pediatric thrombosis and bleeding- case studies · a2 1 22 a1 2 3 2 6 a3 1 22 2 3 2 6 a3 a2 a1...
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![Page 1: Pediatric Thrombosis and Bleeding- case studies · A2 1 22 A1 2 3 2 6 A3 1 22 2 3 2 6 A3 A2 A1 FVIII A2 A3 1 22 2 3 2 6 A1 A2 2 3 2 6 A1 22 1 3 Inversion Type 1. Recurrent joint bleed](https://reader034.vdocuments.us/reader034/viewer/2022051919/600beda30e7f4417d263fdd4/html5/thumbnails/1.jpg)
מחלות דמם
מודי משגב
המרכז הארצי להמופיליה
והמכון לקרישת הדם
תל השומר, שיבא
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Blood coagulation – Fast, Strong and Precise
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Primary Hemostasis - Vascular endothelium & Platelets
Adhesion
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Aggregation
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Secondary Hemostasis - Coagulation system
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Fibrin clot
Secondary Hemostasis - Coagulation system
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Normal fibrin networkFibrin clot
Secondary Hemostasis - Coagulation system
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♦ Type - Petechiae / Purpura / Ecchymosis
♦ Site - Predominantly skin, nose, GI / urinary tract
♦ Trigger - Immediate onset of bleeding usually after trauma
Platelets quantity or quality defects
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Petechiae
Pinpoint bruise less than 4 mm in diameter
Do not blanch with pressure (angiomas)
Not palpable (Vasculitis)
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Pinpoint bruise less than 4 mm in diameter
Petechiae
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Pinpoint bruise less than 4 mm in diameter
Petechiae
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Purpura
0.4 - 1 cm, generally round in shape usually (purple)
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‘Wet’ Purpura – Buccal mucosa, Gingiva, palate
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Sub-cutaneous bleeding
Ecchymosis
Blood in a thin layer under the skin, over 1 cm in diameter
("black and blue“)
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Gums bleeding
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Epistaxis
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Menstrual Bleeding
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♦ Type - Soft tissue hematomas, “Deep” Bleeding
♦ Site - Joints, muscles, intra-abdominal , ICH
♦ Trigger – Spontaneous or trauma related may be delayed
.
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Secondary hemostasis
Joint Bleed
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• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital (or acquired) ?
• Disease ?
• Drug (OTC supplements) ?
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• Abnormal bleeding symptoms ?
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• Bleeding type ?
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A negative family history does not rule out a hereditary BD
• New mutations
• Patients may be unaware of relatives with bleeding disorders
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
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• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
osler-weber-rendu disease Ehler danlos
arteriovenous malformation avm
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• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
Garlic, Ginger, Ginkgo, Ginseng
Green tea, kava, saw palmetto
St John’s wort, Valerian
Omega-3 fatty acids
SSRI’s
Medicines (Basel) 2015
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• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
Curcumin
Biochem Pharmacol 1999
Inhibitory effect of curcumin, a food spice from turmeric, on platelet-
activating factor- and arachidonic acid-mediated platelet aggregation
through inhibition of thromboxane formation and Ca2+ signaling.
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Coagulation
PT, aPTT
Fibrinogen (Quantity)
Thrombin Time (Quality)
CBC
Hb / Hct
Platelets
Routine Tests
Special tests
Coagulation factors
Platelets (Quality)
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ADP Collagen Epinephrin Ristocetin
Platelet aggregation
Shape
changeAggregation
Photo
detectorPlatelet Rich Plasma
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Vascular
lesion
Effect of Hct on platelet deposition on damaged arterial segments
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Effect of Hct on platelet deposition on damaged arterial segments
Hct = 40%, PLTs = 200,000/mcL
Hct = 20%, PLTs = 200,000/mcL
Hct = 20%, PLTs = 50,000/mcL
Transfusion 1994; 34:542-9
1
2
3
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PTT – 80s
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital or acquired ?
• Disease causing bleeding ?
• Drug cause of bleeding ?
TT – 14s
ח שנים8-בן שנה ו
2 לברך ולמרפק תוך חודש ימים ללא חבלה–דימומים
על הזרוע והירך" סימן כחול"פעמיים
מדממים מאד"סבא של הילד ודוד של אמא -משפחה."
PT – 12s
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PTT – 80s
ממוצא אשכנזי72בן
דםבילדות כריתת שקדים ניתוח חוזר עקב דימום קיבל עירוי
דימום לאחר עקירת שן באופן שחייב הסתכלות נוספת ותפרים
צ עבר ללא כל דימום"תיקון הרנייה מפשעתית דו
ללא הסטוריה של דמם–משפחה
. בירור המטולוגי לקראת ניתוח כריתת ערמונית<
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital or acquired ?
• Disease causing bleeding ?
• Drug cause of bleeding ?
TT – 14s
PT – 12s
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PT PTT
PT↑ & PTT ↑
TT
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TFFVIIa
XXa IXaIXVIIIa
Va
FIIaFII Fibrinogen
Fibrin
פיסיולוגיה של מערכת קרישת הדם
XIaXI
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TFFVIIa
XXaVa
FIIaFII Fibrinogen
Fibrin
פיסיולוגיה של מערכת קרישת הדם
המופיליה XIaXI
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PTT – 80s• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital or acquired ?
• Disease causing bleeding ?
• Drug cause of bleeding ?
FVIII – 1%
שנים3בן
2 לברך ולמרפק תוך חודש ימים ללא חבלה–דימומים
על הזרוע והירך" סימן כחול"פעמיים
מדממים מאד"סבא של הילד ודוד של אמא -משפחה."
