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

3. 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.

4. 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.

5. 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

6. 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.

7. 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.

8. 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

9. 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

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

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 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

33. Treatment Guidelines in VWD
TYPE 1 2A 2B 2M 2N 3
TREATMENT
DDAVP
DDAVP/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 ( 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 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
% 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
2nd generation has no B domain – shorter molecule

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

47. Clinical Severity

50. Chronic Joint

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

52. 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

53. 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

54. The Past…

55. Present
…the promise of achieving your potential

56. Made possible by a STRONG & Dedicated Hemophilia parent association and dedicated NJHA staff

57. Thank you