hemophilia vwd
TRANSCRIPT
-
7/30/2019 Hemophilia VWD
1/38
HEMOPHILIA
Inherited deficiency of factor VIII (hemophilia A) or
factor IX (hemophilia B)
Sex-linked inheritance; almost all patients male
Female carriers may have mild symptoms
Most bleeding into joints, muscles; mucosal andCNS bleeding uncommon
Severity inversely proportional to factor level
< 1%: severe, bleeding after minimal injury
1-5%: moderate, bleeding after mild injury> 5%: mild, bleeding after significant trauma or surgery
-
7/30/2019 Hemophilia VWD
2/38
GENETICS OF HEMOPHILIA
About half of cases of hemophilia A due toan inversion mutation in intron 1 or 22
Remainder genetically heterogeneous
Nonsense/stop mutations prevent factor
production Missense mutations may affect factor activity
rather than production
15-20% of cases due to new mutations
-
7/30/2019 Hemophilia VWD
3/38
IX
X
Fibrinogen Fibrin
PT
XIa
Xa
V
VIII
XIInjury
TF
VIIaIXaVIIIa
Xa
Va
ThrombinPropagation
Initiation
Deficiency of factor VIII or IX affects the propagation phase of
coagulation
Most likely to cause bleeding in situations where tissue factor
exposure is relatively low
-
7/30/2019 Hemophilia VWD
4/38
ACUTE COMPLICATIONS OF HEMOPHILIA
Muscle hematoma (pseudotumor)Hemarthrosis
(joint bleeding)
-
7/30/2019 Hemophilia VWD
5/38
LONG-TERM COMPLICATIONS OF
HEMOPHILIA
Joint destruction Nerve damage
-
7/30/2019 Hemophilia VWD
6/38
Hemophilic arthropathy
Target joint = irreversibly damaged
joint with vicious cycle of injury and
repeated bleeding
-
7/30/2019 Hemophilia VWD
7/38
Hemophilic arthropathy
J Throm b Hemost 2010;8:1895
H hili th th
-
7/30/2019 Hemophilia VWD
8/38
Hemophilic arthropathyVariable relationship between # of joint bleeds and severity
J Throm b Hemost 2010;8:1895
Green line: Evidence of early joint
damage with relatively few bleeds
Yellow line: Linear relationship
between # of bleeds and joint
damage
Red line: Joint damage occurs after
threshold # bleeds
Blue line: Little joint damage
despite many bleeds
-
7/30/2019 Hemophilia VWD
9/38
-
7/30/2019 Hemophilia VWD
10/38
Management of hemophilic arthropathy
Physical therapy Weight control
COX-2 inhibitors safe and effective
Judicious use of opioids
Surgical or radionuclide synovectomy
Joint replacement
-
7/30/2019 Hemophilia VWD
11/38
-
7/30/2019 Hemophilia VWD
12/38
OTHER COMPLICATIONS OF HEMOPHILIA
Pseudotumor: gradually enlarging cyst in
soft tissue or bone (requires surgery)
Retroperitoneal hemorrhage
Bowel wall hematoma
Hematuria renal colic (rule out structural
lesion)
Intracranial or intraspinal bleeding (rare but
deadly) usually after trauma
HEMOPHILIA
-
7/30/2019 Hemophilia VWD
13/38
HEMOPHILIATreatment of bleeding episodes
Unexplained pain in a hemophilia should be
considered due to bleeding unless proven
otherwise
External signs of bleeding may be absent
Treatment: factor replacement, pain control,rest or immobilize joint
Test for inhibitor if unexpectedly low
response to factor replacement
-
7/30/2019 Hemophilia VWD
14/38
Dosing clotting factor concentrate
1 U/kg of factor VIII should
increase plasma level by about2% (vs 1% for factor IX)
Half-life of factor VIII 8-12hours, factor IX 18-24 hours
Volume of distribution of factor
IX about twice as high as forfactor VIII
Steady state dosing about thesame for both factors initialdose of factor IX should be
higher
F t l t i h hili A
-
7/30/2019 Hemophilia VWD
15/38
Factor replacement in severe hemophilia A
Site of bleed Desired factor lev el Dose Other
Joint 40-50% 20-40 U/kg/day Rest, immobilization,
Muscle 40-50% 20-40 U/kg/day
Risk of compartment
syndrome or neurocompromise
Oral mucosa 50% initially 25 U/kg x 1Follow with
antifibrinolytic thera
EpistaxisIni tially 80-100%, then 30%
until h ealed40-50 U/kg then 30-40
U/kg dailyPressure, packing,
cautery
GIInitially 100%, then 30%
until h ealed
40-50 U/kg then 30-40
U/kg daily
Endoscopy to find
lesion
GUInitially100%, then 30%
until h ealed40-50 U/kg then 30-40
U/kg dailyR/O stones, UTI
CNSInitially100%, then 50%
until h ealed50 U/kg then 25 U/kg q
12h infusion
Trauma or surgeryInitially100%, then 50%
until h ealed50 U/kg then 25 U/kg q
12h infusionTest for inhibitor befo
surgery!