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Hemophilia
♦ Hemophilia A - FVIII
♦ The term Hemophilia was first used in 1828
♦ Hemophilia B - FIX
In 1952 was named after Stephen Christmas “Christmas disease”
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♦ Hemophilia A (FVIII) 1:5,000 male births
♦ Hemophilia B (FIX) 1:25,000 male births
Severity (According to Factor level)
Severe < 1% - Moderate 2 - 5% - Mild 6 - 30%
Incidence
Hemophilia
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בן בריא
גן תקיןמוטציה להמופיליה
אמא אבא
בן בריא נשאית נשאית
X X XY
Y
X
Y
X X X X X
תורשה-המופיליה
8
Obligatory carrier
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בן חולה
גן תקיןמוטציה להמופיליה
אמא אבא
בן בריא בת נשאית לא נשאית
X X XY
Y
X
Y
X X X X X
8 8
50%
תורשה-המופיליה
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3 2
22
Male
Female Carrier
HA/B FVIII – 1%
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Aהבסיס המולקולרי של המופיליה
Aמכלל מקרי המופיליה 90%–מוטציות נקודתיות
5-10%–מוטציות חסר
Inversions–ותר נדיריםי
Inversion40%-מהווה סיבה למחלה ב22באינטרון
קשהAמהמקרים של המופיליה
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CentromereTelomere
Factor VIII
186kb
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A2
A11 22
2
3
2
6
A3
1 22 2
3
2
6
A1A2A3
FVIII
A2 A3
1 22 2
3
2
6
A1
A2 2
3
2
6
A3A1 122
Inversion Type 1
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Recurrent joint bleed
Target joint
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Hemophilia
Ancient disease - new treatments
1975 2019
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TFFVIIa
XXaVa
פיסיולוגיה של מערכת קרישת הדם
FIIaFII
Fibrinogen
FVIII / FIX
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Replacement of F8 / F9 protein
Hemophilia - treatment
1840 1950 1960 1970 1984 1990
Recombinant
products
Cloning of
FVIII geneLow-purity
FVIII
concentrate
1980
High purity
FVIII
concentrate
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Treatment of Hemophilia
Factor VIII/IX Concentrate
♦ Plasma derived
♦ Recombinant
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Treatment of HemophiliaProphylaxis
T1/2 ~ 8-12 hours
72h48h24h0hT1/2
01.512.5100%8
1.56.2525100%12
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♦ Long-Acting factors
Treatment of Hemophilia
Replacement of F8 / F9 protein
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Long-acting FVIII / FIX concentrateExtended-half life (EHL) concentrates
FVIII / IX - Fc
FIX - Albumin
FVIII / IX - PEG
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Long-acting FVIII
Blood 2013
T1/2 rFVIIIFc - 19.0 h (1.5 fold, P<.001)
T1/2 rFVIII - 12.4 h
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Long-acting FVIIIExtended-half life (EHL) concentrates
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1.6 1.773.6 3.57
33.6
25
0
5
10
15
20
25
30
35
40
rFVIII-Fc rFVIII-PEG
Every 3-5d Once a week On-demand
Long-acting FVIII / FIX concentrateExtended-half life (EHL) concentrates
1 Blood 2013, 2T&H 2017 2Hemophilia 2019
Annualized bleeding rate (ABR)
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Replacement of F8 / F9 protein
Hemophilia - treatment
1840 1950 1960 1970 1984 1990
rFVIII / FIX
products
Cloning of
FVIII geneLow-purity
FVIII
concentrate
1980
High purity
FVIII
concentrate
2010
EHL
products
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Hemophilia treatment state of the art
Hemophilia A Hemophilia B
25 - 30% 1 - 5%
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Hemophilia treatment state of the art
Immune tolerance induction
Inhibitors
Low dose: 25u/kg every other day
Intermediate dose: 50 / 100u/kg every other day
High dose: 200 / 300u/kg every other day
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TFFVIIa
XXaVa
FIIaFII Fibrinogen
Fibrin
FVIIa
(Novo Seven)
Treatment of bleeding episodesInhibitors -
Hemophilia treatment state of the art
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0 µg/mL 4.9 µg/mL 9.8 µg/mLrVIIa:
He et al. 2003
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TFFVIIa
XXaVa
FIIaFII Fibrinogen
FibrinFIEBA- Xa
Treatment of bleeding episodesInhibitors -
Hemophilia treatment state of the art
FIEBA- IIa
FIEBA- IXa
FIEBA- FVIIa
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Replacement Therapy
Treatment of Hemophilia
Antibodies
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Treatment of Hemophilia
Antibodies
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Treatment of Hemophilia
Bi-specific Ab
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A bi-specific Antibody to factors IXa and X restores
FVIII hemostatic activity in a hemophilia A model
Nature medicine Oct 2012
Takehisa Kitazawa (n= 32) Kunihiro hattori
https://www.chugai-
pharm.co.jp/english/profile/ad/index.html
Emicizumab
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Once weekly S.C Injection
NEJM Jul 2017
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1.6 1.773.6 3.57 2.9
33.6
2523
0
5
10
15
20
25
30
35
40
rFVIII-Fc rFVIII - PEG Emicizumab
Every 3-5d Once a week On-demand
Treatment of Hemophilia
1 Blood 2013, 2T&H 2017 2Hemophilia 2019, 4NEJM 2017
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Treatment of Hemophilia Emicizumab - no Inhibitors
NEJM 2018
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Treatment of Hemophilia Emicizumab - no Inhibitors
NEJM 2018
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Treatment of Hemophilia
Emicizumab
NEJM 2018
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Emicizumab – HA with inhibitor
ROTEM - NATEM
- Emicizumab + Emicizumab
Sheba Medical Center
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Emicizumab – HA with inhibitor
Livnat T . Sheba Medical Center
P = 0 . 0 1 7
Co
ntro
l
Be
fo
re
2 w
ee
ks
5 w
ee
ks
0
1 0 0
2 0 0
3 0 0
4 0 0
Pe
ak
h
ei
gh
t,
n
M
P < 0 . 0 0 1
P = 0 . 4 0 9
P a t i e n t s
* * *
* * *
* *
P = 0 . 0 4 2
Co
ntro
l
Be
fo
re
2 w
ee
ks
5 w
ee
ks
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
2 5 0 0
ET
P,
n
M
mi
n
P < 0 . 0 0 1
P = 0 . 2 2 1
P a t i e n t s
* * *
* * *
* *
![Page 77: Pediatric Thrombosis and Bleeding- case studies · A2 1 22 A1 2 3 2 6 A3 1 22 2 3 2 6 A3 A2 A1 FVIII A2 A3 1 22 2 3 2 6 A1 A2 2 3 2 6 A1 22 1 3 Inversion Type 1. Recurrent joint bleed](https://reader034.vdocuments.us/reader034/viewer/2022051919/600beda30e7f4417d263fdd4/html5/thumbnails/77.jpg)
Treatment of Hemophilia
Emicizumab
Loading dose: 3mg/kg/week
Maintenance dose: 1.5mg/kg/week
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Cure Hemophilia
Gene Therapy
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Cure HemophiliaGene Therapy using Adeno-associated virus (AAV)
AAV belongs to the parvovirus family
sDNA genome of approximately 4.8 kb.
