1100_Dentoni_AD5D1
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Transcript 1100_Dentoni_AD5D1
Stephanie M. Dentoni, MD, FSVM
California Vein & Vascular Institute
ACP Annual Congress 2016
I do not have any relevant financial relationships with any
commercial interests.
Objectives
Thrombophilia
Hemostasis
Overview
Coagulation Cascade
Congenital Disorders
Mixed Congenital and Acquired Disorders
Acquired Disorders
Thrombophilia
Rudolph Virchow
Thrombosis is due to a triad of factors;
1. Venous stasis,
2. Inflammation from vascular endothelia injury
3. Changes in the composition of the blood.
It is an imbalance of the natural mechanisms that maintain blood
fluidity
Hemostasis
Inherent mechanisms that allow blood to go from a fluid state to a solid
state.
The ability of damaged vessels to maintain blood within the vessel by
forming a clot.
Overview of Thrombosis
Platelet plug/coagulation cascade
Initial presentation lower extremity DVT
Arterial and Venous Thrombosis
Severe consequences: unusual site involvement
60% of patients with an idiopathic DVT have an
identifiable thrombophilia
Inherited, Acquired, Mixed
Epidemology
Approximately 2 million cases of venous
thromboembolism (VTE) in the US annually
Annual mortality of 60,000 from pulmonary embolism
(PE)
Annual mortality exceeds that of breast cancer
Schafer et al. Hematology. 2003 (1):520
Risk Factor Identitification
Preventable
High recurrence rate
Post-thrombotic syndrome
High mortality rate
Platelet Plug
Primary hemostasis
Vascular endothelial injury
Collagen and von Willebrand factor
Platelet aggregation, adhesion, and activation
Glycoprotein IIb/IIIa mediates crosslinking of platelets
and fibrin
Coagulation Cascade
Secondary Hemostasis
Extrinsic Pathway
PT
Tissue Factor
Vascular injury
Factor VII
Intrinsic Pathway
aPTT
Multiple factors
Common Final Pathway
Factors I, II, X, XIII
Extrinsic Pathway
VIIa
Activated II, VII, IX, X
Vascular injury
Tissue Factor
VII Cmplx
Xa
Va/PL
IIa
XIIIa
Fibin
Fibrin cross
linked
Intrinsic Pathway
Thrombin or Vessel endothelium
XIa
IXa
VIIIa/PL
Xa
V/PL
IIa
XIIIa
Fibrin
Fibrin CrossLinked
Thrombin-Factor II
Positive and negative feedback mechanism of the
coagulation cascade
Strongly potentiates thrombus formation
Interacts with factors I (fibrin), V, VIII, XI, XIII
Final Common Pathway for the intrinsic and
extrinsic pathways
Natural Anticoagulants
Plasmin – Inhibits Fibrin
Antithrombin III (ATIII) – Inhibits Factor II, IX, and X
Protein C
Protein S
Tissue factor pathway inhibitor (TFPI)
Protein Z-dependent protease inhibitor (ZIP protein)
Hypercoagulable Disorder
Inherited
Acquired
Mixed
Hypercoagulable States
Deficiency or underproduction of a protein
OR
Over production of a protein
OR
Genetic defect that changes a protein
Congenital Hypercoagulable
Disorders
Exclusively inherited hypercoagulable disorders
FVL and PTGM are single point mutations
Factor V Leiden Mutation
Prothrombin Gene Mutation
Methylenetetrahydrofolate Reductase Mutation
(677TT)
Factor V Leiden Mutation
Glycoprotein synthesized by the liver
Point mutation
G (guanine) to A (adenine) at nucleotide 1691 (G1691A)
Exon 10
glutamine replacing arginie at position 506
The mutant form is resistant to inactivation by protein C therefore
induces a pro-coagulant state
Autosomal dominant
Predilection in Caucasians
FVL and APC-R
Factor V Leiden leaves factor V partially resistant to
protein C and therefore referred to as activated protein
C resistance (APC-R)
CAUTION: Only 92% of the cases of activated
protein C resistance is from FVL
Other causes of activated protein C resistance are
acquired causes
Pregnancy
Malignancy
Antiphospholipid antibodies
Other factor V mutations
FVL Epidemiology
FVL with APC-R is the most common, inherited defect
Commonly in Caucasian (3-7%), Northern and Western Europeans with the
highest prevalence in Sweden (15%)
Also common in Cyprus, Turkey, and the Middle East
Rare in Asian and African descent in the United States but they can be
affected
FVL
Heterozygous and Homozygous states
Heterozygotes 5-7 fold increased risk for thrombosis
Homogygotes 80 fold increased risk for thrombosis
Thrombotic risk increases with a compound heterozygous state:
PTGM or MTHFR
The mutation affects factor V in the activated and inactivated
state
APC inactivates factor V in a series of 3 sequential arginine
