Download Protein C Deficiency - Saint Francis Hospital and Medical Center

Stroke Education Series - 2010
Hypercoaguable states & Stroke
Phaniraj Iyengar MD
Director
Disclosure
• I am on the speaker panel for Bristol
Myers and Sanofi Aventis
Discussion Points
1.
2.
3.
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8.
Introduction
Hemostasis
Thrombosis
Neurologist workup philosophy
Inherited hypercoaguable states
Acquired hypercoaguable states
Case presentations (Two)
Final summary
Hypercoaguable states & Stroke
• Coagulation disorders that predispose to
strokes remain POORLY DEFINED.
• They may have been implicated in venous
strokes (Cerebral venous thrombosis) rather
than arterial strokes.
• Known hematological abnormalities are
estimated to account for about 4% of all
strokes. This proportion may be higher for
younger people.
Hypercoaguability and Stroke
Hemostasis
Introduction
• The ability of blood to coagulate is
ESSENTIAL to the survival of the species.
• In humans, when coagulation is TOO
EFFICIENT, thrombosis becomes one of
THE MOST COMMON CAUSES of
morbidity and mortality in developed
countries – specifically CAD & STROKE.
Hemostatic Process
The Three main Steps
1. Primary hemostasis

Local vasoconstriction
& platelet plug
formation.
2. Coagulation cascade.
3. Fibrinolysis
Hemostasis
A very complex process!!!
Rube Goldberg Machine
Pencil Sharpener
Open window (A) and fly kite (B). String (C) lifts small door (D) allowing moths (E) to escape and
eat red flannel shirt (F). As weight of shirt becomes less, shoe (G) steps on switch (H) which heats
electric iron (I) and burns hole in pants (J). Smoke (K) enters hole in tree (L), smoking out
opossum (M) which jumps into basket (N), pulling rope (O) and lifting cage (P), allowing
woodpecker (Q) to chew wood from pencil (R), exposing lead. Emergency knife (S) is always
handy in case opossum or the woodpecker gets sick and can't work.
Platelet Activation & Aggregation
First Step
Exposed endothelial surface
Platelets exposed to collagen
Platelets are activated
Release contents of cytoplasmic granules
Adenosine Diphosphate (ADP)
Accelerates
Platelet activation
Platelet aggregation
Thromboxane (TxA2)
Vasoconstriction
Increases ADP release
from Platelets
Hemostatic Process
Coagulation Cascade



To stabilize and reinforce the weak platelet
plug
Fibrinogen → fibrin
Three main steps:
1. Formation of prothrombin activator
2. Conversion of prothrombin into thrombin
3. Conversion of fibrinogen to fibrin
Coagulation
Cascade
TF =tissue factor
PK = prekallikrein
HK=high molecular kininogen
a = activated
Roberts HR, et al. Current Concepts for
Hemostasis. Anesthesiology 2004;100:3.
722-30.
Coagulation Pathways
Intrinsic Pathway
“Contact
Activation”
IX
“TF Pathway”
XI
XIIa
Prekallikrein
HMW
Kininogen
Extrinsic Pathway
TF-VIIa
Ca2+
Tissue Factor + VII
X
Common Pathway
PL
Prothrombin
XIa
PL, Ca2+ (Tenase)
IXa
PL, Ca2+
VIIIa
Xa
Anticoagulation proteins:
Protein C, Protein S,
(Prothrombinase) Va
Antithrombin III, TFPI
XIII
Thrombin
Fibrinogen
XLXIII
a
Fibrin
Fibrin
Monomer
Polymer
Coagulation
Some facts to consider…
Coagulation is a MULTIFACTORIAL PATHWAY of
"accelerators".
Coagulation is TIGHTLY REGULATED and only a
SMALL quantity of each coagulation enzyme is
converted to its active form.
Regulation is important - there is enough clotting
potential in 1 mL of blood to CLOT ALL THE
FIBRINOGEN IN THE BODY in 10 to 15 seconds!
Hypercoaguability and Stroke
Thrombosis
Thrombosis
An Eye Opener
Thrombosis
Is
Clotting
In
the Wrong Place
Introduction
• Thrombosis can be divided anatomically into
VENOUS and ARTERIAL thrombosis.
• Pathophysiology of these two types of clotting is
quite different.
• Clotting in the low flow venous system is generally
associated with DEPOSITION OF FIBRIN,
whereas in the arterial system, thrombosis is
associated with PLATELET REACTIVITY AND
VASCULAR WALL DAMAGE.
Arterial Thrombosis
Pathophysiology
 Arterial thrombosis is the result of an
Atheromatous plaque rupture that causes
platelet activation and aggregation resulting
in an obstructive lesion that subsequently
leads to tissue damage.