Dependent on co-infection with other viruses, mainly adenoviruses to replicate.
Episomal DNA >> does not integrate into host genomes
![Page 80: Pediatric Thrombosis and Bleeding- case studies · A2 1 22 A1 2 3 2 6 A3 1 22 2 3 2 6 A3 A2 A1 FVIII A2 A3 1 22 2 3 2 6 A1 A2 2 3 2 6 A1 22 1 3 Inversion Type 1. Recurrent joint bleed](https://reader034.vdocuments.us/reader034/viewer/2022051919/600beda30e7f4417d263fdd4/html5/thumbnails/80.jpg)
Cure Hemophilia
Gene Therapy – Hemophilia B
NEJM 2011
♦ Six men with severe hemophilia B (FIX <1% )
♦ Infusion of 2×1011 vg / Kg
♦ Infusion of 6×1011 vg / Kg
♦ Infusion of 2×1012 vg / Kg
AAV serotype 8
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NEJM 2014
The 6 + 4 subjects (6 pt. in the high-dose 10^12 group)
■ Severe hemophilia < 1%
■ Moderate – mild hemophilia
Cure Hemophilia
Gene Therapy – Hemophilia B
In the high-dose group
Steady-state FIX plasma level of 5.1±1.7%
Follow-up for a median 3.2 years
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NEJM 2017
Cure Hemophilia
Gene Therapy – Hemophilia A
♦ 6×1012 vg / Kg
♦ 2×1013 vg / Kg
♦ 6×1013 vg / Kg
Total of 9 patients
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Cure Hemophilia
Gene Therapy – Hemophilia A
Annualized Bleeding rate
0
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Cure Hemophilia
Gene Therapy – Hemophilia A
A 3years update for the higher dose 6x10^13 vg/kg
Factor VIII levels appeared to be approaching a plateau:
After 2y mean 36.4 IU/dL and median 26.2 IU/dL
After 3y mean 32.7 IU/dL and median 19.9 IU/dl.
Bleeding: median ABR was 0 (mean - 0.7).
6x10^13 vg/kg Year 1 Year 2 Year 3
Mean (Median) FVIII activity
(IU/dL) Chromogenic Assay64.3 (60.3) 36.4 (26.2) 32.7 (19.9)
Mean (Median) F VIII Activity
(IU/dL)
One-Stage Assay
103.8 (88.6) 59.0 (45.7) 52.3 (29.8)
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Cure Hemophilia
Gene Therapy – Hemophilia A
A 3years update for the higher dose 6x10^13 vg/kg
6x10^13
vg/kg Before During Year 1 During Year 2 During Year 3
Median
(mean, SD)
Median
(mean, SD)
Median
(mean, SD)
Median
(mean, SD)
Annualized Bleeding
Rate
16.5
(16.3 ,15.7)
0.0
(0.9 ,2.2)
0.0
(0.2 ,0.4)
0.0
(0.7 ,1.6)
Annualized FVIII
Infusions
138.5
(136.7 ,22.4)
0.0
(2.1 ,5.3)
0.0
(8.8 ,21.0)
0.0
(5.5 ,9.4)
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Hemophilia
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ממוצא אשכנזי72בן
דםבילדות כריתת שקדים ניתוח חוזר עקב דימום קיבל עירוי
דימום לאחר עקירת שן באופן שחייב הסתכלות נוספת ותפרים
צ עבר ללא כל דימום"תיקון הרנייה מפשעתית דו
ללא הסטוריה של דמם–משפחה
. בירור המטולוגי לקראת ניתוח כריתת ערמונית<
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital or acquired ?
• Disease causing bleeding ?
• Drug cause of bleeding ?
PTT – 80s
FXI – 1%
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FXI deficiency (Hemophilia C)
Described in three members of Jewish family in the USA
Laboratory defect was corrected by mixing with HA and HB plasmas.
Bleeding phenotype in both men and women
Mild bleeding phenotype - tonsillectomy and dental extractions in
two sisters. Their uncle bled after dental extractions but had a
normal circumcision.
Rosenthal R et al, Blood. 1955.
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Ramot B, Angelopoulos B, Athens, Singer K, 1955
“ Clinically, this disorder manifests itself as a tendency to severe
bleeding following surgical procedures but not leading to
spontaneous hemorrhages”.
A new hemophilia like disease caused by deficiency of
a third plasma thromboplastin factor.
