factor (TF) present in the injured vascular wall and
1

Childrens Hospital of Michigan, Detroit, MI, USA

Corresponding Author: Amit Sarnaik, Childrens Hospital of Michigan, 3901, Beaubien, Detroit, MI 48201, USA Email:asarnaik@dmc.org

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Sarnaik et al

423

Intrinsic pathway

Extrinsic pathway

Inhibitors of intrinsic pathway Antithrombin FXa

Inhibitors of extrinsic pathway Tissue factor pathway inhibitor (TFPI)

Endothelial trauma, Tissue cells FXII FXI FXIIa FXIa TF/FVIIa FVIII FIX FVIIIa FX FV FIXa FVa + Prothrombin FXa THROMBIN Common pathway FVII

Protein C
TF

Thrombin Activated Protein C + Protein S

TF/FVIIa

FVIIIa, FVa

Fibrinogen FXIII

Fibrin

Figure 2. Physiological inhibitors of coagulation: green arrows indicate positive regulation, and red arrows indicate counterregulation

Stabilized Fibrin Clot

Figure 1. The coagulation cascade representing the secondary phase of hemostasis: the green lines indicate positive regulatory mechanisms of thrombin on other elements of the coagulation cascade

its interaction with factor VII (FVII). This interaction, mediated by plateletderived phospholipids and calcium, leads to activation of factor X (FX). FX subsequently interacts with factor V (FV) along with prothrombin, cal cium, and phospholipids to generate thrombin, which in turn mediates the conversion of fibrinogen to fibrin and activates factor XIII (FXIII), which leads to the cross linking and stabilization of fibrin. This cascade is referred to as the extrinsic pathway. Thrombin plays an important role in triggering addi tional thrombin production by the contact factor cascade (intrinsic pathway). This is achieved by activating factor XI (FXI), which activates factor IX (FIX), which in turn influences FX production and thrombin synthesis. The intrinsic and extrinsic pathways merge at the common pathway. The interplay of these pathways and cascades ensures stable and effective fibrin clot formation. Throm bin also activates factor VIII (FVIII) and FV. Activated FVIII (FVIIIa) serves as a catalyst for significantly enhancing the proteolytic activity of activated FIX (FIXa) on FX. Activated FV (FVa) enhances the proteo lytic activity of activated FX (FXa) on prothrombin. (Figure 1) The plasma kallikrein/kinin system compris ing FXII, FXI, and prekallikrein has to be taken into consideration because of its contribution to the intrinsic coagulation pathway. It has, however, been shown to have no physiological influence on hemostasis.24 The clotting cascades are held in check by the presence of inhibitors of the coagulation system, which help

modulate and optimize clotting and prevent complications resulting from uninhibited clotting, such as thrombosis and tissue damage. TF inhibitor inhibits TF/FVIIa and FXa, thereby limiting propagation of the extrinsic pathway. Thrombin underscores its importance as a key component of the coagulation pathway by activating anticoagulant protein C, which along with its cofactor protein S, inacti vates FVIIIa and FVa, thereby limiting progression of the intrinsic pathway. Antithrombin plays an inhibitory role in the common pathway by inactivating FXa and thrombin.4 The presence of a fibrinolytic pathway mediated by plas min ensures dissolution of the clot and patency of the vessel wall after successful hemostasis (Figure 2). Additional physiological consideration includes the understanding of the dynamic nature of the hemostatic system in the pediatric age group. The immediate post natal period and early infancy are characterized by relative deficiency of vitamin Kdependent factors (FII, FVII, FIX, and FX), whose concentrations are appro ximately 50% of adult values. The concentrations of protein C and S are also approximately 50% of adult values during this time period. In contrast, fibrinogen, FVIII, FV, FXIII, and inhibitor concentrations are at the same level or are above adult levels. Clinically, these variations translate into higher protection against throm boembolic phenomena in children when compared with adults. vWF concentrations are also significantly higher immediately after birth and during early infancy. These physiological differences also underscore the importance of using ageadjusted values while interpreting these laboratory parameters.24

Evaluation of a Bleeding Child

The child health care provider should be comfortable in deciding, based on history and physical findings, whether

