Bumps, Bruises, and Bloody Noses Evaluation of Pediatric Bleeding Disorders Because bruising and bleeding are normal events of childhood, the pediatrician.

Bumps, Bruises, and Bloody Noses Evaluation of Pediatric Bleeding Disorders
Because bruising and bleeding are normal events of childhood, the pediatrician must be able to determine whether a child's symptoms are normal or perhaps indicative of a defective hemostasis. A thorough medical history and physical examination should enable the clinician to choose those patients warranting further evaluation. Rather than referral to a hematologist at that point in time, pediatricians should be quite capable of performing the initial laboratory evaluation and making the correct diagnosis in a majority of cases. Bradley denardo, md Assistant professor of pediatrics Division of pediatric hematology/oncology The warren alpert medical school of brown university Speaker disclosure: no conflicts of interest to disclose

Learning Objectives Recognize the signs and symptoms of an underlying coagulopathy in children. Discuss the diagnostic testing and clinical approach for suspected bleeding disorders. Review the most common pediatric bleeding disorders in children and how they are managed.

Understanding Hemostasis
Four Main Components Vascular Constriction Primary Hemostasis: platelet plug formation Secondary Hemostasis: clot formation Tertiary Hemostasis: fibrinolysis

Vascular Constriction
Immediate response to vascular wall damage. Blood vessel wall: inherent contraction. Mechanism: Neuron reflexes Myogenic contraction Secretion of vasoconstrictors Thromboxane A2 Serotonin Reduces blood loss Allows more time for platelet adhesion/activation Pain nerve impulses originating from the damaged blood vessel trigger neuron reflexes. Direct damage to a blood vessel triggers local myogenic contraction Vascular spasm is powerful enough that patients with lower extremity crush injuries have intense vascular constriction of large arteries (anterior tibial) to such a degree that prevents lethal blood loss

Primary Hemostasis Endothelial damage von Willebrand Factor (vWF)
Exposure of collagen von Willebrand Factor (vWF) Binds exposed collagen Uncoils Platelet Plug Formation

Primary Hemostasis: Platelet Phase
Adhesion Binding to vWF-collagen GPIb receptor Activation Shape change: ↑ binding Release of chemicals: granules ADP, TXA2 Aggregation ADP attracts more Plts vWF bridges Plts Platelets alone are responsible for stopping the bleeding of unnoticed wear and tear of our skin on a daily basis. Disorders of primary hemostasis: mucocutaneous bleeding and bruising/petechiae

Mucocutaneous Bleeding = Bruising and Petechiae
Primary Hemostasis Platelets alone are responsible for stopping the bleeding of unnoticed wear and tear of our skin on a daily basis. Disorders of primary hemostasis: mucocutaneous bleeding and bruising/petechiae Collagen Disorders Ehlers Danlos Osteogenesis Imperfect Platelet Disorders ITP Glanzmann, Bernard Soulier Platelet function disorders Von Willebrand Disease Mucocutaneous Bleeding = Bruising and Petechiae Collagen Ehlers Danlos Osteogenesis Imperfecta Platelets Quantity Quality Von Willebrand Disease

Secondary Hemostasis Delayed Bleeding Hematomas Skin Ecchymoses
Formation of Fibrin Thrombus Tissue Factor Clotting Cascade Fibrin Strands Stabilize the Platelet Plug Delayed Bleeding Hematomas Skin Ecchymoses

Classical Clotting Cascade

Physiologic Coagulation
Propagation Phase: Occurs on activated platelet surface Activated FVIII + IX generate activated FX FXa results in massive thrombin generation Initiation Phase: Tissue factor exposed on subendothelial cells Activates Factor VII Generates small amount of thrombin Amplification Phase: Thrombin exposed on platelet surface Fully activates platelets and enhances adhesion Activates factors V, VIII, and XI