Hypercoaguability
 Factors that ACCELERATE the hemostatic
mechanism or INHIBIT mechanisms that
counteract hemostasis CONTRIBUTE to an
INCREASED state of THROMBOGENICITY
or HYPERCOAGUABILITY, and thereby play
an etiological role in strokes.
Hypercoaguable Workup in Stroke
Is Challenging because of
 The relative LOW PREVALENCE of these
disorders in stroke patients
 Their UNCERTAIN SIGNIFICANCE
 Their POTENTIAL INTERACTION with traditional
stroke risk factors
 The HIGH COST of testing
 The LACK OF diagnostic gold standards
 The DIFFICULTY WITH INTERPRETATION of
some tests in the setting of acute thrombosis.*
Brigden ML. The hypercoagulable state: who, how, and when to
test and treat. Postgrad Med.1997; 101: 249–267.
Bushnell CD, Goldstein LB. Diagnostic testing for coagulopathies
in patients with ischemic stroke. Stroke. 2000; 31: 3067–3078.
Bushnell CD, Siddiqi Z, Morgenlander JC, Goldstein LB. Use of
specialized coagulation testing in the evaluation of patients
with acute ischemic stroke. Neurology. 2001; 56: 624–627.
Before ordering please………
 Attempt to connect the dots by asking
the right questions especially in the
context of
 History
 Presentation
 Imaging
Because these tests are expensive!!!
Cost of Hypercoaguabilty workup
Test
Natural anticoagulants
(antithrombin, protein C, protein S):
Genetic tests
(factor V Leiden, prothrombin G20210A):
Antiphospholipid antibodies:
Other (factor VIII, homocysteine):
TOTAL PANEL COST
Approximate
Cost*
$450-750
$600
$1000-1500
$200
$2250-3050
* Duke Coagulation Laboratory
Hypercoaguability and Stroke
Neurologists
Hypercoaguability Workup
philosophy
Workup of a suspected
Hypercoaguable state causing Stroke
 Fifty-nine (75%) surveys were completed.
 Specialized coagulation tests were reported
to INFREQUENTLY influence stroke patient
management (<25% of the time or NEVER
for 95% of respondents).
 Factors reported to INCREASE test-ordering
included young patient age (76%), history of
thrombosis (46%), history of miscarriages
(36%), and HAVING FEW traditional stroke
risk factors (35%).
Workup of a suspected
Hypercoaguable state causing Stroke
 MOST (88%) indicated they would order
specialized coagulation tests for a
hypothetical young patient with NO known
stroke risk factors.
 In contrast, ONLY A FEW (14%) would obtain
the tests for a patient having traditional stroke
risk factors, and
 NONE would order the tests for a stroke
patient with Atrial fibrillation.
Laboratory Evaluation
RISK FACTOR
LABORATORY ASSAY
Antithrombin Deficiency
AT activity
Protein C Deficiency
Protein C Deficiency PC activity (clotting or
chromogenic)
Protein S Deficiency
Protein S Free Antigen (ELISA, LIA)
APC Resistance / Factor V
Leiden Mutation
APC Resistance (aPTT); FV Leiden genetic
test if abnormal
Prothrombin Mutation G20210A
Genetic Test
Hypherhomocysteinemia
EIA, HPLC
Lupus Anticoagulant
DRVVT Clotting Assay
Anticardiolipin Antibody, IgG /
IgM
aCL IgG / IgM Antigen ELISA
Hypercoaguability and Stroke
Evaluation for Causes of a
Hypercoaguable State is
Complicated
What the Mind Does Not Know,
The Eye Does Not See
Factors leading to Thrombosis








Inherited Risk Factors
APC resistance-Factor V
Leiden
Anti-Thrombin deficiency
Protein C deficiency
Protein S deficiency
Prothrombin Mutation
Fibrinogen Mutations
Platelet protein
polymorphisms
Sickle cell disease









Acquired Risk Factors
Age
Malignancy
Immobilization
Trauma, Post-op
Pregnancy
Estrogen use
Antiphospholipid Antibodies
Long distance flights
Hematologic Diseases
 TTP
Inherited or Acquired Risk Factors
Hyperhomocystenemia
Elevated levels of Factor VIII, IX,XI
Hypercoaguability and Stroke
Inherited
Hypercoaguable
States
Inherited Hypercoaguable States
MUTATIONS
RARE
 Antithrombin III
deficiency.
 Protein C deficiency.
 Protein S deficiency
POLYMORPHISMS
COMMON
 Factor V Leiden.
 Prothrombin gene
polymorphism.
 Thermolabile MTHFR
variant.
