Transcript Factor VIII Deficiency

Disorders of Coagulation and
Thrombosis
Courtney Bunevich, D.O.
October 24, 2007
Secondary Hemostasis
Initiation Phase
Factor X
Factor VIIa
Tissue Factor
Factor Xa
Prothrombin
Thrombin
Secondary Hemostasis
Amplification Phase
Thrombin
Factor XI
Factor XIa
Thrombin
Factor VIII
Factor VIIIa
Thrombin
Factor V
Factor Va
Secondary Hemostasis
Final Pathway
Factor X
Factor VIIIa
Factor XIa
Factor IX
Factor IXa
Ca2+, PL
Factor Xa
Prothrombin
Factor Va
Ca2+, PL
Thrombin
Inherited
hypercoagulable
states
Acquired
hypercoagulable
states
Thrombosis
Antithrombin III
Serine proteinase inactivation
Antithrombin III
(Heparin)
Factor X
Factor IXa
2+, PL
Ca
Factor VIIIa
Factor Xa
Prothrombin
Thrombin
Factor Va
Ca2+, PL
Fibrinolysis
Thrombin
Fibrinogen
Fibrin
t-PA, Urokinase
Plasminogen
Plasmin
Fibrin Degradation Products
Protein C deficiency
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Prevalence in the normal population ~0.2-0.4%
Present in ~3-4% of patients with venous
thromboembolism.
Homozygosity is associated with neonatal purpura
fulminans and neonatal DIC.
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These patients require periodic plasma transfusion and not oral
warfarin to prevent thrombosis.
50% of patients with protein C deficiency will have a
thrombosis by age 36 years.
Proteoloyze Factor Va and VIIIa.
These patients are at risk for warfarin skin necrosis.
Protein S deficiency
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Prevalence in the normal population ~0.003%
Present in ~2-3% of patients with venous
thromboembolism.
Homozygosity is associated with neonatal purpura
fulminans and DIC.
50% of patients with protein S deficiency will have a
thrombosis by age 36 years.
Activated Protein C Resistance
Factor V Leiden
Arg-506
Factor V
A1
A2
Ca2+
A3
C1
APC
-Ser-Arg-Ser-Leu-Asp-Arg-Arg-Gly-Ile-Gln-
Factor VLeiden
-Ser-Arg-Ser-Leu-Asp-Arg-
-Gly-Ile-Gln-
C2
APC Resistance
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Amino acid substitution abolishes the cleavage site for APC.
Approximately 3% of the population is heterozygous for this
mutation.
Absent is Asians, African Americans, and Native Americans.
Can account for up to 25% of VTE disease.
Homozygotes have 20 times increased risk of VTE
Heterzygotes on OCP or pregnant have a 15 times higher risk
of VTE.
Factor V Leiden and venous
thromboembolism
Idiopathic thrombosis
Relative
risk
3.5
p
0.004
Secondary thrombosis
1.7
0.3
Idiopathic thrombosis,
age > 70 yr
7.0
<0.001
Hyperhomocysteimenia
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Prevalence of 10-20% in the general population.
Can be associated with increased VTE disease and
arterial thrombosis.
Can be associated with early onset of CVA and CAD.
Prothrombin Gene Mutation
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Point mutation in prothrombin gene mutation with
conversion of G to A at position 20210
Results in 30% increase in plasma prothrombin
levels.
Heterozygotes account for about 18% of cases of
VTE disease in patients who have a family history of
VTE disease
Dysfibrinogenemia
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Familial defects in fibrinogen, plasminogen, or
decrease synthesis or release of t-PA.
Most dysfibrinogemeias cause bleeding but some can
cause VTE.
Treated usually with heparin and warfarin.
Antithrombin III Deficiency
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Antithrombin III combines with activated
coagulation proteins and blocks biological activity.
Heparin enhance this activity.
Treat VTE disease with heparin and life long
warfarin therapy.
Plasma content is 5-15 mg/L, levels slightly below
normal promote thrombosis
Inherited Prothrombotic State
Defect
Prevalence
Site of Thrombosis
Factor V Leiden
12-40%
Venous
Prothrombin Gene Mutation 6-18%
Venous
Protein C deficiency,
Protein S deficiency, and
Antithrombin III deficiency
5-15%
Venous
Antiphospholipid antibody
Syndrome
10/20%
Venous and Arterial
Dysfibrinogenemia
rare
Venous
Inherited Hypercoagulable States
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Mutations:
Rare
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Polymorphisms:
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Antithrombin III deficiency.
Protein C deficiency.
Protein S deficiency.
Common
Factor V Leiden.
Prothrombin gene polymorphism.
Hyperhomocysteinemia.
Who should get a
thrombophilia (Inherited
Hypercoagulable State) workup?
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Single episode of idiopathic venous
thromboembolism and one or more of the following:
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Positive family history.
Young age (less than 50 years).
Thrombosis at an unusual site.
Massive thrombosis.
Recurrent episodes of venous thromboembolism.
Inherited Thrombophilia
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Activated protein C resistance with factor V
genotype confirmation for resistant results.
Homocysteine analysis with MTHFR genotype
evaluation for elevated results.
Antiphospholipid antibody analysis by lupus
anticoagulant and anticardiolipin antibody testing.
Inherited Thrombophilia
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Prothrombin gene analysis by PCR.
Functional assays for protein C, antithrombin III,
plasminogen, and fibrinogen.
Functional protein S analysis with free and total
antigen analysis if activity decreased.
Factor VIII level and CRP.
