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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 and CNS 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
GENETICS OF HEMOPHILIA
About half of cases of hemophilia A due to an 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
XI XIa VIII
IX TF VIIa X
Injury
IXa VIIIa
Initiation
V Xa Va
PT Xa
Propagation
Fibrinogen
Thrombi n Fibrin
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
Joint destruction
Nerve damage
Hemophilic arthropathy
Target joint = irreversibly damaged joint with vicious cycle of injury and repeated bleeding
Hemophilic arthropathy
Hemophilic arthropathy
Variable relationship between # of joint bleeds and severity
Green line: Evidence of early joint damage with relatively few bleeds Yellow line: Linear relationship between # of bleeds and joint damage
HEMOPHILIA
Treatment 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
Dose
20-40 U /kg/day 20-40 U /kg/day 25 U /kg x 1
Other
R est, immobilization, PT R isk of compartment syndrome or neuro compromise Follow with antifibrinolytic therapy Pressure, packing, cautery Endoscopy to find lesion R /O stones, U TI
Initially 80-100%, then 30% 40-50 U /kg then 30-40 until healed U /kg daily Initially 100%, then 30% 40-50 U /kg then 30-40 until healed U /kg daily Initially100%, then 30% 40-50 U /kg then 30-40 until healed U /kg daily Initially100%, then 50% 50 U /kg then 25 U /kg q until healed 12h infusion
Initially100%, then 50% 50 U /kg then 25 U /kg qTest for inhibitor before until healed 12h infusion surgery!
Give factor q 12 hours for 2-3 days after major surgery, continue with daily infusions for 7-10 days Trough 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
Highly purified
Solvent/detergent treated, no reports of HIV or hepatitis transmission
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
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%) prior to dental work, minor surgery etc Trial dose needed to ensure adequate response Cardiovascular complications possible in older patients
Bethesda Assay
Residual factor activity
50%
Type 2 vWD
2A: Selective deficiency of large multimers
Defective assembly Increased susceptibility to proteolysis
2M: Decreased vWF function but no loss of large multimers 2N: Decreased binding of factor VIII to vWF (recessive)
Weibel-Palade body (arrows) in the cytoplasm of endothelial cell. N - nucleus. Scale = 100 nm. (Human, skin.)
Typically causes 2-4 fold increase in blood levels of vWF (in type 1 vWD), with half-life of 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
NEJM 2009;361:1887