Tertiary Hemostasis

Understanding Hemostasis
Primary hemostasis disorders Secondary hemostasis disorders Petechiae typical Bruising: scattered and small Epistaxis/gum bleeding common Joint bleeding not seen Muscle/soft tissue hematoma rare Menorrhagia typical Not usually seen Large ecchymoses of skin Epistaxis/gum bleeding atypical Hemarthroses hallmark feature Muscle hematoma characteristic Menorrhagia typical

The Bleeding Child Bruising and bleeding are normal events of childhood. Frequencies vary: age, developmental stage, gender Recurrent bleeding and easy bruising → diagnostic challenge. Epistaxis is common: rhinitis, dry air, prominent blood vessels Easy bruising along bony prominences typical: 1-10 years. Lack of surgeries/trauma as hemostatic challenges. Nonaccidental Injury (NAI): always be considered. Best screening test for a bleeding disorder: Comprehensive History Focused Physical Exam

History Age, gender, mobility, medications. Bleeding Episodes:
Site Frequency Duration Severity Unprovoked or triggered? How did the bleeding stop? Bruising: Location Extent Spontaneous or traumatic Other Bleeding Episodes: Epistaxis Gingival bleeding Hemoptysis Menses Joints and muscles Stool and urine Hemostatic Challenges: Circumcision Abrasion/lacerations Dental work and extractions Trauma Surgery Neonatal: umbilical cord, heelstick, IM Vit K, cephalohematoma

Family History Known familial bleeding disorders are rare: Mother
Exception of hemophilia Diagnostic testing historically limited Subtle symptoms and variable phenotypes Older patients: labeled “von Willebrand disease” Mother Postpartum hemorrhage Miscarriages or neonatal demise Menorrhagia 1st degree male and female members Bleeding episodes Dental extractions Surgical complications Blood transfusions

Physical Exam *

Bruising Normal bruising Abnormal bruising
Bruising is expected in all children Bony prominences More commonly reported: Increased family size Summer months Caucasian ethnicity No validated tool to score bruising Non-mobile infants Uncommon locations Back Buttocks Arm Abdomen Other Large cumulative size of bruising Spontaneous bruising in older children

Epistaxis Local Causes Systemic Causes Concerning Findings:
Nose picking Foreign body Allergic rhinitis Upper respiratory infection Dry air Prominent vasculature Systemic Causes Bleeding disorders Medications Systemic imflammator disorder Hypertension Hereditary hemorrhagic telangiectasia Concerning Findings: Prolonged Epistaxis >15-30 minutes Despite correct local pressure Frequent Epistaxis >2-3 episodes/week >2-3 weeks Difficult to manage Epistaxis Epistaxis <2 years old Other bleeding symptoms

Check Labs??? History and Physical Low Suspicion Observe and Reassure
High Suspicion Abnormal Bruising Pattern Concerning Epistaxis Menorrhagia (OCP’s) Combination of sx’s and FHx Concerning hemostatic challenge Any bleeding in non-mobile child Low Suspicion Observe and Reassure CBC and diff with smear Laboratory Evaluation Prothrombin Time (PT) Partial Thromboplastin Time (PTT)

Complete Blood Count Platelet Count Not all low platelet counts….
Thrombocytopenia Not all low platelet counts…. Platelet clumping Type 2B vWD Pseudo vWD Other uses for the CBC: Mean Platelet Volume (MPV) Platelet morphology Blasts → leukemia

Coagulation Lab Testing
Clotting Times: Measurement of the time it takes plasma to clot after exposure to stimulus. Samples Collected in sodium citrate tubes Chelates Calcium in plasma → inhibits coagulation Handling Blood volume → ensure appropriate plasma:citrate ratio Mixing → gently inverted to avoid hemolysis Elapsed time → timely processing to avoid degradation of clotting factors Avoid sources of interference (heparin, hyperbilirubinemia, lipemic blood) Fixed amount of citrate in each tube (9:1 ratio of plasma to citrate) heparinized CVL’s, lipemic samples, hyperbili, anticoagulants Labile clotting factors = FV, FVIII, Protein S