Rosenthal et al, Blood 1955
1927 - 2006
FXI deficiency
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♦ High gene frequency of FXI in Ashkenazi Jews
♦ The frequency of heterozygotes is 5.5%-11%
Seligsohn Blood 1978
♦ Frequency of Homozygous is 0.1%-0.3 %
♦ Severe deficiency 1:400
FXI deficiency
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FXI deficiency
■ Severe factor XI deficiency ► <15%
■ Hemophilia C is an injury-related bleeding
■ The deficiency is common in Ashkenazi and Iraqi Jews
■Ashkenazi Jews have 2 common mutations:
Type II Nonsense mutation Glu117Stop
Type III missense mutation Phe283Leu
■ Iraqi Jews have only type II mutation
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FXI deficiency
■ Type II/II homozygous have factor XI activity 1-2 U/dL
■ Type II/III have factor XI activity ~6 U/dL
■ Type III/III homozygous have factor XI activity 8-10 U/dL
Ashkenazi Jews –
• Carrier 1:10
• Severe deficiency 1:400
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FXI deficiency
To reduce fibrinolysis by promoting thrombin activatable
fibrinolytic inhibitor (TAFI).
Greater amounts of thrombin are required for this reaction
The intrinsic pathway feedback via FXI is important for this.
FXI-deficient individuals are prone to excessive bleeding after surgery
or injuries to areas with high levels of fibrinolysis.
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Bleeding following surgical procedures
Hemophilia 2006
Fibrinolytic sites – 62.5%
Non Fibrinolytic sites – 9.6%
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FXI deficiency
Surgical procedures in fibrinolytic tissues
Tonsilectomy, Nose & throat, complicated dental procedures, prostatectomy
■ Replacement therapy: FFP 10-15 ml/kg/d + TA (1gm x3-4/d)
■ Factor 11 concentrate (not available in Israel)
■ TA is sufficient for minor surgical procedures (Tooth extractions)
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Inhibitor
7
Genotype II/II
21
Genotype II/III
27
Genotype III/III
14
Other types
4
Transfused
64
Non-transfused
54
Unknown
4
Patients
122
Blood 2003
FXI deficiency
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T&H 2009
FXI deficiency
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לפני גיוס ללא מחלות רקע18בת
בוסת" כבד"דימום .
"עם וללא חבלה" סמנים כחולים
פעמים בשנה ודימום מחניכיים5-6אפיסטקסיס.
לא -תרופות
אין -סיפור משפחתי של דמם
PTT – 56s
CBC: Hb 9, MCV 72, RDW 19%, PLT 280
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
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4בן ■
פעמיים דימום למפרק הברך, מילדות דימום מריריות■
אין –סיפור משפחתי של דמם ■PTT – 62s
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
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4מקרה ■
vWF:Ag 4%, vWF:Rco <5%
FVIII – 5%FXI – 72% FIX – 83%
3מקרה ■
FVIII – 40%FXI – 72%
vWFAg 35% , vWF:Rco 30%
FIX – 83%
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Von-Willebrand factor
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Von-Willebrand factor
NEJM 2016
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Von-Willebrand factor
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Von-Willebrand factor
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Von-Willebrand factorA carrier of factor 8
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Von Willebrand E.A.
HEREDITAR PSEUDO-HAMOFILI
Finska Laeksaellsk Handl 68:87-112, 1926
Von-Willebrand disease
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Most common inherited bleeding disorder (0.6-1.3%)
► Defect in platelet adhesion / aggregation primary hemoestasis
► Secondary hemoestasis due to low levels of FVIII.
Type I (70-80%): reduced level of normally function vWF
Type II (15-20%): Impaired function
Type III (~5%): Severe deficiency of vWF
Von-Willebrand disease
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Blood
group
N vWF:Ag
mean %
Range ± 2SD
O 456 74.6 35.6-157
A 340 105.9 48-233.9
B 196 116.9 56.8-241
AB 109 123.3 63.8-238.2
vWF Levels
Blood 1987
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vWF Levels
50<10 40 60
vWF levels
Normal
VWD
O
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Conditions associated with higher VWF levels
Age
Acute and chronic inflammation
Diabetes
Malignancy
Pregnancy or oral contraceptive use
Stress; exercise
Hyperthyroidism
Conditions associated with reduced VWF levels
Hypothyroidism
Blood type O
Blood 1999
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Von-Willebrand disease
Type Definition Genetics
Type I Partial quantitative •Dominant
•Diverse phenotype
Type II
2A Absence of large multimers •Dominant
2M Decreased platelet dependent
function w/ large multimer
•Dominant
2B Increased vWF affinity for GPIb •Dominant
2N Decreased vWF affinity for FVIII •Recessive
Type III Complete deficiency of vWF •Recessive
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vWF
Platelet GPIb
Type 2N
Type 2B
Type 2 Variants - Qualitative abnormality
Type 2M
Factor VIII
15% - 20% of patients
vWF
Type 2A
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Type 2 Variants - Qualitative abnormality
Hoffman- Hematology Basic Principles and Practice,2009
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Type 2 Variants - Qualitative abnormality
• Fixed platelets (Formalin)
• Ristocetin
• Patient plasma
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Colman RW, et al: Hemostasis and Thrombosis, Principles and Clinical Practice, Williams and Wilkins, 2001
Type 2 Variants - Qualitative abnormality
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Von-Willebrand disease
Type FVIII vWF Ag vWF:RCo
Normal 100% 100% 100%
Hem A Low <1% 100% 100%
Type I Low Low LowvWF:R / vWFAg > 0.6
Type III ~5% ~5% Low <10%
Type 2A Low - Normal Low - Normal LowvWF:R / vWFAg < 0.6
Type 2M Low - Normal Low - Normal LowvWF:R / vWFAg < 0.6
Type 2B Low - Normal Low - Normal LowvWF:R / vWFAg < 0.6
Type 2N Low 10 - 20% Low - Normal Low - Normal
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♦ Tranexamic acid (Hexakapron) - In all vWD types
♦ vWF concentrate - Type II & III
Von-Willebrand disease treatment
♦ Desmopressin (DDAVP IV - 0.3µg/kg)
Low levels vWF and Type I
For some cases of Type II
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77בת ♦
ספיקת לב -מתאשפז במחלקה של החמרה באי♦
אין הסטוריה משפחתית של נטייה לדמם♦
אספירין♦
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital or acquired ?