Give factor q 12 hours for 2-3 days after major surgery, continue with daily infusions for 7-10 daysTrough factor levels with q 12 h dosing after major surgery should be at least 50-75%
Most joint and muscle bleeds can be treated with minor (50%) doses for 1-3 days without
monitoring
-
7/30/2019 Hemophilia VWD
16/38
FACTOR VIII CONCENTRATE
Recombinant
Virus-free, most expensive replacement
Treatment of choice for younger/newly diagnosedhemophiliacs
Somewhat lower plasma recovery than with plasma-derived concentrate
Highly purified
Solvent/detergent treated, no reports of HIV or hepatitistransmission
Intermediate purity (Humate-P)
Contains both factor VIII and von Willebrand factor Solvent/detergent treated, no reports of HIV or hepatitis
transmission
Mainly used to treat von Willebrand disease
-
7/30/2019 Hemophilia VWD
17/38
FACTOR IX CONCENTRATE
Recombinant (slightly lower plasma recovery)
Highly purified (solvent/detergent treated, no
reports of virus transmission)
Prothrombin complex concentrate
Mixture of IX, X, II, VII Low risk of virus transmission
Some risk of thrombosis
-
7/30/2019 Hemophilia VWD
18/38
DDAVP
Releases vWF/fVIII from endothelial cells
Factor VIII levels typically rise 2-4 fold after 30-60
min (IV form) or 60-90 min (intranasal)
Enhanced platelet adhesion due to vWF
Useful for mild hemophilia (VIII activity > 5%) priorto dental work, minor surgery etc
Trial dose needed to ensure adequate response
Cardiovascular complications possible in older
patients
-
7/30/2019 Hemophilia VWD
19/38
Bethesda Assay for Inhibitors
Serial dilutions of patient plasma in normalplasma
Incubate 2 hours
Assay residual factor activity
1 Bethesda Unit neutralizes 50% of factor inan equivalent volume of normal plasma
Example: 1:100 dilution of patient plasma +normal plasma 50% residual factor
activity, so inhibitor titer is 100 BU
-
7/30/2019 Hemophilia VWD
20/38
Residualfactoractivity
dilution pt plasma
50%
1:1 1:10 1:100 1:1000
Bethesda Assay
100 BU
TREATMENT OF HEMOPHILIACS WITH
-
7/30/2019 Hemophilia VWD
21/38
TREATMENT OF HEMOPHILIACS WITH
INHIBITORS
Recombinant factor VIIa
FEIBA (Factor Eight Inhibitor Bypassing Activity)
Mixture of partially activated vitamin K-
dependent clotting proteases including VIIa
High dose factor VIII (if low titer inhibitor) Induction of tolerance with daily factor VIII
infusions
Optimal dose not established
Role for concomitant immunosuppression?