Clotting Times Prothrombin Time (PT)
Plasma mixed with Tissue Factor (thromboplastin) Assesses extrinsic pathway Activated Partial Thromboplastin Time (aPTT) Plasma mixed with contact factor activators (silica) Assesses intrinsic pathway Thrombin Time Plasma mixed with dilute thrombin Assesses conversion of fibrinogen to fibrin phospholipid reagent, Ca2 silica, soy extract

Problems with Clotting Times
Inaccurate clotting times common… Sample relies on proper ratio of plasma:citrate Too little plasma → too much citrate → falsely prolonged Underfilled tube Polycythemia Too much plasma → too little citrate → falsely shortened Overfilled tube Severe anemia Other causes of falsely prolonged PT/aPTT/TT: Difficult lab draws Sample begins to clot, consuming clotting factors Prolonged time to run sample Degradation of labile clotting factors Sample drawn from a heparinized catheter

Interpreting Coags Prolonged PT/INR Prolonged aPTT
Factor 7 deficiency Acquired inhibitor Mixing Study Prolonged aPTT Factor 8 deficiency (Hemophilia A) Factor 9 deficiency (Hemophilia B) Factor 11 and 12 deficiency Acquired inhibitors von Willebrand disease Lupus Anticoagulant Antiphospholipid antibody No clinical consequence PT and aPTT Prolonged Deficiency of common pathway: Fibrinogen Prothrombin Factor 5 Factor 10 Acquired inhibitors Sick Child: DIC Liver failure Vitamin K deficiency Factor 13 Deficiency Normal PT and aPTT Urea Clot Solubility

Hemophilia Most common inherited bleeding disorders X-linked recessive
Factor 8 deficiency → Hemophilia A Factor 9 deficiency → Hemophilia B X-linked recessive 70% positive FHx 30% de novo germline mutation Definitions: <1% severe 1-5% moderate 5-40% mild

Hemophilia: Symptoms Disorder of secondary hemostasis:
Delayed bleeding: days to weeks after injury/trauma Location: joint, soft tissue, intracranial Epistaxis, oropharyngeal, GI, hematuria Depends on severity Mild In response to trauma, injury, procedure Asymptomatic until later in life Severe spontaneous bleed or severe delayed bleed Slow oozing days to weeks after trauma Massive bleeding hours after trauma

Hemophilia: Symptoms Toddlers and Children: mild and moderate
Non-mobile Frenulum and oral injuries Excessive bruising and joint/muscle bleeds Forehead hematomas (initial site in 25%) Neonates and Infants: severe 75% “severe” hemophilia dx by 1 month of age 50% excessive circumcision bleeding Bleeding sites Venipuncture, heel sticks Cephalohematomas CNS bleeds

Intracranial Hemorrhage
Occurs in individuals of all ages and severity 5-12% lifetime rate Spontaneous or post-traumatic Cohort of 3600 hemophilia patients ICH rate of 2.7% over 5 years 69% in severe 18% in mild 78.4% not associated with trauma Trauma implicated in all epidural hemorrhages ICH from birth trauma 3-4% overall incidence Risk factors: unawareness of diagnosis, severe disease, prolonged labor, forceps/vacuum Present at birth or up to 4 weeks from delivery 8 mo with massive subdural hematoma and midline shift after traumatic fall requiring urgent craniectomy

Hemophilia: Diagnosis
Isolated Prolongation of aPTT Moderate and severe: definitively prolonged. Mild: prolonged or normal Factor 8 and 9 Activity Levels ELISA-based assay measuring enzymatic activity Factor 8: Acute phase reactant Falsely normal in mild disease Mixing study Rule out acquired inhibitor Neonate Prenatal DNA-based testing via CVS Umbilical cord blood testing at birth: Factor 8 similar infancy → adults Factor 9 low in infancy → 6 mo repeat Mild-moderate hemophilia B cannot be diagnosed at birth; wait until 6 months when F9 levels rise to adult levels