• Disease causing bleeding ?
• Drug cause of bleeding ? PTT >150s
PT - 14s
INR – 1.3
Fibrinogen - 324mg
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שארית של הפרין במבחנה ♦
יש לחזור עליה-כאשר בדיקה לא מתאימה לנתונים הרפואיים ♦
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מאושפז בטיפול נמרץ לב בשל 67בןVT עם רגל איסכמית
ל מושתל "אס, מחלת לב אסכמית מספר צינתורים וניתוחי מעקפיםICD
פקקת ביד משנית לפיקליין
צינתורים קודמים/אין הסטוריה של דמם ולא היה דימום חריג בניתוח
PTT - 150s
FXII <1%• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
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PTT – 100s
ממוצא עירקי 43בן
מאושפז בנוירולוגיה באבחנה שלAutoimmune cerebelitis
פרזיס-עובר טיפול פלסמה
לקראת בדיקתLP נלקחו בדיקות קרישה
PTT on admission - 32s• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
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עם יתר לחץ דם69בן ♦
מתאשפז במחלקה עקב דימומים ואנמיה ♦
אין הסטוריה משפחתית של נטייה לדמם♦
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
• PTT – 84s
• PT - 14s, INR – 1.2
• Fibrinogen – 350mg/dl
• Hb - 9 gr%
• PLT – 312,000
• Platelet function - Normal
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2+נ, 37בת .
לאחר לידה שלישית המטומות על היד רגל דופן בטן ומנדיבולה מימין'שב7-כ .
.שוללת דימום מריריות. אין קשר לחבלות
מיילדותית#
6הפלה ספונטנית בשבוע -2014הריון ראשון -
. צוואר פעור בוצע תפר23בשבוע . בהריון השני דימומים מתחילתו-
.גר ששרד641לידה מוקדמת של עובר במשקל 25בשבוע
. צירים34בשבוע . תפר צווארי מניעתי2016הריון שלישי -
. 'גר1899נולד פג במשקל . חשד לאמניוניטיס
ניתוח אף אלקטיבי .
אסתמה, דלקות גרון, ברונכיטיס, בילדות סינוסיטיס
מוצא אשכנזי אין נטייה לדמם –משפחה
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
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PTT – 94s
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PTT – 94s
Inhibitor = 20BU
Bethesda UniteThe amount of inhibitor that will
inactivate half of FVIII activity
FVIII < 1%
PTT – 84s
Inhibitor = 8BU
FVIII - 12%
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Pati
ents
(%
)
Age of onset (years)
Incidence ~ 1/106/y
Age of onset
Mean ~ 65 y
Range ~ 2 to 90 y
Bimodal distribution
Young adults, F > M
Older patients, M > F
Morrison AE, et al. Blood. 1993;81:1513-1520.
0
10
20
30
40
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Idiopathic ~50%
Auto-Immune Disorders ~ 14%
Malignancy ~ 11.5%
Pregnancy ~ 10%
MGUS ~ 7.8%
Drug Induced (penicillin, sulfonamides , phenytoin…) ~3.3%
Blood 2012
Inhibitor may be first
manifestation of malignancy or
autoimmune disorder
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Sites of bleeding in patients with acquired haemophilia
In 8% bleeding was the primary cause of death.
Peter W. Collins et al. Blood 2007
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* Spontaneously remission possible if the inhibitor is low titers < 5BU
Treatment
Stop bleeding
Inhibitor eradication
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TFFVIIa
XXaVa
FIIaFII Fibrinogen
Fibrin
FVIIa
(Novo Seven)
Treatment of bleeding episodesInhibitors -
Hemophilia treatment state of the art
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TFFVIIa
XXaVa
FIIaFII Fibrinogen
FibrinFIEBA- Xa
Treatment of bleeding episodesInhibitors -
Hemophilia treatment state of the art
FIEBA- IIa
FIEBA- IXa
FIEBA- FVIIa
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TFFVIIa
XXa IXaIXVa
FIIaFII Fibrinogen
Fibrin
פיסיולוגיה של מערכת קרישת הדם
Porcine FVIII
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Journal of Immunology Research 2014
FVIII concentrate (if inhibitor < 5BU)
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Neutralizations studies
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Treatment
Stop bleeding
Inhibitor eradication
Steroids Steroids + Cyclophosphamide
First line treatment
Rituximab
Second line treatment
Alternative treatments
Azathioprine Vincristine Mycophenolate Cyclosporine
Immune globulin are not recommended
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Rituximab 200mg times 4 one a week
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בריאה ממוצא אשכנזי 22בת ♦
מגיע לחדר מיון גניקולוגי עקב דימום וגינלי♦
4-5האבחנה הפלה בשבוע ♦
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
PTT – 74s
אין הסטוריה משפחתית של דמם ♦
PT - 13s, INR – 0.97
Fibrinogen – 234mg%
Factor XI – 26%
Factor VIII - 135%
Factor IX - 36%
vWF - 98%
Lupus anticoagulant
RVVT ratio -3.2, SCT ratio - 2.8
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aPTT PT- N PLT - N
Bleeding
Deficiency contact factors
Lupus anticoagulant
Heparin
Severe factor XI deficiency
Mild to moderate HA/HB
Mild vWD
Unprovoked
Severe hemophilia A & B
Severe vWD
Acquired inhibitors
No Bleeding
Trauma related
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משפחה מרוקאית 54בן
דיסליפדמיה ללא נטייה לדמם בעבר, ד"יל: ברקע
מתאשפז עקב כאבים בחזה נקבע כי יעבור צנתור לב
• PT – 26% , INR – 2.48
• PTT - 30s, Fibrinogen - 350mg/dl
● Hb – 12.8 gr%, PLT – 285K
● LFT’s – N
FVII – 4%
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
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Poor correlation between FVII activity and bleeding
tendency.
