Practical approach to a bleeding child

1. 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

2. 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

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

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

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

11. 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

12. 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

13. . 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

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

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

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

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

18. 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

19. 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

20. 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.

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

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

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

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

28. 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

29. Inheritance of Type 1 vWD

30. 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

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

32. 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

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

34. 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 )

35. Hemophilia

36. 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

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

38. Inheritance

39. Inheritance

40. 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)

41. 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

42. 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

43. 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

44. 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

45. 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

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

47. Clinical Severity

50. Chronic Joint