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424 a child who presents with bleeding warrants evalua tion for a significant bleeding problem. The childs age, gender, and family history provide important clues in decision making. As a general rule, the provider should be concerned about bleeding if it seems to be excessive in terms of duration and quantity than what is expected. Exaggerated bleeding responses to commonly encoun tered events are suggestive of an underlying bleeding disorder. Examples of these include epistaxis lasting for more than 15 minutes despite pressure application on the side of the nostril, significant blood loss from a dental procedure lasting more than 24 hours or requiring blood transfusion, bruising out of proportion to inflicted trauma, and menorrhagia characterized by heavy men strual bleeding lasting for 7 days or loss of more than 80 mL of blood per cycle.2 The American College of Obstet rics and Gynecology has recommended that all women with menorrhagia be evaluated for von Willebrand dis ease (vWD).5 It is important to realize patterns of bruising sec ondary to nonaccidental trauma and child abuse, which unfortunately are more common than bleeding disorders. These bruises are typically seen on areas that are not gen erally involved in accidental injuries, such as on the scalp, back, and chest. There may be imprints of objects that may have been used to inflict the trauma. Bruises from underlying bleeding disorders are encountered on areas that are more typically involved in falls or trauma such as shins and bony prominences. Any bruise not limited to the distal extremities, larger than the size of a quarter, and out of proportion to mechanism should trigger suspicion for a bleeding disorder.4 A detailed family history is of particular importance because it may help uncover congenital bleeding disorders that may have gone undiagnosed or misdiagnosed in other family members. All the relevant family members of both sexes should be questioned for any abnormal bleed ing tendencies as mentioned above. This is particularly important, considering that female carriers of hemo philia, a bleeding disorder that affects males, can have abnormal bleeding symptoms.6 Generally for Xlinked disorders, detailed history should be sought with regard to bleeding problems in the maternal grandfather, uncles, and cousins, whereas history of consanguinity is impor tant for autosomal recessive conditions such as FXIII deficiency. The type and pattern of bleeding may offer valuable diagnostic clues to the underlying bleeding disorder. Mucosal bleeding involving gums or nasal mucosa, pete chiae, and bruising suggest disorders of platelets and blood vessels or vWD. On the other hand, spontaneous or excessive bleeding into soft tissues, muscles, and joint as well as persistent or delayed surgical bleeding can

Clinical Pediatrics 49(5) be suggestive of disorders of coagulation factor, such as hemophilia. Onset of bleeding symptoms and acuity can also aid in directing toward specific diagnoses. Acquired disor ders such as immune thrombocytopenic purpura (ITP) usually present over days as compared with inherited disorders such as vWD or hemophilia, where symptoms are present over months to years. It is important to real ize that the hemostatic system needs to be adequately challenged for the bleeding disorder to become evident. Therefore, in contrast to a severe bleeding disorder manifesting in infancy or early childhood, a mild bleed ing disorder may not manifest until later in childhood. In contrast, bleeding problems that manifest in the neo natal period as prolonged bleeding at the circumcision site, cephalohematomas, or prolonged umbilical stump bleeding should alert the provider to inherited bleeding disorders. Site of bleeding can also help diagnose a spe cific bleeding disorder: for example, in FXIII deficiency, prolonged umbilical stump bleeding and delayed wound healing are common manifestations. Age at presentation and gender of patients should be taken into consider ation to decide whether it is a hereditary or acquired condition. A male infant presenting with painful bleed ing in the joint after a fall should be promptly evaluated for hemophilia, whereas an otherwise well appearing child with purpuric rash following a viral syndrome may suggest the diagnosis of ITP. A teenage girl with exces sive menstrual bleeding and pallor should raise suspicion for vWD, whereas petechial rash and severe circulatory collapse in a teenager could be a presentation of vascu litis as well as disseminated intravascular coagulation (DIC) from meningococcemia or sepsis. It is also important to ask for and note the presence of any coexisting illnesses in a child presenting with a bleeding problem. Inherited bleeding disorders and ITP generally manifest in otherwise healthy looking children, whereas DIC is seen in association with other critical illnesses. Presence of hepatosplenomegaly, lymphadenopathy, and pallor in association with throm bocytopenic manifestations such as petechiae or purpura should raise suspicion for malignancies such as leuke mia and lymphoma. Other comorbidities such as liver disease can contribute to bleeding problems as a result of disturbance in vitamin K metabolism, whereas renal dis ease can contribute to bleeding problems by affecting platelet function. Medication history is also important. Medications such as aspirin affect platelet function and can exacerbate bleeding by affecting primary hemostasis or by unmasking underlying coagulation disorders such as vWD. A prospective study by Rohrer et al7 concluded that a detailed history is superior to routine preoperative testing in detecting significant coagulation problems.