Inherited Hypercoaguable States
Defect
Incidence % of
Hypercoaguable
States
Factor V Leiden
Prothtombin Gene Mutation
Protein C deficiency
Protein S deficiency
2–8%
40-60%
1-2 %
?10%
1: 200
5-10%
1: 5,000
5-10%
Antithrombin III deficiency
Dysfibrinogenemia
1: 2- 5000
1-3%
rare
1%
Inherited Hypercoaguable States
Polymorphisms of coagulation proteins
• The MOST common cause of venous
thrombosis is Activated Protein C resistance
(APC Resistance) which is MOST OFTEN
associated with a single mutation causing
substitution of arginine by glutamine at
residue 506 of Factor V gene (Factor V
Leiden).
Inherited Hypercoaguable States
Factor V Leiden
 Most common inherited cause of thrombosis
in Caucasians
 3-8% Caucasians carry the mutation and
0.1% are homozygotes
 Homozygotes have 80 fold increased risk of
thrombosis
Inherited Hypercoaguable States
Factor V Leiden
 Occurs in 5-7% of the population
 Occurs in 20% of patients with DVT.
 Occurs in 60% of patients with recurrent
DVT’s.
 Incidence of Factor V Leiden with stroke is
UNKNOWN.
Inherited Hypercoaguable States
Factor V Leiden
 Factor V Leiden is suspected to be
associated with paradoxical emboli or with
venous sinus thrombosis.
 At this time, the data available DO NOT
suggest any role between factor V Leiden
and arterial thrombosis (stroke, heart attack).
Inherited Hypercoaguable States
Factor V Leiden
 Treatment
 Warfarin x 6 months or until thrombosis
free for 2 months
 LMWH x 2 wks after Warfarin
 then retested
 Long term anticoagulation if persist or
recurrent thrombotic event
Inherited Hypercoaguable States
Antithrombin deficiency
 1965 - First inherited trait associated with
thrombophilia.
 Although called anti-thrombin, it actually
serves to inhibit virtually ALL of the
coagulation enzymes to at least some extent.
Inherited Hypercoaguable States
Antithrombin deficiency
• Although isolated reports exist of arterial
disease in patients with heterozygous
antithrombin deficiency, there is NO clear
evidence of increased arterial disease in
antithrombin deficiency.
Inherited Hypercoaguable States
Prothrombin Gene Mutation
 Genetic defect at nucleotide position 20210A
in prothrombin gene
 results in high prothrombin levels which causes
increased thrombin generation
 2-3% in Caucasians, 4-5% in Mediterranean
 Less severe clinical manifestation
Inherited Hypercoaguable States
Prothrombin Gene Mutation
 At this time, there is CONTRADICTING
evidence regarding the role of the
Prothrombin Gene mutation and arterial
thrombosis (stroke, heart attack).
Inherited Hypercoaguable States
Prothrombin Gene Mutation and Stroke
 Based on these data, for persons with the
prothrombin gene mutation, the MOST
IMPORTANT preventive steps for the
purposes of arterial disease are controlling
other risk factors including: Smoking,
Hypertension, Hyperlipidemia, Obesity and a
sedentary lifestyle (limited activity).
Inherited Hypercoaguable States
Protein C
 Vitamin K dependent plasma glycoprotein
 Functions by inactivating factors Va and
VIIIa
 Protein C activity is enhanced by Protein S
 Autosomal dominant inheritance
Inherited Hypercoaguable States
Protein C deficiency
 Prevalence in normal population ~0.2-0.4%
 Present in ~3-4% of patients with venous
thromboembolism.
 Homozygosity is associated with neonatal
purpura fulminans.
 50% of patients with protein C deficiency
WILL have a thrombosis by age 36 years.
Inherited Hypercoaguable States
Protein C deficiency
• At this time, the data available DO NOT
suggest any role between protein C
deficiency and arterial thrombosis (stroke,
heart attack).
Inherited Hypercoaguable States
Protein S
 Vitamin K dependent anticoagulant
 Cofactor to protein C and enhances its
activity against factors Va and VIIIa.
Inherited Hypercoaguable States
Protein S Deficiency
 Prevalence in the normal population ~0.003%
 Present in ~2-3% of patients with venous
thromboembolism.
 Homozygosity is associated with neonatal
purpura fulminans.
 50% of patients with protein S deficiency
WILL have a thrombosis by age 36 years.
Inherited Hypercoaguable States
Protein S Deficiency and Stroke
 A prospective study did find free Protein S
deficiency in 23% of young patients with
Stroke of Uncertain Cause, but this finding
could be associated with higher levels of C4b
(an acute phase reactant that decreases free
Protein S Levels).
Inherited Hypercoaguable States
Protein S Deficiency and Stroke
 At this time, the data available DO NOT
suggest any role between protein S
deficiency and arterial thrombosis (stroke,
heart attack).
Inherited Hypercoaguable States
Fibrinogen
 Elevated Fibrinogen levels are a common and
consistent finding in patients with Stroke
 Serum fibrinogen levels are variable and can
increase in response to infectious or
inflammatory conditions as part of the acute
phase response.
 Polymorphisms within the Fibrinogen gene
have been associated with Stroke.
