Practical approach to a bleeding child Peri Kamalakar,MD Director The Valerie Fund Children’s Centers For Cancer &Blood Disorders At Saint Barnabas Health Care System Associate Director, Hemophilia Center Newark Beth israel Medical Center

Practical approach to a bleeding child OBJECTIVES: Overview of hemostasis Clinical approach in making a diagnosis Review the most common bleeding conditions Discuss the current treatment strategies

Note the central location of red blood cells and the peripheral margination of platelets. This radial distribution of cells results from a fluid dynamic effect called rheophoresis. The location of plasma and platelets at the vessel surface is important for efficient repair of the vessel injury.

With an injury to the endothelial lining of the vessel at least two parameters are changed. First collagen is exposed to the platelets that are spatially approximated to the vessel surface. Secondly, rheologic factors further enhance platelet activation.

Overview of Haemostasis INJURY Collagen Exposure Tissue Factor VASOCONSTRICTION Platelet Adhesion and release reaction Serotonin Platelet Phospolipid Coagulation Thromboxane A2 ADP Platelet aggregation Thrombin Primary haemostatic plug Fibrin Stable haemostatic plug Fibrinolysis

Once thrombin is present fibrin can be formed Once thrombin is present fibrin can be formed. Thrombin leads to numerous other important events, including activation and recruitment of other platelets to the injury site.

This scanning electron micrograph shows the consequences of exposure of the sub endothelial basement membrane. Once collagen is presented to platelets under mechanical shear, platelet activation and adhesion occur. Fibrin assembly will shortly follow.

Overview of Haemostasis INJURY Collagen Exposure Tissue Factor VASOCONSTRICTION Platelet Adhesion and release reaction Serotonin Platelet Phospolipid Coagulation Thromboxane A2 ADP Platelet aggregation Thrombin Primary haemostatic plug Fibrin Stable haemostatic plug Fibrinolysis

Coagulation cascade XIIa Kinins HMW Kininogen Intrinsic Pathway Kinins HMW Kininogen Kallikrein Contact Activation XII Prekallikrein XIIa XIa XI IXa Ca++ IX VIIIa VIII Ca++ Phospholipid Extrinsic Pathway VII VIIa Ca++ Tissue Factor Common Pathway Xa X Va V Ca++ Phospholipid XIII II IIa XIIa Fibrinogen Fibrin XIII

Within a few minutes the entire injury site is covered by confluent activated platelets.

PRACTICAL APPROACH TO A CHILD WITH BLEEDING HISTORY HISTORY – HISTORY – HISTORY >AGE OF ONSET > SEX >FREQUENCY >LOCATION / TYPE OF BLEEDING >DURATION OF BLEEDING > MEDICATIONS > ASSOCIATED SYMPTOMS > REVIEW OF SYSTEMS

Approach to a bleeding patient What is the type of bleeding disorder? Primary hemostasis – Vascular causes Platelets-Number vs. Function Fibrin formation – clotting factors Premature clot dissolution- post clot formation

. Approach to a bleeding patient Is a bleeding tendency present? Easy Bruising Mucosal bleeding Menorrhagia Surgical Hemorrhage – Procedure vs.Diathesis Postpartum Hemorrhage Joint and Muscle bleed –Severity of trauama

. Approach to a bleeding patient Is the disorder Familial or Acquired? Family history – MOTHER & OTHER FEMALE MEMBERS IN THE IMMEDIATE FAMILY – Detailed Menstrual history

Vascular causes – First and foremost rule out infectious causes – “Meningococcemia” Vasculitis – Henoch-Schonlein Purpura Hemangiomas- Kassalback-Merritt syndrome

Petechiae and Purpura 􀂄 Infectious – Meningococcemia – Rocky mountain spotted fever – Group A strep – Atypical measles – Echovirus 9, 4, 7 – Epstein-Barr virus – Coxsackie virus A9

􀂄 Non-infectious – Normal platelets 􀂄 HSP 􀂄 Coagulation disorders 􀂄 Trauma – Low platelets 􀂄 ITP 􀂄 Leukemia

PRACTICAL APPROACH TO A CHILD WITH BLEEDING HISTORY PHYSICAL EXAMINATION- > PETICHEAE >ECHYMOSES >JOINT BLEED &DEEPSEATED HEMATOMAS > HEPATOSPLENOMEGALY >SIGNIFICANT LYMPHADENOPATHY > ACTIVE AND PLAYFUL VS. ILL LOOKING > DYSMORPHIC FEATURES > CAFÉ-AU-LAIT SPOTS >TELANGIECATIC VESSELS >HEMANGIOMAS

PRACTICAL APPROACH TO A CHILD WITH BLEEDING HISTORY LABORATORY WORK UP- P.M.D - > C.B.C./PLATELET COUNT >PERIPHERAL SMEAR- MORPHOLOGY > P.T. [Prothrombin time] > a.P.T.T. [ Activated partial thromboplastin time] ----------------------------------------------------------------- Hemophilia service -- > T.T. [Thrombin time] > Bleeding time >Platelet aggregation studies > Factor assay

Pandora’s box: coagulation test The results are as good as the sample is. Standards: Time from sample to test: PT 24 hours ,PTT 4 hours. Blood/citrate ratio: 9 :1.