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Sarnaik et al

425 report PT as an international normalized ratio (ie, INR) to allow standardization and comparison of results between different laboratories. aPTT measures the functioning of intrinsic and com mon pathways of coagulation and, therefore, is sensitive to deficiencies of factors XII, XI, IX, and VIII, X, V, II, and I as well as their inhibitors such as heparin. How ever, it is less sensitive than the PT to deficiencies within the common pathway, that is, factors X, V, prothrombin, and fibrinogen.8,9 A mixing study should be performed in the event of abnormal PT or aPTT, which essentially consists of mixing the patients plasma and normal plasma, 1:1. In the event of coagulation factor deficiency, mixing replen ishes the level of missing factor(s) by 50% and normalizes the PT or aPTT. However, persistent prolongation of PT or aPTT may indicate the presence of inhibitor or an anti body to one or more coagulation factors.10 Incidental prolongation of aPTT in the clinical setting is often a result of lupus anticoagulants, which are transient anti bodies seen in association with infection and are directed against the proteins that bind to phospholipid surfaces. It is important to understand that the sensitivities of various PT and aPTT reagents may vary and yield falsely normal results in patients with mild deficiencies. There fore, when a coagulation defect is strongly suspected, specific factor assays should be performed to rule out bleeding disorders. It is also important to understand that these screening tests do not assess FXIII activity, and therefore, a specific assay may be necessary to assess activity of this factor. Factor levels can be assessed qual itatively by functional assays and quantitatively by immunological assays. Functional analysis is performed by comparing test results (mixing of patient plasma with commercially available plasma deficient in known fac tors) with standard curves generated by mixing serially diluted normal plasma and factordeficient plasma. Quantitative and functional assays should give equiva lent results when a factor deficiency is present. Reduction in a functional assay with a normal quantitative assay suggests the presence of a functionally abnormal factor.8

Laboratory Evaluation Screening Tests

Evaluation of bleeding disorder can be initiated at the doctors office or at the emergency department by per forming screening tests. These tests should include complete blood count (CBC), peripheral blood smear (PBS), prothrombin time (PT), and activated partial thromboplastin time (aPTT). Bleeding time and platelet function analyzers (PFAs) are not routinely included in this list as they are limited by their low specificity and sensitivity. Subsequent evaluation for specific bleeding disorders will depend on the results of these screening tests. CBC helps determine platelet count. Presence of anemia, especially the microcytic hypochromic type, may be caused by chronic blood loss and therefore suggest an underlying bleeding disorder. Bleeding mani festations in the face of suppression of all blood cell lines is suggestive of malignancies such as leukemia and lymphoma. PBS evaluation will help confirm thrombo cytopenia and rule out factitious thrombocytopenia that can occur from clumping of platelets. This is commonly seen if there has been a difficulty with the blood draw. Platelet morphology can also be analyzed on PBS to rule out giant platelet disorders such as Bernard Soulier dis ease. Similarly, ITP is characterized by normal as well as large platelets. Presence of smaller than normal platelets is suggestive of Wiskott Aldrich syndrome. PBS evalua tion also helps identify abnormal cells such as blasts. PT and aPTT serve as screening tests for the evalua tion of the secondary phase of hemostasis. It is important to realize that proper collection of blood samples is nec essary for accurate interpretation of these tests. A blood sample drawn from the heparinized line will yield grossly abnormal results. 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 anticoagu lated with a solution of sodium citrate in a ratio of 9 parts of blood to 1 part of citrate.8 In newborns and chil dren with cyanotic heart disease in whom the hematocrit is high, the amount of citrate has to be reduced to pro vide a proper ratio.9 PT evaluates the function of the extrinsic and common pathways of coagulation, and therefore, an abnormally elevated value may indicate a defect in the component(s) of these pathways. PT, thus, measures the functioning of TF, FVII and FX, FV, prothrombin, and fibrinogen. PT also serves to indicate integrity of the vitamin K dependent coagulation factors (II, VII, and X) and, therefore, can be used to monitor treatment with vitamin K antagonists such as warfarin. Most laboratories also

Fibrinogen Measurement and Thrombin Time (TT)

Thrombin time is a measure of time required to form a clot on addition of thrombin to plasma and, therefore, represents fibrin formation. Prolonged TT suggests low fibrinogen level or activity. Similar to other factors,, quantitative analysis of fibrinogen is performed by immunological assay. Conditions such as dysfibrino genemia are characterized by abnormal functional assay but normal quantitative assay.