Inherited Hypercoaguable States
Fibrinogen Polymorphisms and Stroke
 Results from the Austrian Stroke Study
showed an association between a
polymorphism in the beta chain of fibrinogen
at position 148 and Carotid atherosclerosis.
 Results from a Japanese study showed an
association between a polymorphism at
position 455 with cerebrovascular disease.
Inherited Hypercoaguable States
Fibrinogen Polymorphisms and Stroke
 Over time, more polymorphisms are likely to
be discovered in the Fibrinogen gene that are
related to stroke.
Inherited Hypercoaguable States
Polymorphisms of Platelet Proteins & CAD
 A common point mutation in glycoprotein IIIa,
termed PLA2, leads to a substitution of
proline for leucine at position 33.
 PLA2 has been suggested as a risk factor for
CAD1.
 Although potentially associated with CAD,
several studies have suggested that this
polymorphism is UNLIKELY to be associated
with Stroke2.
1Wciss
EJ et al. N Engl J Med 1996;334:1090-1094
2Carlsson LE at al. Stroke 1997;28:1392-1395
Inherited Hypercoaguable States
Platelet Protein Polymorphisms & Stroke
 The Glycoprotein Ib/IX/V complex is a platelet
protein responsible for platelet adhesion using vWF
as the ligand.
 A polymorphism in the region of the glycoprotein Lb
gene responsible for keeping the ligand binding
region distal to the platelet surface leads to a
variable number (1,2,3,4) of tandem repeats.
 There appears to be an association of repeat
number genotype with Cerebrovascular disease1.
Gonzalez-ConejeroR et al. Blood 1998;92:2771-2776
Inherited Hypercoaguable States
Hyperhomocysteinemia
 Hyperhomocystenemia is associated with a
Vasculopathy.
 Unlike most other hypercoaguable states, it
causes more arterial strokes than venous
strokes.
 Elevated levels of Homocysteine and related
disulfitide compounds are clear risk factors
for Stroke
Inherited Hypercoaguable States
Hyperhomocysteinemia
Mutations, Polymorphisms
heterozygotic
30-40%
1-2%
Mutations,
homozygotic
<<1%
Nutrition
30-40%
Renal
insufficiency
Homocysteine
Oxidative
stress
Endothelial Venous
dysfunction thrombosis
PVD
CVD
CAD
Inherited Hypercoaguable States
Homocysteinemia

Caused by two primary enzyme defects
1. Cystathionine Beta-Synthase (CBS)
2. Methylene-Tetra-Hydro-Folate Reductase
(MTHFR),
Inherited Homocysteinemia
Clinical Manifestations
1. Ocular
manifestations
– ectopia lentis
Inherited Homocysteinemia
Clinical Manifestations
2. Marfanoid appearance
combined with CNS
manifestations, like
mental retardation
Inherited Homocysteinemia
Clinical Manifestations
3. Musculo-skeletal
manifestations osteoporosis
Inherited Homocysteinemia
Clinical Manifestations
4. Vascular
manifestations –
vascular occlusions,
thromboembolism
Inherited Hypercoaguable States
Homocysteinemia from CBS
Polymorphisms




Most common genetic cause of severe
homocysteinemia.
Classic homocystinuria is homozygous
deficiency of CBS.
Inherited as autosomal recessive trait.
Occurs in 1 in 100,000 live births.
Inherited Hypercoaguable States
Homocysteinemia from CBS
Polymorphisms - Homozygotes
 Fasting tHcy levels up to 40 fold seen
 A vascular event occurs before the age of 30
in over 50% of untreated homozygotes.
Inherited Hypercoaguable States
Homocysteinemia from CBS
Polymorphisms - Heterozygotes
 Risk of vascular events is unclear as it is
often associated with normal tHcy levels and
may present with a mild clinical picture.
 Over 60 mutations of CBS gene have been
described with the most common being
I278T and G307S.
Inherited Hypercoaguable States
Homocysteinemia from MTHFR
Polymorphisms
 Homozygous deficiency is extremely rare
and results in early death.
 10-30% of white population is homozygous
for this mutation.
 This defect in the presence of suboptimal
folate intake will result in moderately
elevated tHcy plasma levels.
Inherited Hypercoaguable States
MTHR Polymorphisms & Stroke
 MTHFR C677T, Homozygous TT or
A1298C are NOT risk factors for
cerebral arterial or venous thrombosis.
Inherited Hypercoaguable States
Homocysteinemia and Stroke
 The incidence of stroke increases with
increasing Homocysteine levels.
 Experimental studies suggest Homocysteine
promotes ATHEROGENESIS and
THROMBOEMBOLISM.
 All young patients with unexplained stroke,
especially those with atherosclerosis,
SHOULD have Homcysteine levels checked.
Inherited Hypercoaguable States
Homocysteinemia Treatment
 Treated directly with vitamin supplementation.
