congenital bleeding disorders
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Congenital BleedingDisorders
Ma. Ysabel Lesaca-Medina, MDPediatric Hematology-Oncology
Prince Leopold
Born
1853
Princess beatrice,9th child
Princess louise
Prince leopold, 8th child
Married to Princess Helene: 1882
Princess Alice Hemophilia carrier
London news:Death of the
duke of albany
March 27, 1884
Villa Nevada
Morphine side effects
Prince charles
Princess alice
Outline What is and how does hemostasis occur?
How does one evaluate a patient presenting with bleeding?
What are the features of the Congenital Bleeding Disorders?
Hemophilia A, Hemophilia B Von Willebrand Disease Platelet function disorders Rare Coagulation Factor Deficiencies
What is Hemostasis ?
Maintenance of fluid blood flow
Prevention of bleeding
Hemostasis – 3 stages
1. Vascular
– vasoconstriction
2. Platelet (PRIMARY HEMOSTASIS)
– Platelet plug formation
3. Coagulation (SECONDARY HEMOSTASIS)
– Fibrin thrombus formation
– Clotting factors
Intact vessel
Platelet Phase
platelet phase
Resting activated platelets
Coagulation phase
Fibrin Clot
PTT
APTT
PT
TT
Factor XIII cross links fibrin
Clinical Evaluation of Bleeding patient
Clinical History
Detailed History Symptoms:
Epistaxis
gum bleeding, easy bruising, menorrhagia, hematuria, GI bleeding
(platelet problem)
hemarthrosis, intramuscular bleed
(coagulation problem)
Delayed onset bleeding
(factor XIII problem)
Detailed History Response to hemostatic challenge:
circumcision, surgery, phlebotomy, immunization, suture placement/removal
Underlying medical conditions : liver disease, renal failure, vitamin K
deficiency
Medications: antiplatelet drugs, anticoagulants,
antimetabolites, antibiotics
Detailed History
Family history:
similar symptoms response to hemostatic challenge, consanguinity Menorrhagia
> 3 soaked pads /day Flooding Hb < 10g/L
Physical Examination
Physical Examination
Petechiae < 2mm Purpura 2mm – 1 cm
Hematoma
Ecchymoses > 1 cm
Physical Examination
HEMARTHROSIS
Physical Examination
INTRAMUSCULAR BLEED, PSOAS
Laboratory evaluation
Laboratory Evaluation Initial lab tests
CBC with platelet PT (extrinsic)- VII, X, V, II, I PTT (intrinsic)- XII, XI, IX, VIII, X, V,II, I
Further work up:
Thrombin time PFA, platelet aggregation Mixing Studies, clotting factor assays, VW
antigen tests, urea clot lysis assay
DDX, based on initial screen
↑ PTNormal
plt, Normal
PTT
↑ PTTNormal plt, Normal PT
↑ PT,PTTNormal plt
•Early Liver Disease
•Early Vit K Def
•F VII Def
•F VIII def(hemophilia or VWD)
•F IX, XI, XII def
•Inhibitors
•Late Liver Disease
•Late Vit K deficiency
•Massive Transfusion
↑ PTT, TTNormal PT, Normal plt
All normal Platelet dec
Heparin - activates AT III AT III inactivates thrombin
- PTT more sensitive to heparin
VWDPlatelet fxn d/oMild factor def (VIII, IX, XI, XIII )
Collagen DisorderVitamin C def
CAMT, TAR,BSSWAS, GPS
ITPInfection
CAMT = Congenital Amegakaryocytic Thrombocytopenia BSS = Bernard Soulier Syndrome
TAR = Thrombocytopenia with Absent Radius
GPS = Gray Platelet Syndrome WAS = Wiskott Aldrich Syndrome
Out Patient Clinic Time
6 year/ M
Needs dental extraction; sent for hematologic clearance
History of easy bruisability
Mother and aunts report easy bruisability and strong menses
2 cousins died during delivery of unknown cause
Labs
CBC Normal
PT Normal
PTT 39.3 (23 – 33 secs)
DDX, Normal plt, Normal PT prolonged PTT,
Dec Factor VIII due to
Hemophilia A VWD
Dec Factor IX, XI, XII
Lupus anticoagulant or other coagulation factor inhibitors
Factor VIII : 0.29 u/ml (0.5 – 1.5 u/ml)
VWF : 1.2 u/ml (0.5 – 1.5 u/ml)
Hemophilia A, mild
Diagnosis
HEMOPHILIA Essentials
Factor VIII (or IX ) deficiency X-linked (2/3) or
spontaneous mutation (1/3) Sxs: Bruising, soft tissue
bleeding, hemarthrosis Labs: Prolonged PTT + dec
factor VIII (or IX) levels
HEMOPHILIA Most common severe congenital
bleeding disorder
Prevalence
Hemophilia A (Factor VIII) 1 / 10,000 males