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426
Table 1. Initial Laboratory Evaluation to Screen for Bleeding Disorders: Analysis and Interpretation PT Normal aPTT Normal Platelet Count Normal

Clinical Pediatrics 49(5)

Possible Bleeding Disorder vWD Platelet function defect Factor XIII deficiency Fibrinolytic defect Hemophilia A Hemophilia B Factor XI deficiency vWD with FVIII dysfunction Lupus anticoagulant Heparin contamination or excess Early vitamin K deficiency Factor VII deficiency Warfarin excess Liver disease Vitamin K deficiency Common pathway factor (factor X,V, prothrombin, fibrinogen) deficiency Dysfibrinogenemia DIC Liver disease Acute ITP Chronic ITP

Normal

Prolonged

Normal

Prolonged Prolonged

Normal Prolonged

Normal Normal

Prolonged Normal

Prolonged Normal

Low Low

PT = prothrombin time; aPTT = activated partial thromboplastin time; vWD = von Willebrand disease; DIC = disseminated intravascular coagulation; ITP = immune thrombocytopenic purpura.

Evaluation of Primary Phase of Hemostasis

These tests are performed to screen for primary hemostatic defects such as vWD or platelet function abnormalities. The bleeding time test, which essentially evaluates platelet interaction with the vascular wall, is limited by its lack of standardization and therefore poor predictability, sensitivity, and specificity and, therefore, cannot be used reliably.2,1113 PFA (PFA100) is a platelet function screening test designed to measure platelet related primary hemostasis and offers good screening for most cases of vWD and platelet function disorders.11,14,15 It is important to note that vWD is much more com mon than platelet dysfunction and, therefore, should be the focus of initial evaluation of primary hemostatic problems.

be more appropriate and meaningful to present a few common clinical scenarios, as described by Allen and Glader,2 that the physician often faces (Table 1).

Case Scenario 1: A Child With Significant History of Bleeding but Normal Screening Laboratory Investigations (Normal PT, aPTT, and Platelet Count)
This scenario may result from defects in the primary phase of hemostasis (vWD and platelet dysfunction), defects in the secondary phase (FXIII deficiency), or defects in the fibrinolytic pathway. vWD is the most common inherited bleeding disor der, with prevalence as high as 1% to 3 % in the general population. It affects both genders and all races and eth nicities.1619 Normally, vWF participates in hemostasis by helping form the initial platelet plug and also by acting as a carrier protein for FVIII and thus helping in stabilizing and prolonging its halflife. vWD results from a qualitative or a quantitative defect in the vWF and is classified into 3 subtypes: vWD type 1, found in 70% to 80% of the cases, is characterized by partial deficiency of vWF; vWD type 2 is characterized by functional defects in vWF; and vWD type 3, a rare con dition, is characterized by the almost complete absence

Clinical Cases
It is not uncommon in clinical practice for the physician to be confronted with abnormal laboratory values with or without overt symptoms of bleeding. These are the situations where the physician has to decide if they are dealing with a significant bleeding disorder and, there fore, whether it warrants further evaluation and possibly specialty referral. Rather than providing a description of every significant bleeding disorder, we feel that it would