 Primary vitamin used is folate.
 Taking folate and vitamin B12 can lead to an
additional decrease in Homocysteine levels
above that seen with folate alone.
Inherited Hypercoaguable States
Homocysteinemia Treatment
 Anticoagulation following vascular thrombosis
 Generally used for 3-6 months.
 Further continuation is generally not indicated in
hyperhomocysteinemia after a single
thromboembolic episode given the risk of bleeding
associated with anticoagulation.
 Patients with multiple thromboembolic episodes
may need to be on long-term anticoagulation.
INHERITED RISK FACTOR
Sickle Cell Disease
 Autosomal recessive genetic disease:
 β-globin gene (chromosome 11q) mutation
GAGGTG at 6th codon
 Glutamic Acid  Valine at the 6th amino acid
along the β-globin chain
 α2β2 = normal hemoglobin
 α2βS = heterozygote = Sickle trait
 α2S2 = homozygous recessive = Sickle cell disease
INHERITED RISK FACTOR
Sickle Cell Disease
 Sickle cell disease causes a vasculopathy
that, along with stasis in small arteries, is a
principal mechanism by which it causes
strokes.
 The mechanism is a progressive, segmental
narrowing of the distal internal carotid artery
and portions of the circle of willis and
proximal branches of the major intracranial
arteries.
INHERITED RISK FACTOR
Sickle Cell Disease
 The incidence of brain infarction peaks
around age 10 years.
 The incidence of stroke in patients with Hb
SS is 10% and those with Hb SC is 2-5%.
Hypercoaguability and Stroke
Acquired
Hypercoaguable
States
Hypercoaguability and Stroke
Antiphospholipid Syndrome
Antiphospholipid Syndrome
 Most common acquired thrombophilia
 Described by Dr. Graham Hughes (1983)
now at the Lupus Center, London, UK.
 A syndrome characterized by the association of:
 thrombosis, obstetric complications and/or
thrombocytopenia
 antibodies against phospholipids or against proteins
bound to phospholipids.
Antiphospholipid Syndrome
Etiology
• Combination of genetic background and environmental
factors: infection, trauma, drugs
- infections – molecular mimicry with B2GPI
APS Pathophysiology
aCL
platelets
Coagulation
cascade
Activate
platelet
aggregation
Inhibit Protein C,
Protein S,
thrombomodulin,
antithrombin III
fibrinolysis
Placental
tissue
Complement
system
Endothelial
cells
Trophoblastic
cell growth,
TF, adhesion
molecules and
proinflammatory
cytokines
apoptosis
IL-3
Antiphospholipid Syndrome
Clinical manifestations
• Venous thrombosis:
Most common: deep or superficial
veins of the legs
Less common: IVC, iliofemoral,
axillary, renal, portal, hepatic, or
retinal veins
• Arterial thrombosis:
Most common: Cerebral infarct,
cardiogenic emboli.
Less common: Coronary, retinal,
and visceral artery
• Cutaneous:
Livedo reticularis (up to 80%),
splinter hemorrhages, leg ulcer,
skin insarcts, blue toe syndrome
• Neuro:
Multi-infarct dementia, chorea,
transverse myelopathy,
Pseudotumor cerebri, cerebral
venous thrombosis APLA are
found in as many as 50% of
patients who get migraines
• Cardiac:
CAD, valve vegetations or
thickening 30%, intracardiac
thrombus
• Hematologic:
Thrmobocytopenia (40% of
patients), hemolytic anemia
• Obstetric:
Fetal loss (15-75%), IUGR
Antiphospholipid Antibodies
Three primary classes of Antibodies
1. Lupus Anticoagulant (LA) antibodies are
directed against plasma proteins bound to anionic
phospholipids
2. Anti-Cardiolipin (aCL) antibodies are directed
against phospholipids bound to proteins
 Can be IgA, M, or G (subclasses 1-4)
 IgG (esp G2) associated with a greater risk of APS
3. Anti Beta 2 Glycoprotein (b2GPI) antibodies are
directed against a plasma protein that binds
phospholipid with high affinity
Antiphospholipid Syndrome
Epidemiology
 Many patients have laboratory evidence of APS
antibodies WITHOUT clinical disease.
 APS antibodies found in 10% of healthy donors,
30-50% of SLE patients
 APS may develop in 50 to 70 % of patients with
both SLE and APS antibodies after 20 years of
follow-up.
 Nonetheless, up to 30 percent of patients with SLE
and anticardiolipin antibodies lacked any clinical
evidence of APS over an average follow-up of
seven years.