Hemophilia B (Factor IX) 1 / 50,000 males
HEMOPHILIA – severity classification
Factor VIII – reported in units / ml ( 1 unit/ml = 100%
factor activity)
- Normal range: 0.5 – 1.5 IU/ml (50 – 150%)
Classification
- Severe (60% of cases) : < 1% factor VIII (spontaneous bleeding)
- Moderate : 1 to < 5%
- Mild : 5 – 50 % ( only with trauma and surgery)
HEMOPHILIA- Lab findings
PTT (normal plt; normal PT)
Dx is confirmed by Factor Assay
F VIII ( with normal VWF ) = Hemophilia A
Dec F IX = Hemophilia B
HEMOPHILIA- S/Sx Severe Hemophiliacs
Usually initial presentation in 1st 2 years of life ( severe bruising and joint bleeds)
40 – 50% present in the 1st month of life
1- 4% present in the neonatal period (birth trauma)
HEMOPHILIA Mild or Moderate
Boys Trauma related bruising or bleeding
Excessive bleeding following surgery or dental extraction
Girls ( carriers )
~ Often with Factor VIII < normal
Mild bruising or bleeding
Heavy menstrual periods
HEMOPHILIA-Cxs Hemarthroses
If recurrent joint destruction Intracranial hemorrhage
Leading cause of death among hemophilliacs
Intramuscular hematomas
Compartment syndrome muscle and nerve death ( anterior forearm, anterior tibial compartment)
HEMOPHILIA-Cxs• Infection
• HIV, Hep B, Hep C• Not at risk, With current donor screening and
viral inactivation of factor concentrates,
• But still at risk for:
• Hepatitis A• Creutzfeld-Jakob Disease• Parvovirus B-19
• Recommend Hep A and Hep B vaccines for all pxs
HEMOPHILIA-Cxs
• Acquired antibody to Factor VIII
• Antibody that inactivates F VIII function
• Develops in
• 30% of pxs with severe hemophilia
• < 5% of Hemophilia B
Antibody to factor VIII
• Quantified by Bethesda units• 1 Bethesda unit – inactivates 50% of F VIII
function
• TREATMENT:
• < 5 B.U.
• Increase dose of F VIII
• > 5 BU
• Bypass agents: prothrombin complex conc ; FVII
• ITI (immune tolerance induction)
HEMOPHILIA-Tx
General aim of Mx:
correct factor VIII to w/in normal limits prevent or stop bleeding
Mild
May respond to desmopressin (ADH)
- Releases endothelial stores of VWF
Most still need exogenous F VIII after
HEMOPHILIA-Tx• Factor VIII dose
• Non-life/limb threatening bleed• 20 to 30 u/kg 40 – 60% F VIII activity
• Large hemarthrosis and life/limb threatening bleed• 50 u/KG 100% F VIII activity
• Cryoprecipitate • 100 u F VIII / unit• e.g. 10 kg child –> 20 u/kg =
• 200 u F VIII -> 2 u cryoppt)
• (FFP (contains factor IX) – used for Hemophilia B)
HEMOPHILIA-Tx Prophylaxis
Preventive F VIII infusions 2 to 3x, weekly To achieve F VIII level >1% Expensive Initiate after 1st joint bleed Do not start before 6 months of
age – increases risk of inhibitor devlpt
HEMOPHILIA TREATMENT
in the pipe line
GENE THERAPY
NEXT PATIENT please…
13 / female
Cc: menometrorhagia
Easy bruising and occasional epistaxis since childhood
Gum bleeding on toothbrushing
No previous BT
Iron supplement in the past
Family History
Maternal grandmother and mother with epistaxis and heavy menses
3 brothers and 2 sisters normal
Hb 114
Platelet 300 (150 – 450)
PT : normal; 12.9 sec INR 1.1
PTT : normal; 32.5 (23.5 – 33.5)
↑ PTT, TT
Normal PT, platelet
All normal Platelet dec
Heparin VWDPlatelet fxn d/o
Mild factor def (VIII, IX, XI, XIII )
Collagen Disorder
Vitamin C def
CAMT, TAR,BSS
WAS, GPS
ITP
2 Infection
VIII
0.48 u /ml (0.5 – 1.5 u/ml)
VWF Ag
0.20 u /ml (0.5 – 1.5 u/ml)
VonWillebrand Disease,
type 1DIAGNOSIS
Von Willebrand Disease
Most common inherited bleeding disorder (Prevalence: 1% - by lab def’n; only 10% symptomatic)
Quantitative or Qualitative deficiency of vWF
Easy bruising / epistaxis from childhood / menorrhagia
Dr. Erik Von Willebrand, 1926
Diagnosis
Criteria VWF Ag < 30% Or VWF Ag 30-50% , in
patient with clinical symptoms supportive of VWF
The Von Willebrand Factor
Protein in plasma
Function
1. Tethers platelets to damaged endothelium
2. Binds and protects Factor VIII
Endothelial cells w/stored VWF
vWD
vWD- Classification Type 1