Bleeding disorders Platelets– Acquired causes much more common Thrombocytopenia more common than functional defects Inherited disorders – both number &functional defects are extremely rare

PLATELETS – NUMBER Acquired causes are most common I.T.P. Infections CONGENITAL THROMBOCYTOPENIAS T.A.R. syndrome

I.T.P.- Most have benign &limited course Treatment options- Conservative –wait &watch Aggressive- Steroids IvIGG Rhogam Rituximab

PLATELETS Functional disorders- Acquired- Aspirin; Uremia Inherited – Glanzman’s Bernard-Soulier Gray platelet syndrome

von Willebrand Disease The most common inherited bleeding disorder Occurs in 1% of the population Less than 10% of patients have bleeding events due to vWD

Inheritance of Type 1 vWD

Functions of vWF Binds to platelet receptor GP Ib and to subendothelial structures such as collagen serving as bridge between platelets and subendothelium in damaged vessels Acts as bridge between adjacent platelets in vessels with high shear (arterioles) forming small platelet aggregates Binds to circulating factor VIII protecting it and prolonging FVIII t1/2 in the circulation from 2 to 8-12 hours

Symptoms of vWD Easy bruisability Epistaxis or gingival bleeding Menorrhagia Post-partum hemorrhage Post-surgical bleeding Bleeding post-dental extraction

Classification of vWD Sub types of VW Type 1 Partial quantitative deficiency of vWF Type 2 Qualitative variants of vWF A Absence of HMW vWF multimers B Same as 2A and increased affinity for platelet gp Ib M Abnormal function not caused by absence of HMW multimers N Decreased affinity for factor VIII Type 3 Complete deficiencey of vWF & Behave as Severe Hemophilia A Classification of vWD

Treatment Guidelines in VWD TYPE 1 2A 2B 2M 2N 3 TREATMENT DDAVP DDAVP/FVIII-VWF FVIII-VWF

DDAVP (1-desamino-8-D-arginine vasopressin) Parenteral form: DDAVP (for IV or SC use, 0.3 ug/kg) Highly concentrated intranasal spray form: Stimate nasal spray (150-300 ug )

Hemophilia

Hemophilia Caused by an absence or decreased amount of a procoagulant – VIII -Hemophilia A affects ~ 1:5000 males XI -Hemophilia B affects ~ 1:30000 males XI –Hemophilia C – Rare /Ethnicity

Epidemiology Incidence: Hemophilia A - 1:5,000 Hempohilia B – 1: 30, 000 Hemophilia A Other Hemophilia B

Inheritance

Inheritance

Woman can have hemophilia Lyonization of the normal X chromosome Turner syndrome ( XO) Father with hemophilia/ mom as a carrier vW type 2 N ( Normandy)

HEMOPHILIA SEVERITY LEVELS Severe <1% activity level - Spontaneous bleeds Moderate 1 to 5% activity --Trauma/surgery bleeds Occasional joint bleeds Mild 5 to 30% activity - Major trauma/surgery Rare joint bleeds

Factor replacement 1 u/kg raises FVIII levels 2% 1/2 life : 12 hrs 1 u/kg raises FIX levels 1 % 1/2 life 20-24 hrs

Minor Bleeding Episodes Early joint bleeds Soft tissue & muscle bleeds Nose & gum bleeding not responding to local measures Treatment of minor bleeding episodes 40 - 50% correction FVIII : 25 units / kg FIX : 50 units / kg

Major Bleeding Episodes Advanced soft tissue & muscle bleeds Head & neck injuries Gastrointestinal bleeding Advanced joint bleeding Treatment of major bleeding episodes 80 – 100 % correction FVIII : 50 units / kg FIX : 100 units / kg

Current Products Plasma Products: plasma-derived factor VIII concentrate Porcine Factor: Use was halted due to parvovirus/retrovirus sequences discovered Recombinant products: First Generation: Recombinate, Kogenate, Helixate Second Generation: Kogenate FS, Helixate FS Third Generation: Advate DDAVP: Causes release of factor VIII/vWF Increased factor activity in 30-60” For mild hemophiliacs and mild bleeding symptoms 2nd generation has no B domain – shorter molecule

Replacement therapy: Joint disease Prophylaxis Primary Secondary Intensive infusion therapy Dose escalation modified prophylaxis

Clinical Severity

Chronic Joint

Hemophilia Treatment Center Team Members Patient / Family Hematologist Nurse Social Worker Physical Therapist Orthopedist Primary Care Infectious Disease Genetics Pharmacy Dental Hepatologist

Basis for Comprehensive Care Hematologist Assumes overall care Musculoskeletal Orthopedic Surgeon, Physical therapist Nursing Coordination of home/clinic care for rapid treatment at the earliest symptoms suggestive of a bleed Dental Genetic Counseling Infectious Disease Psychosocial social worker

Role of Hemophilia Treatment Centers State-of-the-art medical treatment for persons with hemophilia through out the life span Education Research Outreach Model of comprehensive care for chronic disease

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