Antiphospholipid Syndrome
Frequency of APS antibodies in different
populations
Population
aCL
LA
Normal individuals:
2-5%
0-1%
Normal pregnancy:
1-10%
-
Elderly (>70 years of age):
>50%
-
Patients with SLE:
17-86%
7-65%
Family members of patients with APS:
8-31%
-
Antiphospholipid Syndrome
Risk of thrombosis in patients with APS
antibodies
Odds Ratios for VTE
SLE with lupus anticoagulant
6.32 (3.80-8.27)*
Non-SLE with lupus
anticoagulant
11.1 (3.81-32.3)**
 Incidence of thrombosis: ~2-2.5%†.
 Coincident risk factors for thrombosis: up to 50%‡.
Lupus (1997) 6: 467.
** Lupus (1998) 7: 15.
† Am J Med (1996) 100: 530. ‡ J Rheumatol (2004) 31: 1560.
Antiphospholipid Antibodies
Detection & Clinical Relevance
 Despite the frequent concordance between
lupus anticoagulant antibodies and either
anticardiolipin or anti– B 2 Glycoprotein I
antibodies, these antibodies are NOT
identical.
 In general, lupus anticoagulant antibodies are
MORE SPECIFIC for the antiphospholipid
syndrome, whereas anticardiolipin antibodies
are MORE SENSITIVE.
Antiphospholipid Antibodies
Detection & Clinical Relevance
 The SPECIFICITY of anti-cardiolipin
antibodies for APS INCREASES WITH
TITER and is HIGHER for IgG than for the
IgM isotope.
 MULTIPLE TESTS for antiphospholipid
antibodies SHOULD BE USED, since
patients may be negative according to one
test yet positive according to another.
Antiphospholipid Syndrome
Classification
 Primary APS
 If the patient HAS NO known underlying
autoimmune disorder.
 Secondary APS
 If the patient HAS an underlying
autoimmune disorder, such as SLE.
Antiphospholipid Syndrome
Classification
 Studies have NOT SHOWN any clear
differences between patients with Primary
APS versus Secondary APS.
 A risk of recurrent thrombi, both arterial and
venous, is associated with both types of
APS.
 Most studies suggest that patients who have
a recurrent episode will have it in a similar
blood vessel type.
Antiphospholipid Syndrome
Diagnosis - Clinical Criteria
 Vascular thrombosis:
 One episode of arterial, venous, or small vessel, in any
tissue or organ, confirmed by objective validated criteria
 Pregnancy morbidity:
 Unexplained fetal death at or beyond 10 weeks gestation
 Premature birth before 34 weeks gestation because of
eclampsia, severe pre-eclampsia, or placental
insufficiency
 Three or more consecutive spontaneous abortions
before 10 weeks gestation
International Consensus Statement on Classification Criteria for APS (2006).
Miyakis, et al., J.Thromb.Haemost., 2006; 4: 295-306
Antiphospholipid Syndrome
Diagnosis - Laboratory Criteria
• Lupus anticoagulant (LA), present on at least 2
occasions, at least 12 weeks apart
• Anticardiolipin antibodies (aCL), IgG or IgM >30
units for both, present on at least 2 occasions, at
least 12 weeks apart
• Anti-beta-2-glycoprotein I antibodies (antiB2GPI), IgG or IgM >20 units for both, present on
at least 2 occasions, at least 12 wks apart
International Consensus Statement on Classification Criteria for APS (2006).
Miyakis, et al., J.Thromb.Haemost., 2006; 4: 295-306
Antiphospholipid Syndrome
Diagnosis
 A diagnosis of Antiphospholipid Syndrome should
NOT be made if a period of greater than five years
separates the clinical event and positive laboratory
test.
 Although antiphospholipid antibodies ALSO
OCCUR in association with other conditions
(including infections, cancer, and the use of drugs
or hemodialysis), they are usually IgM antibodies
that are present at low levels and ARE NOT
associated with thrombotic events.
Hypercoaguability and Stroke
Antiphospholipid
Syndrome and Stroke
Antiphospholipid Syndrome & Stroke
Incidence
• Published figures range from 7% of all
strokes1 to 41% of all strokes2 (study relied
on one single aPL assessment)
• In the younger population (under 45), it
may be as high as one in 5 of all strokes
associated with aPL.
1Montalban
J et al. Stroke 1991;22:750-753
2Levine SR et al. JAMA 2004;291:576-584
Antiphospholipid Syndrome & Stroke
APASS Study 2004
 Only RCT Study (prospective cohort study).
 Conducted within the WARSS study.
 720 of the 1770 patients in WARSS tested positive
for aPL (41%)
 Compared warfarin (target INR 1.4 to 2.8) vs. ASA.
 Analyzed antiphospholipid status after stroke.
 Composite outcome measure including death,
ischemic stroke, or other thromboembolic events.
APASS Study
Outcomes
Proportion with
Event at 2 Years
30
20
10
aPL +
aPL -
0
Warfarin
Aspirin
Treatment Group
APASS Investigators, JAMA, 2004; 291: 576.
