1. Bleeding Diathesis: Recognition, Evaluation & Treatment of Hemophilia & von Willebrand Disease
Renee Marlette APRN, FNP-BC
Hemophilia Treatment Center
Hematology/Oncology
Primary Children’s Medical Center

2. Bleeding Diathesis: Recognition, Evaluation & Treatment of Hemophilia & von Willebrand Disease
Identify red flags indicative of a bleeding diathesis in pediatric patients
Identify critical components of history, physical examination and laboratory studies
Pearls on recognition & management of Hemophilia
Pearls on recognition & management of von Willebrand Disease

3. Hemophilia Treatment Center Primary Children’s Medical Center Hematology/Oncology

4. Red Flags: History* Ecchymosis? Soft tissue hematoma?
Joint hemorrhages?
Delayed bleeding?
Bleeding from superficial skin abrasions?
Bleeding from tooth extraction/T&A/surgery?
Menorrhagia? (define)
Male or Female?
Medications? (NSAIDS, ASA, herbals)
*Not all bleeding episodes suggest a bleeding disorder!
Bleeding into the skin and mucous membranes is characteristic of disorders of platelets and blood vessels (purpuric disorders) and may be manifested as Petechiae and/or ecchymosis.
Bleeding into soft tissue, muscle, and joints suggests the presence of hemophilia or other disorders of coagulation
*EPISTAXIS: 1979 study found that 30 percent of children younger than five years and 56 percent of children aged 6 to 10 years had had at least one nosebleed [2]. The incidence of epistaxis declines in adulthood, but approximately one-half of all adults with epistaxis had nosebleeds during childhood [3]. Epistaxis is rare in children younger than two years (approximately 1 per 10,000) and should prompt consideration of trauma (intentional or unintentional) or serious illness (e.g., thrombocytopenia)

5. WHO Bleeding Scale

6. Red Flags: Family History
X-linked recessive inheritance?
Male siblings and maternal uncles/grandfather
Hemophilia
Autosomal dominant inheritance?
Mother or father may transmit
Mucocutaneous symptoms
vWD,
Autosomal recessive & Negative inheritance
30% of Hemophilia de novo
Autosomal dominant: vWD, hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease)
Autosomal recessive: rarer factor deficiencies VII, XI

7. Red Flags: Physical Exam
Is this bruising within normal limits?
Indurations
Placement
Petechiae
Wet purpura
Epistaxis
Hemarthrosis vs. soft tissue bleeds
Hyperflexibility of small joints and skin tissue laxity

8. Differentiation of Symptoms
Common to all
Differentiating “easy/prolonged” bleeding
Mucocutaneous Symptoms
Excessive bruising- indurations
Excessive initial bleeding
Petechiae
Oral, nasal mucosa
Genital tract (menorrhagia)
Hemarthrosis
Excessive bruising
Excessive continued bleeding
PAIN with compression
Differentiate from soft tissue bleeding

9. Coagulation screening in Children

10. Laboratory & Diagnostic Studies
Level I
CBC (Hgb/Hct/MCV/MCH/RBC/Plt) PT
PTT
Level 1.5
vWP, TSH
PFA-100
Fibrinogen (TT)
Level II
vWP with multimers, ABO
PT mixing study factor VII
PTT mixing study factors IX, X (XI, others)
PT & PTT prolonged factors II, V, X
DRVVT /Lupus anticoagulants
TT with RT
CBC: Psuedothrombocytopenia—examine peripheral smear
The reptilase time (RT) is similar to the TT in measuring the conversion of fibrinogen to fibrin [27]. The reptilase time is useful for detecting abnormalities in fibrinogen (in which case the TT is also prolonged) and in detecting the presence of heparin (heparin will cause prolongation of the TT but not reptilase time). Thus, the RT is most useful for determining if heparin is the cause of a prolonged TT
Reptilase time:Reptilase is an enzyme similar to thrombin that is found in the venom of Bothrops snakes. However, it differs from thrombin by generating fibrinopeptide A but not fibrinopeptide B from fibrinogen and by resisting inhibition by heparin via antithrombin.