Hemophilia in Female Patients
Female carriers (heterozygous) expected to have factor activity of 50%. Sufficient to prevent bleeding Symptoms not expected Mild hemophilia symptoms reported in 25% female carriers: Compound heterozygous genotypes Extreme X-inactivation (lyonization) X chromosome loss (Turner’s Syndrome) Diagnostic Considerations: Suspected carrier → genetic testing (screening and detection) Factor levels vary and the normal ranges are wide Known carrier → factor activity testing (prognosis and management)

Hemophilia: Treatment
DNA Recombinant Factor Purified Factor Concentrate Self-Infusion of Factor Prophylactic infusion On-demand infusion Adjunctive Therapy: Desmopressin (DDAVP) Antifibrinolytics

Bleeding Disorders “Common” Rare Acute ITP Common vWD Type 1 1/1000
vWD Type 2 (A,B,M,N) 1/5000 Hemophilia A 1/5000 Hemophilia B 1/30,000 Factor XI deficiency /100,000 Factor VII deficiency /300,000 Afibrinogenemia /500,000 vWD Type 3 1/1 million Factor V deficiency 1/1 million Factor X deficiency 1/1 million Factor V/VIII deficiency 1/1 million Dysfibrinogenemia 1/1 million Factor II deficiency 1/1-2 million Factor XIII deficiency 1/2-5 million Platelet function unknown Bernard-Soulier syndrome rare Glanzmann thrombasthenia very rare α2-Antiplasmin deficiency 40 cases PAI-1 deficiency very rare

von Willebrand Disease
Most common bleeding disorder 1% population von Willebrand Factor Plasma glycoprotein Composed of multimers Functions: Platelet adhesion (GpIb) Platelet aggregation (GpIIbIIIa) Carrier of Factor 8 in blood

Classification of vWD Type 1 (80%, AD) Type 3 (extremely rare, AR)
Partial quantitative decrease in vWF Mild symptoms Type 3 (extremely rare, AR) Near-complete absence of vWF Hemophilia-like severe symptoms Type 2 (15-20%, AD-AR): qualitative defects Type 2A: lack large multimers; defective platelet adhesion Type 2B: increased affinity for GpIb; thrombocytopenia Type 2M: decreased affinity for GpIb; defective platelet adhesion Type 2N: defective binding to Factor 8; low Factor 8 levels Pseudo vWD: GpIb mutation causing increased affinity

vWD: Symptoms Disorder of primary hemostasis (most of the time):
Immediate bleeding Mucocutaneous bleeding: epistaxis, gingival bleeding, menorrhagia Low vWF levels are common → 1% population Only % present with symptoms Only % present to a hematologist Many vWD patients never present with clinically significant symptoms Bleeding symptoms depend on type: Type 1: generally mild, but wide range Type 2: variable severity Type 3: severe bleeding

vWD Laboratory Evaluation
vWF Antigen Quantitative measure of vWF ELISA-based assay Ristocetan Cofactor Activity Qualitative measure of vWF activity Tests ability of vWF to bind Plts Factor VIII Activity vWF carrier protein FVIII Other testing: PFA-100 vWF Multimers Ristocetan Induced Plt Aggregation Collagen Binding Assay

vWD Diagnosis Lab-based diagnosis is challenging: Diagnostic dilemma
vWF: acute phase reactant Variability in an individual patient Variability between “normal” patients Diagnostic dilemma Type O blood: vWF 30-50% Is this disease? Very low hereditability Do not correlate with bleeding symptoms Rarely demonstrate polymorphisms at VWF locus “Low vWF” NHLBI Expert Panel on vWD: Diagnostic criteria: vWF level <30% Hereditable disorder Identifiable mutations of VWF Screening for vWD: vWF level (antigen) Ristocetan cofactor assay FVIII level PFA100 Repeat testing Additional: Collagen binding assay Multimer analysis National Heart Lung and Blood Institute Expert Panel on vWD evidenced based diagnosis guidelines Elevation of vWF is not indicative of a bleeding disorder

vWD Treatment Depends on the type and severity of symptoms.
Desmopressin Induces vWF and F8 release from endothelium IV (DDAVP) or Intranasal (Stimate) Effective for Type 1 “Stimate Challenges” Worsen some Type 2 Tranexamic Acid or Aminocaproic Acid Inhibits conversion of plasminogen to plasmin PO Menorrhagia OCP’s + Antifibrinolytic (menses) + Stimate (menses)