cleavages at different animo acid residues:
Arg506
Arg306
Arg679
The sequential processing slows and the rate of inactivation of factor
V and leaves more activated factor V for thrombin production
FVL Clinical Presentation
Deep venous thrombosis usually of the lower extremities
Recurrent superficial thrombophlebitis
Prothrombin Gene Mutation (PTGM)
Single point mutation G to A
Nucleotide 20210
Factor II
Synthesized in the liver
Vitamin K dependent
Autosomal dominant
PTGM Epidemiology
2nd to FVL as the most common inherited
hypercoagulable defect
Almost twice as common in Caucasians of Southern
European descent when compared to Northern
European descent
May be seen in Middle East and Indian regions
Rare Asian and African descent
PTGM
Heterozygous state: 2 fold increase risk for thrombosis
Homozygous state: 10 fold increase risk for thrombosis
Presence of thrombophilia in Caucsian populations is 1-7%
Found in 2% of the US Caucasian population
Mechanism of action is unclear
Postulated that increased concentrations of prothrombin renders more
substrate for the conversion to thrombin
PTGM
Pregnancy complications:
Lowe birth weight
Pregnancy loss after 20 weeks
Placental abruption
Pre-eclampsia
Risk factors that increase incidence of VTE
Estrogen containing hormone replacement: 2-4 times increased risk
Oral contraceptives
Pregnancy
PTGM Clinical Manifestations
Deep venous thrombosis usually in the lower
extremities
Cerebral venous thrombosis especially in combination
with oral contraceptives
Mixed
Inherited or Acquired
Hypercoagulable Disorders
Protein C Deficiency
Protein S Deficiency
Antithrombin Deficiency
Lupus Anticoagulant
Hyperhomocysteinemia
Dysfibrogenemia
Protein C Deficiency
Protein S Deficiency
Protein S is a cofactor for protein C
Natural anticoagulants
Autosomal dominant with incomplete penetrance
High degree of penetrance when Protein C is
coinheritance with factor V Leiden: doubleheterozygous carriers
Vitamin K dependent
Synthesized in the liver
More than 100 different mutations described
Types of Deficiencies
Protein C and S
Type I
quantitative reduction in the amount of protein
produced
TypeII
adequate amounts produced that are qualitatively
dysfunctional
Type III
adequate amounts of total protein with reduced
amounts of free, active protein (applies to cofactors such
as protein S)
Epidemiology
Protein C and S
American and European Caucasians highest group
affected
Japanese populations are now identified as the highest
prevalence of protein S deficiency which is
approximately 5-10 times more frequent than seen in
Caucasians.
Protein C and S Deficiencies
Protein C inactivates activated factors V and VIII
Protein C stimulates the release of t-PA
Protein S is a cofactor for Protein C
Two genes identified on chromosome 3 for human protein S
active gene, PROS-b
pseudogene (named for its multiple coding errors), PROS-b
Deletions and point mutation cause phenotypic variation
Independent Protein S
Protein S can function independently from protein C
Direct inhibition of factor X clotting factor-activating
complex and prothrombin-activating complex
Inheritance Patterns
Protein C and S
Heterozygous is rare in otherwise healthy individuals
Homozygous state is thought to be incompatable with
life resulting in purpura fulminans
Acquired Protein C and S deficiencies
Acute Thrombosis
DIC
Severe liver disease
Malignancy
Infection
Hemolytic uremic syndrome
ARDS
Vitamin K deficiency/vitamin K antagonist
Post-operative state
Clinical Manifestations
Protein C and S defieciency
Deep venous thrombosis
Warfarin skin necrosis
Neonatal purpura fulminans
Venous thromboembolism at a young age (<45yo)
Antithrombin Deficiency
First described genetic abnormality linked to thrombophilia
Congenital acquisition is rare compared to the acquired state
Complete deficiency results in intrauterine fetal demise
Type I and Type II are present
Inhibitor of:
Thrombin
Activated factors IX-XII
Antithrombin III Deficiency
Prevalence of Thrombophilia in Caucasian
populations is 0.5 -2%
Prevalence in pregnancy is 1-5%
Risk of thrombosis when combined with Factor V
Leiden is up to 92%
Antithrombin Deficiency
Mechanism of Action
The addition of heparin induces a conformational change in the
thrombin-antithrombin complex and increases the affinity for thrombin
binding
Heparin enhances antithrombin properties to 2000 times.