Severe bleeding occur most often with FVII activity <2%.
Hemostasis can be achieved with FVII >15% of normal.
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rFVII the recommended dose is 15-30µg/kg every 4-6h
Fresh Frozen Plasma
FVII concentrate
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PT PTT- N PLT - N
Bleeding
FVII deficiency
Warfarin
Liver disease
Vitamin K deficiency
No Bleeding
FVII deficiency
Warfarin
Liver disease
* Liver disease – Prolonged PTT, low platelet count
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2הורים בני דודים מדרגה . מוצא אירני43בן .
שינייםאחרי טיפולי דמם
בילדותואפיסטקסיס.
חבלהבעיקר לאחר עוריות אכימוזות .
שבועיים לאחר הכריתה דימום מסיבי . עם כריתת פוליפקולונסקופיה(Hb5%)
• PT – 58% , INR – 1.41, PTT - 42s
• Fibrinogen - 350mg/dl
● Hb – 12.8 gr%, PLT – 285K
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
בעיית דמם"אחות עם "
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PT PTT
PT , PTT
• PT – 58% , INR – 1.41, PTT - 42s
• Factor V - 10% , FVIII - 28%
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Combined FV+FVIII deficiency
Autosomal recessive
Jews from the middle east origin
Factor levels 5-30% LMAN1 or ERGIC-53
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Bleeding
Hypofibrinogenemia
Mild factors deficiencies
Liver disease
No Bleeding
Afibrinogenemia
Vit K dependent factors deficiency
FII or FV auto-ab’s
Combined FV & FVIII (congenital)
Liver disease
PT PTT PLT N
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PT PTT PLT ↓
Bleeding or not
Liver disease
Lupus anticoagulant
Disseminated intravascular coagulation - DIC
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בריאה, 18בת ■
מטרורגיות-מטרת הביקור הפנייה מגניקולוג בשל מנורגיות ■
. חניכיים, אפיסטקסיס-מילדות דימום מריריות ■
לא נוטלת-תרופות ■
אחים גדולים ממנה בריאים2-סיפור משפחתי ■
. בת דודה שאומרים שיש לה בעייה בוסת
PT - 87%, PTT – 25s
Fibrinogen – 350mg/dl TT – 17s
Hb – 9.8 gr%, MCV – 74, MCH – 20
PLT – 213,000
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
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ADP Collagen Epinephrin Ristocetin
Platelet aggregation
Shape
changeAggregation
Photo
detectorPlatelet Rich Plasma
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Platelet aggregation
Ristocetin
Collagen
ADP
Epinephrine
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ADP Collagen Arachidonate Ristocetin
Glanzmann
Thrombastenia
Bernard-soulier
Syndrum
Normal
Platelet aggregation
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Glanzmann Thrombasthenia
◘ Severe bleeding disorder
◘ Pattern of inheritance: Autosomal recessive
◘ Loss of platelet aggregation
◘Absent or dysfunction of the fibrinogen receptor
(GPIIb/IIIa; Integrin aIIb/b3, CD41 / CD61)
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Diagnosis:
• Normal platelet count and morphology
• Defective platelet aggregation in response
to all physiologic agonists but normal with ristocetin
• Defective clot retraction
• Prolonged bleeding time
Glanzmann Thrombasthenia
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Symptoms:
Bleeding from mucous membranes and sub-coetaneous tissues
Symptoms begin in early childhood:
Purpura, epistaxis, gingival bleeding
bleeding after tooth extraction, menorrhagia
Glanzmann Thrombasthenia
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Thrombasthenia in Israel (2009)
ArabsIraqi-Jews
3444Patients
1832Families
00Aggregation with
ADP
00α2β complex
FACS
TracesTracesα2β Immuneblot
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Preventive measures:
♦ Dental hygien, contraceptive pills
♦ Iron and folate supplementation
Glanzmann Thrombasthenia - Treatment
♦Anti-fibrinolytic agents (TA- Hexakapron 0.5-1gm 3-4/d))
or mouth wash
♦ Desmopressin (DDAVP)
♦ Topical agents
♦ rFVIIa
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Platelets
Glanzmann Thrombasthenia - Treatment
♦Allo-immunization
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Glanzmann Thrombasthenia
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ממוצא ערבי17בת .
אשפוז נוסף בגלל דימום תוך בטני. בילדות דימום תוך מוחי.
לא מדממים, שני ההורים קרובי משפחה: סיפור משפחתי .
אח ואחות עם דימומים דומים-אחים 6במשפחה.
PT - 87%, PTT – 25s
Fibrinogen - 350mg/dl, TT - 16s
FXIII < 5%
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
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Autosomal recessive disorder
Prevalence: 1:1,000,000
Severe life-long bleeding: bleeding from the stump of umbilical cord, intracranial, intra-abdominal, hemarthrosis, delayed bleeding
Homozygous females suffer recurrent abortions
Delayed wound repair
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FXIII concentrate
Dose 10 -20 u/ kg /month
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PT -N PTT- N PLT - N
Bleeding
Factor XIII deficiency
Hyperfibrinolysis (α2-AP deff.)