11. Coagulation Cascade
Prothrombin time (PT) — The production of fibrin via the extrinsic pathway and the final common pathway requires tissue thromboplastin (tissue factor), factor VII, factors X, V, prothrombin (factor II), and fibrinogen. The functioning of these pathways is measured by the PT (figure 1). This test bypasses the intrinsic pathway and uses "complete" thromboplastins (ie, tissue factor) capable of activating the extrinsic pathway.
Activated partial thromboplastin time (aPTT) The PT is sensitive to alterations in the vitamin K-dependent coagulation factors, especially factors II, VII, and X, and is used to monitor treatment with vitamin K antagonists.
Activated partial thromboplastin time (aPTT) measures the intrinsic and common pathways of coagulation (figure 1). It is called "partial" because clotting is initiated in vitro with agents that are only partial thromboplastins (ie, they are incapable of activating the extrinsic pathway). This aPTT is routinely used to evaluate intrinsic coagulation and the degree of heparin anticoagulation. (See "Clinical use of coagulation tests", section on 'Activated partial thromboplastin time'.)
The aPTT is sensitive to deficiencies of factors XII, XI, IX, and VIII and to inhibitors such as heparin (figure 1). It is less sensitive than the PT to deficiencies within the common pathway (eg, factors X, V, prothrombin, and fibrinogen) and is unaffected by alterations in factors VII and XIII.

13. Hemophilia- Diagnosis
X-linked genetic disorder
Factor Deficiency
Prolonged PTT
CORRECTS with 1:1 mixing study
Bleeding symptoms
Prevalence
1 in 5,000 male births
Estimated in US 20,000

14. Hemophilia- Definitions
Factor Deficiency
Hemophilia A: FVIII
Hemophilia B: FIX
Hemophilia C: FXI
Severity
Mild > 5% - 50%
Moderate 1 – 5%
Severe < 1%

15. Hemophilia – Presentations
X-linked Family History
30% new mutations
Symptoms
Bruising/bleeding
*Hemarthrosis (joint) – *Hallmark
Soft tissue/deep muscle
Nose/mouth, other bleeds
However, clotting factor levels vary from one carrier to another due to lyonization [2], in which the
expression of one of the two X chromosomes is randomly suppressed.
Hemizygosity of X chromosome in Turner’s syndrome XO
Homozygosity in a female
VWD type 3 or 2 N
Testicular feminization syndrome

16. Hemophilia – Presentations
Severity of clinical bleeding symptoms
Genetics
Hemophilia A vs. Hemophilia B
Female:
Symptomatic carriers d/t Lionization
Expression of one of the X chromosomes is randomly suppressed
However, clotting factor levels vary from one carrier to another due to lyonization [2], in which the
expression of one of the two X chromosomes is randomly suppressed.
Hemizygosity of X chromosome in Turner’s syndrome XO
Homozygosity in a female
VWD type 3 or 2 N
Testicular feminization syndrome

17. Hemophilia – Presentations
5 major emergent bleeds:
Head
Eye
Neck/Throat
Abdominal/Stomach
Kidney/Bladder

18. Hemophilia- Tx with FACTOR
Factor Replacement
Percent correction
50% correction
100% correction
Products based on purity
Whole-molecule
Recombinant
Dosing
Factor VIII: 1 mg/kg  2% increase
Factor IX: 1 mg/kg  1% increase

19. Hemophilia- Treatment
Treatment Options
RICE – rest, ice, compression, elevation
Factor replacement
Prophylaxis
For Severe (<1% factor) patients
Prior to aggressive activities
DDAVP (Stimate)
Mild Hemophilia A
Topical Measures
Antifibrinolytics: Amicar, Lysteda

20. Hemophilia – Clinical Situations
Newborn Protocol
Cord blood for PTT, factor level if +FHx
Factor only if bleeding
DELAY circumcision for 1 year
Yes Vit K, Hep B SQ
Immunizations
SQ injections, pressure 10 min, ice (not direct) 10 min, call if swelling
Dental procedure
Ab coverage (ports)
+/- factor
+/- antifibrinolytic
Surgery /Trauma
IHTC consultation – notify early

21. Hemophilia INHIBITORS
Development of autoimmune response with antibody development
30% of Hemophilia A patients lifetime
Level
Low-level <5 BU
High/responder >5 BU
Treat with bypassing agent for bleeding
ITT – Immune Tolerance Therapy

22. Hemophilia OUTCOMES FUTURE THERAPIES
Improved morbidity and mortality when connected with IHTC
Role of PCP/specialty groups
FUTURE THERAPIES
Long-Acting Factors
Factor IX
Factor VIII
Gene Therapy
Europe, factor IX
Factor purity