Sarnaik et al of vWF. The spectrum of clinical presentations varies from mucocutaneous bleeding such as epistaxis or easy bruising, menorrhagia in women,20,21 to bleeding into muscles and joints seen in severe forms. Laboratory evaluation generally reveals normal CBC, PT, and aPTT. An aPTT may be prolonged depending on secondary FVIII dysfunction. PFA100 test is abnormal. Specific tests include the plasma levels of vWF antigen, ristocetin cofactor activity, FVIII activity, and vWF multimeric analysis. History of bleeding manifestations, family history of bleeding, and reduced level of ristoce tin cofactor activity establishes the diagnosis of vWD.4 It is important to realize that vWF is also an acute phase reactant and that its level may increase with stress, hor monal therapy with oral contraceptives, exercise, acute inflammation, pregnancy, and menstrual cycles. There fore, a negative test for vWD in the face of overwhelming evidence must prompt repeat testing, preferably in the absence of the aforementioned factors that affect its accuracy. Treatment options for vWD consist of the use of des mopressin (DDAVP), especially in those patients with mild type 1 or type 2 deficiencies. DDAVP raises vWF levels many fold very rapidly and thus can be used for mild bleeding as well as for prophylaxis. Concomitant treatment with antifibrinolytic agents such as aminoca proic acid or tranexamic acid helps stabilize the clot and augment the therapy. Patients with severe type 3 disease need transfusion therapy with vWF as well as FVIII concentrates. This treatment is also necessary for milder disease that does not respond to DDAVP or antifibrinol ytic agents. Platelet function disorders usually manifest with spontaneous mucocutaneous bleeding. Platelet dysfunc tion can be secondary to medication use such as aspirin and valproic acid or from systemic disorders such as uremia and liver disease. Rarely, platelet function disor ders can also be inherited and result in inherent defects with platelet adhesion, aggregation, and metabolism. Bleeding arising from these disorders can be controlled with DDAVP and antifibrinolytic agents. Platelet trans fusions are necessary in conditions such as Bernard Soulier syndrome. Recently FVIIa has been found to be effective in ameliorating symptoms of platelet dysfunc tion caused by inherited platelet disorders.4 FXIII comes into play in the coagulation pathway, after fibrin formation, and therefore its deficiency does not result in prolongation of PT and aPTT. FXIII defi ciency is usually autosomal dominant and should be suspected in any newborn with persistent oozing from the umbilical stump or after circumcision. Its immediate detection and treatment is of paramount importance

427 because of the high incidence of intracranial bleeding (25%30%) associated with its deficiency.22 FXIII defi ciency can also manifest as poor wound healing and delayed separation of umbilical cord in neonates. A spe cific assay for determination of the FXIII level helps in definitive diagnosis. Treatment consists of FXIII replace ment therapy. Defects in the fibrinolytic pathway may lead to signi ficant bleeding problems because of abnormally quick dissolution of the fibrin clot. Excess tissue plasminogen activator or deficient a2antiplasmin and plasminogen activator inhibitor1 can cause this problem. Patients with this problem classically present with rebleeding following initial hemostasis and require a high index of suspicion for diagnosis.2

Case Scenario 2: A Child With Significant Bleeding, Normal PT, Prolonged aPTT, and History of Significant Bleeding
When confronted with this scenario, the clinician should consider the possibility of deficiency of factors in the intrinsic pathway, especially FVIII, FIX, and FXI. Inhibitors such as lupus anticoagulant and heparin con tamination or overdose can have similar consequence. As discussed in the previous case, secondary FVIII defi ciency caused by vWD can also present with these laboratory findings. FVIII deficiency or hemophilia A is the second most common inherited factor deficiency after vWD. It is an Xlinked disorder, with an approximate incidence of 1in 5000.23 Family history may be absent as a result of spon taneous mutations. FIX or hemophilia B deficiency is inherited in similar fashion and is far less common than hemophilia A. The classic presentation is spontaneous bleeding in muscles, deep tissues, or joints. The severity of bleeding depends on levels of factor activity, with severe hemophilia resulting from <1% activity, moder ate hemophilia resulting from 1% to 5% activity, and mild hemophilia characterized by >5% activity. Treat ments consist of recombinant FVIII or FIX administration for acute bleeding episodes. The goal of the treatment is to replenish 50% plasma factor levels for milder and nonlifethreatening bleeds and 100% replenishment for severe or lifethreatening bleeds. Usually 1 unit/kg of recombinant FVIII raises the plasma factor concen tration by 2%, and the same dose of FIX infusion raises the plasma factor concentration by 0.8% to 1%. For severe cases of hemophilia, prophylactic infusion of factors may be administered. Infusion of factor concen trates may lead to the development of antibodies and,

428 thus, over the course of time, can make these traditional treatments ineffective. In these situations bypassing agents such as FVIIa or activated prothrombin complex concentrates may be used.4 FXI deficiency or hemophilia C is extremely rare among Caucasians but has a high carrier rate of about 8% in the Ashkenazi Jew population.24 Inheritance of hemophilia C is autosomal dominant and is character ized by mild bleeding as compared with hemophilia A and B. Unlike in hemophilia A and B, severity of clinical symptoms do not correlate with plasma factor levels. FXI deficiency should be suspected and needs to be ruled out in a child with significant bleeding, prolonged aPTT, and normal FVIII and FIX levels.