Antithrombin binds thrombomodulin and accelerates the neutralization
of the coagulation cascade.
Antithrombin acts as an anticoagulant binds to and irreversibly inhibits
thrombin; low levels of antithrombin change the ratio of unbound
thrombin in favor of thrombosis
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
Initially described as anticoagulants due to their
interference with phospholipid-dependent clotting
assays
Described in patients with systemic lupus
erythematosus with thrombotic events
Antiphopholipid antibody syndrome is associated
with:
Fetal loss
Thrombocytopenia
Thrombosis
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant: double misnomer: Most patients do not have lupus and
it is a hypercoagulable syndrome
Anticardiolipin antibody (ACA-IgG, IgA, IgM, B2 glycoprotein I dependent)
30% lifetime risk of thrombotic event
aPTT may be prolonged at baseline (does not normalize with mixing studies)
Causes a false +VDRL
Clinical Manifestions of APS
Three or more consecutive miscarriages <10 week gestation
Unexplained fetal demise >10 week gestation
Previous arterial and/or venous thrombosis
May or may not be associated with SLE
Livedo reticularis
Migraine, stroke or TIA
Catastrophic antiphospholipid syndrome-rapidly progressive
microvascular thrombosis to multiple organ failure
Antiphospholipid Antibodies
Prevalence of thrombosis in caucasian populations is 2-3%
Ris of recurrent thrombosis is approximately 20-70%
Prevalence of thrombophilia in pregnancy is 10-20%
Prolonged APTT at baseline
Dilute Russel’s viper venom test – prolonged with antibodies present
Most require indefinite anticoagulation especially if another thrombotic
risk is present
Exclusively Acquired
Thrombophilia
Heparin Induced Thrombocytopenia with HITT) or
without thrombosis (HIT)
Heparin Induced
Thrombocytopenia (HIT)
Type I
-nonimmunogenic
-10-20% of patients receiving heparin
-no treatment required
-within the first 48 hours
-platelet count rebounds and rises to pretreatment levels with
continuation of heparin
Type II
-immunogentic/antiplatelet antibodies
-1%-3% some report up to 5% of patients receiving heparin
treatment
Type II HIT
Both arterial and venous thrombosis
Venous thrombosis is 4 times more common
Thrombocytopenia is seen at day 5 of treatment or
after
Early presentation if the patient has a history of
heparin exposure especially within the previous 100
days
Platelet count below 100,000 or decreases by 50% or
more of baseline
30%-50% will develop thrombosis (heparin induced
thrombocytopenia with thrombosis syndrome-HITTS)
Arterial Manifestations of HITTS
Aortic occlusion
Myocardial infarction
Stroke
Intraventricular thrombosis (cardiac)
Upper extremity, lower extremity, mesenteric, renal or spinal arterial
occlusion
“White clot syndrome” fibrin-platelet rich thrombus
Venous Manifestations of HITTS
Upper or lower extremity DVT
PE
Cerebral dural sinus thrombosis
Adrenal infarct
Warning Signs That Warrant a
Thrombophilia Workup
Multiple miscarriages
Unexplained fetal demise
Previous VTE, strong family history of VTE
Recurrent superficial thrombophlebitis or migratory thrombophlebitisTrousseau’ syndrome (cancers, especially adenocarcinoma)
Constitutional symptoms, fever of unknown origin or anemia that is
unexplained and persistent
History of arterial and venous thrombosis
Conclusion
Hypercoagulable disorders are classified and primary or secondary,
inherited or acquired and reversible or irreversible
The coagulation cascade, though confusing, is important to understand
in order to diagnose and treat hypercoagulable disorders
The right timing and appropriate situation is important before
embarking on a hypercoagulable workup
Always beware of warning signs in patients, especially those that are
unexplained.
Thank You For Your Attention