Platelet disorders (GT)
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PTT – 80s
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital or acquired ?
• Disease causing bleeding ?
• Drug cause of bleeding ?
TT – 13s
שנים3בן
2 לברך ולמרפק תוך חודש ימים ללא חבלה–דימומים
על הזרוע והירך" סימן כחול"פעמיים
מדממים מאד"סבא של הילד ודוד של אמא -משפחה."
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PTT – 80s
ממוצא אשכנזי72בן
דםבילדות כריתת שקדים ניתוח חוזר עקב דימום קיבל עירוי
דימום לאחר עקירת שן באופן שחייב הסתכלות נוספת ותפרים
צ עבר ללא כל דימום"תיקון הרנייה מפשעתית דו
ללא הסטוריה של דמם–משפחה
. בירור המטולוגי לקראת ניתוח כריתת ערמונית<
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital or acquired ?
• Disease causing bleeding ?
• Drug cause of bleeding ? TT – 15s
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לפני גיוס ללא מחלות רקע18בת
בוסת" כבד"דימום .
"עם וללא חבלה" סמנים כחולים
פעמים בשנה ודימום מחניכיים5-6אפיסטקסיס.
לא -תרופות
אין -סיפור משפחתי של דמם
PTT – 56s
CBC: Hb 9, MCV 72, RDW 19%, PLT 280
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
![Page 172: Pediatric Thrombosis and Bleeding- case studies · A2 1 22 A1 2 3 2 6 A3 1 22 2 3 2 6 A3 A2 A1 FVIII A2 A3 1 22 2 3 2 6 A1 A2 2 3 2 6 A1 22 1 3 Inversion Type 1. Recurrent joint bleed](https://reader034.vdocuments.us/reader034/viewer/2022051919/600beda30e7f4417d263fdd4/html5/thumbnails/172.jpg)
4בן ■
פעמיים דימום למפרק הברך, מילדות דימום מריריות■
אין –סיפור משפחתי של דמם ■PTT – 62s
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
![Page 173: Pediatric Thrombosis and Bleeding- case studies · A2 1 22 A1 2 3 2 6 A3 1 22 2 3 2 6 A3 A2 A1 FVIII A2 A3 1 22 2 3 2 6 A1 A2 2 3 2 6 A1 22 1 3 Inversion Type 1. Recurrent joint bleed](https://reader034.vdocuments.us/reader034/viewer/2022051919/600beda30e7f4417d263fdd4/html5/thumbnails/173.jpg)
77בת ♦
ספיקת לב -מתאשפז במחלקה של החמרה באי♦
אין הסטוריה משפחתית של נטייה לדמם♦
אספירין♦
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital or acquired ?
• Disease causing bleeding ?
• Drug cause of bleeding ? PTT >150s
PT - 14s
INR – 1.3
Fibrinogen - 324mg
![Page 174: Pediatric Thrombosis and Bleeding- case studies · A2 1 22 A1 2 3 2 6 A3 1 22 2 3 2 6 A3 A2 A1 FVIII A2 A3 1 22 2 3 2 6 A1 A2 2 3 2 6 A1 22 1 3 Inversion Type 1. Recurrent joint bleed](https://reader034.vdocuments.us/reader034/viewer/2022051919/600beda30e7f4417d263fdd4/html5/thumbnails/174.jpg)
מאושפז בטיפול נמרץ לב בשל 67בןVT עם רגל איסכמית
ל מושתל "אס, מחלת לב אסכמית מספר צינתורים וניתוחי מעקפיםICD
פקקת ביד משנית לפיקליין
צינתורים קודמים/אין הסטוריה של דמם ולא היה דימום חריג בניתוח
PTT - 150s
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
![Page 175: Pediatric Thrombosis and Bleeding- case studies · A2 1 22 A1 2 3 2 6 A3 1 22 2 3 2 6 A3 A2 A1 FVIII A2 A3 1 22 2 3 2 6 A1 A2 2 3 2 6 A1 22 1 3 Inversion Type 1. Recurrent joint bleed](https://reader034.vdocuments.us/reader034/viewer/2022051919/600beda30e7f4417d263fdd4/html5/thumbnails/175.jpg)
PTT – 100s
ממוצא עירקי 43בן
מאושפז בנוירולוגיה באבחנה שלAutoimmune cerebelitis
פרזיס-עובר טיפול פלסמה
לקראת בדיקתLP נלקחו בדיקות קרישה
PTT on admission - 32s• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
![Page 176: Pediatric Thrombosis and Bleeding- case studies · A2 1 22 A1 2 3 2 6 A3 1 22 2 3 2 6 A3 A2 A1 FVIII A2 A3 1 22 2 3 2 6 A1 A2 2 3 2 6 A1 22 1 3 Inversion Type 1. Recurrent joint bleed](https://reader034.vdocuments.us/reader034/viewer/2022051919/600beda30e7f4417d263fdd4/html5/thumbnails/176.jpg)
עם יתר לחץ דם69בן ♦
מתאשפז במחלקה עקב דימומים ואנמיה ♦
אין הסטוריה משפחתית של נטייה לדמם♦
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
• PTT – 84s
• PT - 14s, INR – 1.2
• Fibrinogen – 350mg/dl
• Hb - 9 gr%
• PLT – 312,000
• Platelet function - Normal
![Page 177: Pediatric Thrombosis and Bleeding- case studies · A2 1 22 A1 2 3 2 6 A3 1 22 2 3 2 6 A3 A2 A1 FVIII A2 A3 1 22 2 3 2 6 A1 A2 2 3 2 6 A1 22 1 3 Inversion Type 1. Recurrent joint bleed](https://reader034.vdocuments.us/reader034/viewer/2022051919/600beda30e7f4417d263fdd4/html5/thumbnails/177.jpg)
2+נ, 37בת .