Congenital Platelet Disorders
Heterogenous group of platelet function defects: Adhesion Activation Aggregation Secretion Signal Transduction Prevalence Not well established in general population Studies of individuals presenting with bleeding problems: Fairly common Likely underestimated Disorders of primary hemostasis: Mucocutaneous bleeding and bruising Immediate bleeding Excessive bleeding with trauma, surgery, dental procedures

Platelet Function Testing
Bleeding Time Historical relic PFA-100 Automated system of measuring function High negative predictive value Poor screening test Platelet Aggregation Studies Qualitative assessment of function Requires technical expertise Light Transmission Aggregometry

Congenital Platelet Disorders
Bernard-Soulier Syndrome Glanzmann Thrombasthenia Defect in adhesion AR mutation in GP Ib receptor Can’t bind vWF Presentation: infancy Petechiae, bruising, mucous membrane bleeding Epistaxis, menorrhagia common Diagnosis Moderate thrombocytopenia (50-100) Giant platelets Abnormal Plt Aggregation No agglutination to Ristocetan Defect in aggregation AR mutation in GPIIb/IIIa receptor Presentation Indistinguishable from BSS or type 3 vWD Mucocutaneous bleeding in infancy Epistaxis, menorrhagia common Diagnosis Normal platelet count Normal platelet size Abnormal Plt Aggregation Agglutination to Ristocetan only Most severe and best characterized Original BSS patient (described in 1948) presented at 15 days of life, significant bleeding episodes, died of bar room brawl at age 28 BSS heterozygotes have mild macrothrombocytopenia without bleeding symptoms

Acquired Platelet Disorders
Aspirin Irreversible inhibition of COX-1 Effect lasts lifetime of platelet (8-10 days) Ibuprofen Interferes with arachidonic acid generation Transient (<4 hours) Antibiotics Effect is dose dependent High doses only Maximal effect 1-3 days Last 12 days after Abx Clinical relevance is controversial Aspirin irreversibly acetylates COX-1 – inhibits Thromboxane A2 generation thereby inhibiting platelet activation Aspirin effect is irreversible – platelet lifetime 8-10 days NSAID’s interfere with arachidonic acid generation Reversible, transient effect typically <4 hours

Rare Bleeding Disorders
Factor XI (Hemophilia C) Common in Ashkenazi Jewish population 0.2% homozygous: bleeding after surgery, epistaxis, menorrhagia Prolonged aPTT 11% heterozygous minimal symptoms with NSAID’s, ASA Normal aPTT Factor VII Prolonged PT only Bleeding symptoms highly variable Homozygous: FVII <10 Heterozygous: FVII 40-60 Factor XIII Normal PT and aPTT Functions in cross-linking and stabilizing fibrin Diagnosed with clot solubility test 30% intracranial hemorrhage Umbilical cord bleeding and delayed separation Impaired wound healing Afibrinogenemia Complete lack of fibrinogen Bleeding: mild-life threatening 5-10% rate of ICH 85% patients dx in neonatal period with umbilical cord bleeding Diagnosis: Absent fibrinogen levels Prolonged PT and aPTT Prolonged Thrombin Time Age matched norms of FXI and FVII levels need to be used for infants

Evaluation of Infants Challenges:
Age-dependent normal ranges PT, aPTT → prolonged in infancy Factor activity levels → decreased in infancy FVIII and vWF → increased in infancy Fibrinogen and Thrombin Time → variable Blood volume limitations Sampling difficulties Diagnostic evaluation after 1 year old preferred (if possible) vWD Diagnosis Type III present in infancy Decreased levels Type II Apparently normal values Type I Asymptomatic in infancy Physiologically elevated levels of vWF obscures screening Severe platelet function disorders PFA-100 and platelet aggregation reliable in infancy Flow cytometry to eval for BSS and GT in infancy