-
7/30/2019 Hemophilia VWD
22/38
Liver disease in hemophilia
Hepatitis C still a problem, though incidence
falling with safer factor concentrates
Treatment for hepatitis C with interferon
often causes thrombocytopenia
Liver transplantation done occasionally(cures hemophilia)
All newly diagnosed hemophiliacs should
be vaccinated against hepatitis A and B
-
7/30/2019 Hemophilia VWD
23/38
ACQUIRED FACTOR VIII DEFICIENCY
-
7/30/2019 Hemophilia VWD
24/38
ACQUIRED FACTOR VIII DEFICIENCY
Due to antibody to factor VIII (most common
autoimmune factor deficiency) Most patients elderly
Often presents with severe soft tissue or mucosalbleeding (different bleeding pattern than inherited
hemophilia) Laboratory: prolonged aPTT not corrected by
mixing, very low factor VIII activity
Normal INR, thrombin time and platelet count
Treatment: rVIIa, FEIBA, immunosuppression
VON WILLEBRAND DISEASE
-
7/30/2019 Hemophilia VWD
25/38
VON WILLEBRAND DISEASE
Common (most common?) inherited bleeding
disorder Partial lack of VWF causes mild or moderate
bleeding tendency Menorrhagia, bleeding after surgery, bruising
Typically autosomal dominant with variable
penetrance Laboratory:
Defective platelet adherence (PFA-100) or long bleedingtime
Subnormal levels of von Willebrand antigen and factor
VIII in plasma Low Ristocetin cofactor activity or VWF activity
VON WILLEBRAND DISEASE
-
7/30/2019 Hemophilia VWD
26/38
VON WILLEBRAND DISEASE
Type 1 decreased production of vWF
Levels 20-50%, antigen activity
Type 2 qualitative defect (missense mutation)
Several different types
Usually a disproportionate decrease in vWF activity vs
antigen
Type 3 severe deficiency
Antigen, activity and factor VIII levels < 10%
Hemophilia-like phenotype
Recessively inherited
T 2 WD
-
7/30/2019 Hemophilia VWD
27/38
Type 2 vWD
2A: Selective deficiency of large multimers
Defective assembly Increased susceptibility to proteolysis
2B: Increased affinity for platelet Gp Ib
Large multimers bind spontaneously to platelets and
cleared from blood Rarely, a mutation in Gp Ib may have the same effect
(platelet-type vWD)
2M: Decreased vWF function but no loss of largemultimers
2N: Decreased binding of factor VIII to vWF(recessive)
-
7/30/2019 Hemophilia VWD
28/38
-
7/30/2019 Hemophilia VWD
29/38
-
7/30/2019 Hemophilia VWD
30/38
Weibel-Palade bod y(arrows) in the cytoplasm of endothelial
cell. N - nucleus. Scale = 100 nm. (Human, skin.)
Desmopressin (DDAVP) in vWD
-
7/30/2019 Hemophilia VWD
31/38
Desmopressin (DDAVP) in vWD
DDAVP releases vWF from endothelial cells
Can be given IV or intranasally
0.3 mcg/kg IV, or 150 mcg per nostril
Typically causes 2-4 fold increase in blood
levels of vWF (in type 1 vWD), with half-lifeof 8+ hours
Response to DDAVP varies considerably
Administration of a trial dose necessary to
ensure a given patient responds adequately Peak response
Duration of response
-
7/30/2019 Hemophilia VWD
32/38
-
7/30/2019 Hemophilia VWD
33/38
-
7/30/2019 Hemophilia VWD
34/38
Indications for clotting factor concentrate
-
7/30/2019 Hemophilia VWD
35/38
administration in vWD
Type 2 or 3 vWD
Active bleeding
Surgery or other invasive procedure
Type 1 vWD with inadequate response to
DDAVP
-
7/30/2019 Hemophilia VWD
36/38
Acquired von Willebrand disease
-
7/30/2019 Hemophilia VWD
37/38
Acquired von Willebrand disease
Monoclonal gammopathy: vWF neutralized by
paraprotein (?) Autoimmune disorders: Autoantibody to vWF
Myeloproliferative disorder: large multimersabsorbed onto neoplastic cells (platelets?)
Cardiovascular diseases (AS, VSD, etc): High
shear stress causes unfolding/proteolysis of largemultimers
Hypothyroidism: Decreased release of vWF fromendothelial cells
Treatment varies depending on cause/mechanism
ACQUIRED VON WILLEBRAND DISEASE
-
7/30/2019 Hemophilia VWD
38/38
ACQUIRED VON WILLEBRAND DISEASE
NEJM 2009;361:1887