Clinical Pediatrics 49(5) resulting from antagonism of vitamin K activity in neo nates by maternal medications such as anticonvulsants. The classic form, also the most common form, seen bet ween 2 and 7 days is attributed largely to inadequate stores and also to poor transplacental transfer and poor intake, especially in breastfed babies because of low concentrations of vitamin K in breast milk. This is occa sionally seen in infants born at home because of failure to receive vitamin K. The late form can clinically pres ent over several months and could be the result of nutritional deficiency in breastfed infants, poor indige nous synthesis secondary to excess antibiotic use, chronic diarrheas, or malabsorption resulting from con ditions such as cystic fibrosis. Anticoagulants like warfarin are specific antagonists of vitamin K. These agents are used for therapeutic anti coagulation. Warfarins are also the chief ingredient of commonly available rodenticides and are much more potent and have significantly higher halflives than the warfarin used for anticoagulation therapy. Accidental or intentional ingestion or overdose of these agents can lead to serious bleeding problems.26 Treatment consists of vitamin K administration and use of fresh frozen plasma in severe cases for rapid replacement of the affected factors. Deficiencies of factors in the common pathway, such as FV, FX, prothrombin, and fibrinogen, can present with prolongation of both PT as well as aPTT. Functionally defective fibrinogen (dysfibrinogenemia) can present in similar fashion. These entities are inherited and are extre mely rare.

Case Scenario 3: A Child With Significant Bleeding History With Prolonged PT, Normal aPTT, and Normal Platelet Count
This scenario is suggestive of FVII dysfunction. Isolated FVII deficiency is a rare entity.2 FVII also has the short est halflife of all the factors, and therefore, it will be the first to be affected in vitamin K deficiency states. Thus, vitamin K deficiency may present as an isolated prolon gation of PT in the initial stages because FVII deficiency manifests prior to decline in other factor levels.

Case Scenario 4: A Child With Significant History of Bleeding,With Prolongation of PT as Well as aPTT and a Normal Platelet Count
This case scenario is the hallmark of vitamin K defi ciency. Vitamin K orchestrates the functional efficacy of FII, FVII, FIX, and FX, by facilitating calcium binding sites on the respective procoagulants. Functional defects in these factors resulting from Vitamin K deficiency will affect intrinsic, extrinsic, and common pathways and thereby lead to prolongation of both PT and aPTT. Vitamin K deficiency can result from poor intake or absorption, or can be a result of the presence of agents that antagonize its effect. Hemorrhagic disease of the newborn is a clinical manifestation of vitamin K deficiency and can present as severe gastrointestinal, deep tissue, and even serious intracranial bleeding. It has largely been ameliorated because of prophylactic administration of intramuscular vitamin K in the newborn nursery, which continues to be the single most effective means of preventing this poten tially catastrophic problem.25 There are 3 forms described: the early form, seen within the first 24 hours,

Case Scenario 5: Child With Significant Bleeding and Prolongation of PT and aPTT and Thrombocytopenia
This scenario is encountered in DIC or consumptive coagulopathy, which is essentially a thrombotic micro angiopathy. It is characterized by abnormal coagulation in the blood vessels resulting in inappropriate consump tion of coagulant factors, platelets, and anticoagulant proteins. The end result is widespread deposits of fibrin in the vasculature, potentially leading to tissue ischemia and generalized hemorrhage. Laboratory evaluation reveals hemolytic anemia, thrombocytope nia, and prolongation of PT and aPTT. The PBS reveals schistocytes secondary to microangiopathic shearing of RBCs. There is also decreased level of fibrinogen. Acti vation of the fibrinolytic system leads to the appearance of fibrinogen degradation products and Ddimers in the blood.