Acquired Hypercoagulable States
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Antiphospholipid antibody syndromes
Malignancy
Pregnancy
Therapy-related hypercoagulable states
Nephrotic syndrome
Inflammatory bowel syndrome
Stasis
PNH and myeloproliferative syndromes
Antiphospholipid Antibody Syndrome
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Acquires state
Can be associated with Lupus.
Cause arterial and venous thrombosis.
Cause recurrent fetal loss. (Similar to Factor V
Leiden)
Lab testing shows a failure to correct prolonged
APTT and PT with mixing studies.
Russell Viper Venom Test.
Acquired Hypercoagulable States
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OCP: lower Antithrombin III levels
L-asparginase: inhibit production of factors
Tamoxifen: unknown mechanism
Bechet’s syndrome and Kawaski disease: Disrupt
endothelial cells
Acquired Hypercoagulable
Diagnostic workup
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History and physical examination.
Review of medications (e.g., OCP, HRT).
Complete blood count with review of blood film.
Baseline PT and aPTT (prior to starting
anticoagulant therapy).
Malignancy screening appropriate for age.
Therapeutic options for venous
thromboembolism
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Anticoagulant therapy.
Fibrinolytic therapy.
Inferior vena cava filter.
How do heparin and warfarin
work?
Heparin
Accelerates antithrombin III activity
Antithrombin III
(Heparin)
Factor X
Factor IXa
2+, PL
Ca
Factor VIIIa
Factor Xa
Prothrombin
Thrombin
Factor Va
Ca2+, PL
Low molecular weight heparins
Preferential inactivation of factor Xa
Antithrombin III
(LMWH)
Factor X
Factor IXa
2+, PL
Ca
Factor VIIIa
Factor Xa
Prothrombin
Thrombin
Factor Va
Ca2+, PL
Heparin
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Natural anticoagulant
Binds to AT III
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Inactivates factors IIa, Xa, IXa, XIIa.
Binds to platelets
Heparin Side Effects
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Bleeding
Osteoporosis: inhibits osteoblasts, activates osteoclasts
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If treated for > 3 months or > 20,000 units daily dose
Thrombocytopenia
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HIT
Skins lesions- urticaria, papules, necrosis
Hypoaldosteronism and hyperkalemia
Bleeding reversible with protamine
Heparin Weight Adjusted Normogram
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Number of published normograms
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Bolus 80 U/kg
Drip 18 U/kg/hour
Shorter time to therapeutic APTT
No increase in bleeding
LMWH
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Increased bioavailability
More predictable anticoagulant response
Once daily or twice daily, subcutaneous injection
Outpatient management
Not teratogenic
Decreased incidence of HIT (but cross reacts with
antibody when present)
LMWH and Bleeding
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Bleeding
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Only partially reversible with protamine
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30% -60%
Longer half life
Equivalent rates to UFH
Direct thrombin inhibitors
Antithrombin III-independent inhibition
Factor X
Factor IXa
2+, PL
Ca
Factor VIIIa
Hirudin
Bivalirudin
Argatroban
Factor Xa
Prothrombin
Thrombin
Factor Va
Ca2+, PL
Oral anticoagulants
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Warfarin (Coumadin)
Antagonizes the vitamin K-dependent gcarboxylation of factors II, VII, IX, and X (as
well as protein C and protein S).
A narrow-therapeutic-index drug that must be
monitored by the prothrombin time (PT).
Factors Affecting Warfarin Effect
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Drug Interactions
Hereditary Resistance and Hypersensitivity
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cytochrome P450 (CYP2C9 mutation)
Altered liver function
Hypermetabolic state (fever, thyroid disease)
Co-morbid conditions (chemotherapy, albumin)
Caval Filter
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A single randomized trial has defined advantages and
drawbacks of caval filters. The results indicate that
inferior venacaval filters:
a) Prevent recurrent PE in short term
b) Increase the risk of recurrent deep venous
thrombosis (DVT) in the long term
Thrombolytic Therapy
Not often indicated in venous thrombosis
 Useful in major PE
 Possible new indication in submassive PE
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Hemophilia A: Factor VIII Deficiency
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Regulated activation of Factor X.
Circulates bound with vWF.
1:10,000 males
Bleeding in soft tissues, muscles, and weight bearing joints.
Patients with <1% of levels have severe disease, 1-5% have moderate disease, and >
5% of mild disease.
Femoral neuropathy can develop with unrecognized retroperitoneal hematomas,
compartment syndrome, hemarthrosis.
Each unit of Factor VIII replaced with increase plasma level by 2% per kg.
Extensive bleeding: 50%
Less severe bleeding: 15-20%
Half-life of 8-12 hours.
Dental procedures: factor VIII infusion and aminocaproic acid mouthwash
50% hemophiliacs are HIV positive
Develop inhibitors to Factor VIII after multiple transfusions.
Hemophilia B: Factor IX Deficiency
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Factor IXa activates Factor V in conjunction with
activated Factor VIII.
1:100,000 male births
Purified Factor IX preparations available.
Factor XI Deficiency
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Autosomal recessive trait in Askenazi Jews
Correlation between factor level and propensity to
bleed in not precise.
Present with prolonged post surgical bleeding or
menorrhagia.
HIT
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Associate with heparin therapy.
Decrease in platelets and new thrombosis.
Perform a platelet-Factor 4 antibody assay.
Confirm with a serotonin release assay.
Stop heparin, lovenox, heparin coated lines and flushes.
Start argatroban (or lepuridin) immediately and overlap with
warfarin until INR >4 for 2 days. Argatroban with also
increase INR. Monitor for thrombosis.