לאחר לידה שלישית המטומות על היד רגל דופן בטן ומנדיבולה מימין'שב7-כ .
.שוללת דימום מריריות. אין קשר לחבלות
מיילדותית#
6הפלה ספונטנית בשבוע -2014הריון ראשון -
. צוואר פעור בוצע תפר23בשבוע . בהריון השני דימומים מתחילתו-
.גר ששרד641לידה מוקדמת של עובר במשקל 25בשבוע
. צירים34בשבוע . תפר צווארי מניעתי2016הריון שלישי -
. 'גר1899נולד פג במשקל . חשד לאמניוניטיס
ניתוח אף אלקטיבי .
אסתמה, דלקות גרון, ברונכיטיס, בילדות סינוסיטיס
מוצא אשכנזי אין נטייה לדמם –משפחה
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
![Page 178: Pediatric Thrombosis and Bleeding- case studies · A2 1 22 A1 2 3 2 6 A3 1 22 2 3 2 6 A3 A2 A1 FVIII A2 A3 1 22 2 3 2 6 A1 A2 2 3 2 6 A1 22 1 3 Inversion Type 1. Recurrent joint bleed](https://reader034.vdocuments.us/reader034/viewer/2022051919/600beda30e7f4417d263fdd4/html5/thumbnails/178.jpg)
PTT – 94s
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בריאה ממוצא אשכנזי 22בת ♦
מגיע לחדר מיון גניקולוגי עקב דימום וגינלי♦
4-5האבחנה הפלה בשבוע ♦
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
PTT – 74s
אין הסטוריה משפחתית של דמם ♦
PT - 13s, INR – 0.97
Fibrinogen – 234mg%
Factor XI – 26%
Factor VIII - 135%
Factor IX - 36%
vWF - 98%
![Page 180: Pediatric Thrombosis and Bleeding- case studies · A2 1 22 A1 2 3 2 6 A3 1 22 2 3 2 6 A3 A2 A1 FVIII A2 A3 1 22 2 3 2 6 A1 A2 2 3 2 6 A1 22 1 3 Inversion Type 1. Recurrent joint bleed](https://reader034.vdocuments.us/reader034/viewer/2022051919/600beda30e7f4417d263fdd4/html5/thumbnails/180.jpg)
54בן
דיסליפדמיה ללא נטייה לדמם בעבר, ד"יל: ברקע
מתאשפז עקב כאבים בחזה נקבע כי יעבור צנתור לב
• PT – 26% , INR – 2.48
• PTT - 30s, Fibrinogen - 350mg/dl
● Hb – 12.8 gr%, PLT – 285K
● LFT’s – N
FVII – 4%
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
![Page 181: Pediatric Thrombosis and Bleeding- case studies · A2 1 22 A1 2 3 2 6 A3 1 22 2 3 2 6 A3 A2 A1 FVIII A2 A3 1 22 2 3 2 6 A1 A2 2 3 2 6 A1 22 1 3 Inversion Type 1. Recurrent joint bleed](https://reader034.vdocuments.us/reader034/viewer/2022051919/600beda30e7f4417d263fdd4/html5/thumbnails/181.jpg)
2הורים בני דודים מדרגה . מוצא אירני43בן .
שינייםאחרי טיפולי דמם
בילדותואפיסטקסיס.
חבלהבעיקר לאחר עוריות אכימוזות .
שבועיים לאחר הכריתה דימום מסיבי . עם כריתת פוליפקולונסקופיה(Hb5%)
• PT – 58% , INR – 1.41, PTT - 42s
• Fibrinogen - 350mg/dl
● Hb – 12.8 gr%, PLT – 285K
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
![Page 182: Pediatric Thrombosis and Bleeding- case studies · A2 1 22 A1 2 3 2 6 A3 1 22 2 3 2 6 A3 A2 A1 FVIII A2 A3 1 22 2 3 2 6 A1 A2 2 3 2 6 A1 22 1 3 Inversion Type 1. Recurrent joint bleed](https://reader034.vdocuments.us/reader034/viewer/2022051919/600beda30e7f4417d263fdd4/html5/thumbnails/182.jpg)
בריאה, 18בת ■
מטרורגיות-מטרת הביקור הפנייה מגניקולוג בשל מנורגיות ■
. חניכיים, אפיסטקסיס-מילדות דימום מריריות ■
לא נוטלת-תרופות ■
אחים גדולים ממנה בריאים2-סיפור משפחתי ■
. בת דודה שאומרים שיש לה בעייה בוסת
PT - 87%, PTT – 25s
Fibrinogen – 350mg/dl TT – 17s
Hb – 9.8 gr%, MCV – 74, MCH – 20
PLT – 213,000
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?
![Page 183: Pediatric Thrombosis and Bleeding- case studies · A2 1 22 A1 2 3 2 6 A3 1 22 2 3 2 6 A3 A2 A1 FVIII A2 A3 1 22 2 3 2 6 A1 A2 2 3 2 6 A1 22 1 3 Inversion Type 1. Recurrent joint bleed](https://reader034.vdocuments.us/reader034/viewer/2022051919/600beda30e7f4417d263fdd4/html5/thumbnails/183.jpg)
ממוצא ערבי17בת .
אשפוז נוסף בגלל דימום תוך בטני. בילדות דימום תוך מוחי.
לא מדממים, שני ההורים קרובי משפחה: סיפור משפחתי .
אח ואחות עם דימומים דומים-אחים 6במשפחה.
PT - 87%, PTT – 25s
Fibrinogen - 350mg/dl, TT - 16s
• Abnormal bleeding symptoms ?
• Bleeding type ?
• Congenital ?
• Disease ?
• Drug ?