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Sarnaik et al DIC is often seen in association with sepsis, shock, and malignancies such as promyelocytic leukemia.27 The child is usually critically ill and may present with bleeding manifestations such as petechiae and ecchy mosis. Bleeding is often noticed at the sites of surgical incision or venipuncture. Primary or secondary liver diseases manifest with prolongation of PT and aPTT, secondary to decreased synthesis of procoagulants that are active in the intrinsic, extrinsic, and common pathways of coagulation. Throm bocytopenia may also result from hypersplenism, which is often associated with chronic liver disease. Unlike DIC, FVIII levels remain within normal limits.2

429 Persistence of low platelet counts beyond 6 months is suggestive of chronic ITP and most commonly encoun tered in female patients and patients more than 10 years of age. It can be associated with HIV as well as Helicobacter pylori infections.32 Neonatal thrombocytopenia may be experienced by infants born to mothers with a history of chronic ITP. Neonatal thrombocytopenia is a significant clinical entity and commonly seen in critically ill neonates who are suffering from sepsis, hypoxia, respiratory distress syndrome, congenital viral infections, and even congen ital heart disease.2 KasabachMerritt syndrome is seen in neonates as thrombocytopenia secondary to platelet sequestration in giant hemangiomas.33 Wellappearing neonates will occasionally present with severe thrombo cytopenia as a result of alloimmune antibodies that cross the placenta and destroy neonatal platelets.34,35

Case Scenario 6: Child Presenting With Skin or Mucosal Petechiae and Thrombocytopenia, With Normal PT and aPTT
This scenario is generally a result of acute thrombocy topenia in an otherwise well child and is known as immune thrombocytopenic purpura, which was previ ously known as idiopathic thrombocytopenic pupura. This is secondary to the development of autoantibodies to platelets, 1 to 4 weeks after a viral infection.28,29 Acute ITP accounts for 80% to 85% of cases, whereas the rest have chronic ITP, which is defined by persistence of thrombocytopenia beyond 6 months of initial presenta tion. Classic presentation is an otherwise healthy 1 to 4yearold child who has sudden onset of generalized petechiae and purpura. Rarely, bleeding manifestations are severe and consist of epistaxis, gastrointestinal bleed, and menorrhagia.30 Intracranial bleeding is an extremely rare complication and occurs in less than 1% of patients. Absence of hepatosplenomegaly, lymphadenopathy, and pallor helps distinguish this condition from leukemia. CBC reveals isolated thrombocytopenia without affect ing other cell lines. PBS reveals normalappearing as well as large platelets. Most patients recover within 2 months of initial presentation, with 80% recovering completely in 6 months.31 The clinical course is not affected by treatment.2 Treatment is aimed at achieving a theoretically safe platelet level of 20 109/L. This can be achieved by using intravenous immunoglobulin infu sion of 0.8 to 1 g/kg/d for 1 to 2 days or intravenous antiD infusion for Rhpositive individuals at a dose of 50 to 75 mg/kg. Both these interventions cause expected rise in platelet counts, usually within 48 hours. Pred nisone can achieve the same effect but over a longer duration. Platelet transfusion has no role except in cases of lifethreatening bleeding manifestations.

Case Scenario 7: Incidental Finding of Prolonged PT and aPTT in a Child With No Bleeding Symptoms or History
These findings are often encountered as an incidental finding during presurgical laboratory evaluation. Cir culating anticoagulants can cause elevated aPTT with no associated bleeding.36 Rarely, contact factors such as prekallikrein, highmolecularweight kininogen, and FXII deficiency can cause this abnormality without increasing the risk for bleeding.

Conclusion
Children with symptoms of bleeding and bruising are commonly seen in clinical practice. Primary care pro viders should be able to decide when and whether evaluation for bleeding disorders is warranted. This decision depends on ones index of suspicion for bleed ing disorders, based on history, physical examination, and screening laboratory investigations. Once a diagno sis is confirmed or even suspected clinically as well as by screening laboratory tests, referral to a hematologist is recommended for further management. Knowledge of basic treatment principles for management of bleeding/ clotting disorders may prepare the provider to develop appropriate management plans, especially in lifethreat ening situations. Declaration of Conflicting Interests The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

430 Funding The authors received no financial support for the research and/or authorship of this article. References
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