Antiphospholipid Syndrome & Stroke
APASS Study 2004 - Caveats
 Patients from the general population who have
sustained an initial non-cardioembolic stroke and
are POSITIVE for LA and aCL (ELISA – low,
medium or high titers included) within 30 days of
the Stroke (patients tested once) DO NOT have a
different prognosis than those who test NEGATIVE.
 This result was consistent the Aspirin and Warfarin
arms of the trial.
Hypercoaguability and Stroke
Treatment
Antiphospholipid Syndrome
ACCP Guidelines
• Prevention of noncardioembolic cerebral
ischemic events.
– For most patients, we recommend antiplatelet
agents over oral anticoagulation (Grade 1A).
– For patients with ‘well-documented’
prothrombotic disorders, we suggest oral
anticoagulation over antiplatelet agents (Grade
2C).
Albers, et al., Chest, 2004; 126 (Supplement): 483S.
Antiphospholipid Syndrome
Evidence for Treatment Recommendations
• Retrospective studies suggest target INR >
3.0.
– Rosove & Brewer (1992).
– Khamashta, et al. (1995).
• Prospective randomized trials suggest target
INR of 2 to 3.
– Crowther, et al. (2003).
– Finazzi, et al. (2005).
Antiphospholipid Syndrome
Treatment of aPL positive patients
 We conclude that the presence of a
persistent aPL has NOT been demonstrated
as such an important risk factor for recurrent
thrombosis that it warrants more intensive
(and more risk-bearing) treatment1.
 Patients with positive aPL tests would really
be helped with data from studies that enable
evidence based recommendations for
treatment1.
1RHWM
Derkson et al. Lupus 2010 19. 470-474
Hypercoaguability and Stroke
Thrombotic
Thrombocytopenic Purpura
(TTP)
TTP
History
• In 1924, Dr.Eli Moschcowitz described a 16year old girl with abrupt onset of petechiae,
pallor, followed by paralysis, coma, and
death.
• Autopsy showed ‘hyaline’ thrombi occluding
terminal arterioles and capillaries.
TTP
Presentation

Clinical findings
Classic Pentad
1. Fever
2. Neurologic changes All 5 criteria present
3. Renal impairment

Laboratory findings
4. Microangiopathic hemolytic anemia (Hb <
10g/dl)
5. Thrombocytopenia (Platelets < 20,000/µl)
TTP
Clinical Presentation
•
•
•
•
•
•
Approx. 1000 new cases occur each year
Common in middle age; median age = 40
Female : male (2:1)
Acute onset and fulminant course
Mortality rate >90% in pre-pheresis era.
Relapse rates, 10-40% ranging from months
to years have been reported.
TTP
Pathogenesis
 Deficiency of VWF- cleaving protease
 Termed ADAMTS13
 Corresponding gene : chromosome 9q34.
TTP
Pathogenesis – ADAMTS13
Metalloprotease
SP
M
D 1
Thrombospondin 1
Cys Spacer
2 3 4 5 6 7 8
CUB CUB
Disintegrin
A Disintegrin-like And Metalloprotease with
ThromboSpondin-1 repeats (ADAMTS13)
 Discovered in 1996 by Tsai and by Furlan
 Requires Ca2+ and Zn2+ ions
 Cleaves VWF between Tyr1605 - Met1606
 Activated by shear stress, mild denaturants
TTP
Pathogenesis – ADAMTS13
Proteolysis by ADAMTS13
 Cleaves VWF Tyr1605-Met1606
 INCREASE causes VWD (type 2A)
 DECREASE causes TTP
TTP
Primary TTP
1. Familial recurrent TTP: Constitutional
deficiency of VWF
TTP
Secondary TTP
• Drug-induced
– Acute immune mediated:
• Ticlopidine - frequency is 1/2000-1/5000 in pts
receiving ticlid post-coronary stent1.
• Plavix – frequency is <1/20,000. Usually occurs in
first 2 weeks, responds to stopping medication2.
– Dose-related: mitomycin, tacrolimus, pencillin,
cyclosporine, cisplatin, bleomycin, OCP
– Quinine: HUS like illness.
1Bennett
et al Ann Inter Med 1998
2Bennett
et al N Engl J Med 2000
TTP
Secondary TTP
•
•
•
•
Pregnancy and post-partum.
Allogenic bone marrow transplant.
Autoimmune disorders (SLE,scleroderma)
HIV infection.
TTP
Diagnosis – There is no Gold Standard
 Primary diagnostic criteria
 Thrombocytopenia ( often below <20,000)
 Microangiopathic hemolytic anemia
 Negative Coomb’s test.
 Fragmented red cells (schistocytes) on peripheral smear
 LDH elevation is the hallmark of RBC destruction and tissue
injury related to ischemia.
 Presence of above criteria is sufficient to
establish presumptive diagnosis & begin PE
TTP
Diagnosis
• At present there are no confirmatory tests
available.
• Other features in pentad support the
diagnosis.