23. von Willebrand Disease
Inherited bleeding disorder
Genetic mutation
Dysfunction of or deficiency of von Willebrand factor (vWF)
Platelet adhesion
Binds and stabilizes FVIII
Most common genetic bleeding disorder
1:10,000 or 1:1000?
1926. Erik VW , a dedicated physician, evaluated 4 year old girl in 1925 for bleeding lip , has H/O nose bleed and lived in a remote island off the shore of Finland
The 9th of 12 children ,4 died of bleed between 2- 4 y
The same girl bled to death after her 4th M.P
23 members of her family were bleeders (16 women)
He called the condition “Pseudo hemophilia”

24. From The Diagnosis, Evaluation, and Management of von Willebrand Disease, US Dept of HHS 2007

25. Bleeding Score: Modified Vicenza Score

26. Bleeding Score: Modified Vicenza Score
Total all 3 columns
BS >3 in males or >5 in females was 98.6% specific for vWD
BS can be as predictive or superior to vWF level if the bleeding is after tooth extraction or surgery
In pediatrics, a mean BS is 0.5, normal range: 1.5 to 2.5
Children with known vWD: median BS: 7

27. From The Diagnosis, Evaluation, and Management of von Willebrand Disease, US Dept of HHS 2007

29. von Willebrand Disease
vWP testing –do the panel!
Factor VIII
vWAg
Actual protein
vWF (Ristocetin Cofactor /RCo)
Effectiveness of the von Willebrand protein
Look at ratio of vWF (RCo): vWAg
> 0.7 in Type 1
Multimeric analysis

30. von Willebrand Disease
von Willebrand multimers help determine the subtype

31. von Willebrand Disease

32. von Willebrand Disease

33. von Willebrand Disease
Pearls on testing…
Do not treat until confirmed laboratory diagnosis of type and severity (unless emergency)
DDAVP-responsiveness should be tested while non-bleeding
vWF lowest first 1-3 days of menstrual cycle
vWF stress-reactant protein
may need to retest
other platelet disorder?
Can you test on OCPs?

34. von Willebrand Disease- Tx Options
Avoid NSAIDs and other platelet –inhibiting drugs
Hormonal Therapy –pair with OB
OCP – monophasic, active pills to allow menses 1-2x/year
Depo shot, NuvaRing
Levonorgestrel intrauterine system
DDAVP (Stimate)
Concentration 150mcg/spray
Precautions: frequency, storage, dose, fluid restriction
Adjuvant Therapies: Antifibrinolytics
Aminocaproic acid (Amicar)
Tranexamic acid (Lysteda)
von Willebrand FACTOR
Humate P, Alphanate, Koate DVI

35. Fibrinolysis Cascade Aminocaproic Acid (Amicar)
Tranexamic Acid (Lysteda)

36. von Willebrand Disease – Tx Pearls
Goal is cessation of bleeding (prophylaxis for surgical procedures)
no long-term prophylaxis
Immunization Hep A and B
Genetic counseling
Oral surgery:
Antifibrinolytics, DDAVP, topical agents (fibrin sealant, topical thrombin), surgical hemostatic measures
All major surgeries should be Tx in hospitals with monitoring and hematology
Do not exceed vWF: RCo > 200 IU/dL, factor VIII >250%
CALL FOR CONSULTATION - IHTC

37. Von Willebrand Disease
Menorrhagia
Menorrhagia or abnormal vaginal bleeding- full gynecological eval before therapy (grade C, level IV)
Adolescent or adult not desiring pregnancy
OCPs should be first choice
Levonorgestrel intrauterine system
Desire pregnancy
DDAVP, antifibrinolytics, vWF concentrate
D&C is not usually effective in managing excessive uterine bleeding for women with vWD
Labor & Delivery
Plan with hematologist prior to pregnancy, high risk
If vWF:RCo levels & FVIII >50 may consider regional anesthesia
Delivery and post-partum support

38. Von Willebrand Disease
OUTCOMES
Depending on management
FUTURE THERAPIES
Long-Acting von Willebrand Factor
Gene therapy – potentially for vWD type 3
low prevalence, not likely to be high priority

39. Summary - Case Studies
13 month old male infant who is starting to walk and presents with a painful swollen joint after falling down one step…
12 year-old girl with excessive menstrual bleeding from menarche, recurrent nosebleeds, and pallor…
5 year-old girl child who is not clinically ill but presents with moderate Mucocutaneous purpura with a recent viral infection…
-13mo: Hemophilia

40. Bleeding Diathesis: Recognition, Evaluation & Treatment of Hemophilia & von Willebrand Disease
Identify red flags indicative of a bleeding diathesis in pediatric patients
Identify critical components of history, physical examination and laboratory studies
Recognition & Management of Hemophilia
Recognition & Management of von Willebrand Disease
THANK YOU!...Questions?