Classic ; 80% of patients Partial quantitative deficiency
Type 2
Dysfunctional VWF- qualitative
Type 3
Nearly COMPLETE deficiency
vWD-Inheritance Mostly AD ; can be AR
Theoretically, equal males and females But more females dxd (menorrhagia)
Can be acquired
rare Hypothyroidism, Wilms tumor,
Cardiac disease, Renal disease or SLE / Valproic acid
Most often caused by Ab to VWF
vWD- S/Sx Increased bruising and excessive epistaxis
Prolonged bleeding with trauma or surgery
Menorrhagia
Significant menorrhagia from menarche
prompt investigation for congenital bleeding d/o
vWD-Labs Initial screen:
- PT normal
- PTT sometimes prolonged
> in type 3 (factor VIII dec)
- Platelet sometimes dec
> in types 2 and 3
Most of the time: PT, PTT, platelet --- NORMAL
Blood type ‘O ’ – normally lower vWF
VWD Bleeding time
- prolonged
Platelet function analyzer – prolonged
closure time
vWF assay
- Definitive test
vWD -Treatment VWD types 1 and 2
Desmopressin Releases vWF from endothelial stores IV or intranasal ( high concentration spray ) Variable response measure VIII and vWF
60 minutes after May cause fluid shifts (hyponatremia
seizures ) Tachyphylaxis occurs (stored VWF limited)
Further therapy with VWF concentrate or cryoprecipitate
VWD -treatment Intermediate purity F VIII
concentrates
Cryoprecipitate
AdjunctiveTreatment Antifibrinolytic agents
(Tranexamic acid / E-aminocaproic acid ) Prevents plasminogen plasmin For mucosal bleeding
Topical thrombin and fibrin glue Estrogen containing contraceptive tx
For menorrhagia
Rare Coagulation Disorders
Rare coagulation disorders
Other congenital coagulation factor deficiencies Afibrinogenemia /hypofibrinogenemia Deficiencies of factor V, VII, X, XI, XIII
Combined, occur in 1-500,000 to 1:2,000,000 Autosomal recessive
Most common : Factor VII def Causes most bleeding sxs: Factor X and
Factor XIII def
Rare coagulation disorders
S/Sx
Umbilical stump bleeding
Delayed cord separation
Intracranial or intestinal hemorrhage
Muscle hematomas
Easy bruising
Prolonged bleeding ff heelprick
Inherited platelet Disorders
Inherited platelet disorders
Decreased number and abn function
Bernard Soulier Syndrome (BSS) Wiskott Aldrich Syndrome (WAS) Gray Platelet Syndrome (GPS)
Normal number but abn function
Glanzman Thrombasthenia (GT) Storage Pool Disorder (SPD)
Dec # and abn platelet fxnDefect S/Sx Labs
BSS No GPIb/IX plt receptor -> defective binding to VWF
ARecessive
Bruising/ bleeding from infancy
Moderate thrombocytopenia
Large platelets
GPS Alpha granule deficiency
Severe bruising bleeding from early age
Mild thrombocytopenia
Large gray/Agranular platelets
GLANZMANN THROMBASTHENIA
Defect S/Sx Labs
Normal number
Normal morph
Platelet GP IIb/IIIA
(fibrinogen receptor) – FAILS TO AGGREGATE
ARecessive
Severe spont’ mucosal bleeding
Presents in infancy
BT
Flow cytometry
Plt aggregation
SUMMARY
Summary Hemostasis
3 stages Vasoconstriction
Platelet phase
Coagulation phase
Congenital bleeding disorders
Hemophilia A, B VWD Rarer coagulation disorders Inherited platelet disorders
Summary Suspect a congenital bleeding disorder
Symptoms presenting in early infancy/childhood
Similar symptoms in family members Consanguinity
Most common disorders
Hemophilia VWD
Summary Do coagulation screen
Deranged PTT only Think…
Hemophilia – hemarthrosis/intramuscular bleed
VWD – bruising / petechiae, epistaxis
Platelet, PT, PTT all normal Think…
VWD Platelet function disorder Mild coagulation disorders
Hemophilia A or B
(factor VIII /IX def)
VWD
(VWF def or abn)
Inheritance X linked
De novo (1/3)
AD
(few AR)
S/Sx Easy bruisability
Hemarthrosis
Soft tissue bleed
Menorrhagia
Easy bruisability
Epistaxis
Menorrhagia
Labs Prolonged PTT Normal plt, PT, PTT
< Prolonged PTT (few) >
Confirmatory test
Factor VIII /IX assay VWF assay
Treatment Desmopressin (for mild Hemophilia A)
Recomb Factor VIII /IX
Cryoprecipitate /FFP
Desmopressin
Intermediate purity FVIII
Cryoprecipitate
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