Diagnostic Challenges
When coags are not what they seem: Prolonged PT and aPTT → abusive head trauma Coagulopathy induced by parenchymal brain injury Prolonged aPTT Lupus Anticoagulant → false prolongation Factor 12 deficiency → not associated with bleeding Contact factor deficiencies → not associated with bleeding Normal PT and aPTT Factor 13 deficiency Non-Accidental Trauma Presence of bleeding disorder does not rule out a bleeding disorder vWD → high prevalence Bruising Determining causative factor is challenging

Bleeding Disorder Evaluation
History and Physical High Suspicion Low Suspicion Observe CBC and diff with smear Laboratory Evaluation Prothrombin Time (PT) Partial Thromboplastin Time (PTT) Fibrinogen Second Tier Testing von Willebrand Panel vWF antigen Factor 8 Ristocetan cofactor assay Hematology

Take Home Points Distinguishing symptoms of primary hemostasis (easy bruising, bloody noses) from secondary hemostasis (joint bleeds, delayed bleeding) simplifies the work-up. A comprehensive history and thorough physical exam are the best screening tests for a bleeding disorder. CBC and coags (maybe fibrinogen) will rule out most severe bleeding disorders. Add on a von Willebrand panel and you will have made the diagnosis in the majority of cases!

References Allen GA, Glader B. Approach to the bleeding child. Pediatr Clin North Am Dec; 49: Hoyer LW. Hemophilia A. N Engl J Med Jan; 330: Israels SJ, Kahr WH, Blanchette VS, et al. Platelet disorders in children: A diagnostic approach. Pediatr Blood Cancer June; 56: Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (vWD): evidence- based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia Mar; 14: Revel-Vilk S. Clinical and laboratory assessment of the bleeding pediatric patient. Semin Thromb Hemost Oct; 37: Rodriguez V and Warad D. Pediatric coagulation disorders. Pediatr Rev July; 37: Sarnaik A, Kamat D, and Kannikeswaran N. Diagnosis and management of bleeding disorder in a child. Clin Pediatr May; 49:

Post Test Questions A 17 year old girl presents for evaluation of menorrhagia. She has had intermittent epistaxis lasting longer than 20 minutes. In addition, she bled excessively immediately after her wisdom teeth were removed. Her presentation is most consistent with defects in which components of normal hemostasis: Platelets and Prothrombin Factor 8 Fibrinogen and Factor 13 von Willebrand Factor and Platelets Platelet Activation Inhibitor 1

Post Test Questions A mother calls the office to report that her 2 year old son has had easy bruising on his chest and back intermittently for the past few months. He now has a goose egg on his forehead. He was circumcised at birth without any complications. What is the most appropriate next step: Send the child for CBC with smear and PT/INR and aPTT. Ask mom to monitor and record his bruises over the next month. Schedule a sick visit in the office for later this afternoon. Check factor 8 and 9 levels on the son STAT. Check mom’s CBC, coags, and factor 8 level.

Post Test Questions You are evaluating a 7 year old boy with a swollen elbow that occurred after he fell off of his bike. His exam is suggestive of a joint effusion that is warm and tender. You check a CBC with smear and coags. His aPTT is prolonged at 47 seconds (normal sec). His CBC and PT/INR are unremarkable. Which is not a possible cause of his lab abnormality: Factor 7 deficiency Lupus anticoagulant Mild Hemophilia B Factor 11 deficiency von Willebrand disease

Bumps, Bruises, and Bloody Noses Evaluation of Pediatric Bleeding Disorders Because bruising and bleeding are normal events of childhood, the pediatrician.

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Bumps, Bruises, and Bloody Noses Evaluation of Pediatric Bleeding Disorders Because bruising and bleeding are normal events of childhood, the pediatrician.

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Presentation on theme: "Bumps, Bruises, and Bloody Noses Evaluation of Pediatric Bleeding Disorders Because bruising and bleeding are normal events of childhood, the pediatrician."— Presentation transcript:

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