• Tests for ADAMTS13 deficiency or inhibitors
are not readily available and lack
standardization.
TTP
Differential Diagnosis
• Disseminated intravascular coagulation.
• Sepsis: cytomegalovirus, rocky mountain
spotted fever, meningococcemia.
• Preeclampsia/eclampsia, HELLP.
• Disseminated malignancy.
• Hemolytic-uremic syndrome
• Evans syndrome
• Malignant hypertension.
TTP
Treatment
 Plasma exchange:
 Untreated TTP has 80-90% mortality.
 Removes ULvWF multimers, autoantibody
and replaces metalloproteinase.
 Randomized controlled trial (Rock et al, 1991)
 FFP as the replacement fluid is most widely
used and cost effective.
TTP
Response To Treatment
 Mental Status changes improve dramatically.
 Thrombocytopenia require several days.
 Parameters of hemolysis improve promptly, yet
anemia may continue to worsen.
 Recovery from renal failure is unpredictable and
often slow.
 Prolonged courses of Plasma Exchange, with
frequent exacerbations is characteristic of idiopathic
TTP
TTP
Duration of treatment.
 No studies precisely determine optimal schedule
 AABB extracorporeal therapy committee: daily PE
until plt ct > 150k for 2-3 days.
 American Society for Apheresis: daily PE until Plt
> 100k, complete normalization of LDH.
 Tapering schedule to 3 times per week after
sustained response is highly recommended.
TTP
Treatment
 AVOID prophylactic platelet transfusion
UNLESS life-threatening bleeding is
present1,2 because
 Platelet transfusion provides additional
substrate for thrombus formation.
 MI and strokes have reportedly occurred after
transfusion.
1Gordon
et al , 1987;
2Harkness et al 1981
TTP
Treatment
 Plasma exchange DOES NOT address the
underlying autoimmune disorder
 Refractory disease MAY benefit from
immunosuppression
 ADAMTS13 and inhibitor assays MAY
become useful to guide therapy
TTP
Other Treatment Options




Antiplatelet Therapy
Steroids
Splenectomy (Crowther et al, 1996)
Chemotherapy: Cytoxan, Vincristine,
Rituxan, CHOP.
 High- dose IV IgG
 Protein A immunoadsorption columns.
TTP
Follow-up and outcome
 Follow up
 Duration of initial treatment is undefined
 Monitor CBC and LDH
 Outcome
 Relapse rates 29-82%
 Chronic renal insufficiency (~25%)
 Long term neurological effects (incidence ?)
Hypercoaguability and Stroke
Case Presentations
Case #1
Case #1
 Mrs FC
 44y R handed White female, non-smoker with h/o
Migraines on Maxalt who presented with new right
handed numbness and weakness after a week following
an uncomplicated tubal ligation done as an outpatient.
 Past medical history significant for DVT during
pregnancy (2nd and 4th) and had been on anticoagulation
with Coumadin for 6 months after the last pregnancy.
 Extensively worked up for a hypercoaguable state on
multiple occasions including 6 months prior – all
unremarkable / inconclusive.
 Her evaluation during this hospitalization revealed a
cortical infarct in the left hemisphere.
Case #1
 Repeat hypercoaguable work
up – Protein C / S,
Homocysteine, aCL, LA, Factor
V Leiden, Prothrombin gene
mutation, ANA, RA all negative.
 TEE – Normal, No PFO.
 Hematology consultation
 Started on Zocor, ASA and
discharged with 21 day event
monitor set up.
Will this be her last admission for a Stroke?
GOK
Hypercoaguability and Stroke
Case Presentations
Case #2
Case #2
Mrs WW
 55 yr old AA, h/o HTN. Non smoker. Dad had CVA at 50.
 In February 2003, she presented with her first stroke at age
48. After an inconclusive Stroke in the Young, started on
Plavix along with BP meds.
 In July 2005, she presented with her second stroke and
was started on Aggrenox. Had a repeat inconclusive Stroke
in the Young work up.
 In February 2006 presented with TIA like symptoms along
with thrombocytopenia. Aggrenox suspected as cause of
Thrombocytopenia. Seen by Hematology. Started on
Coumadin.
 In May 2007, presented with non-specific complaints,
Platelets down to 13,000. Peripheral smear showed some
hemolysis. Seen by hematologist and diagnosed with TTP.
Started on Plasmapheresis and Steroids. Coumadin
stopped.
Case #2
Mrs WW
 In July 2007 she presented with sepsis / septic shock,
treated and discharged.
 In October 2008, she presented with her third stroke. I saw
her then. Repeated stroke n the young work up again along
with a cardiac MRI – negative. Continued on ASA 81mgs.
 In December 2008, presented with worsening
thrombocytopenia and admitted and started on
plasmapheresis and steroids.
 In April 2009, she presented with her fourth stroke. Started
on Plasmapheresis and steroids and continued on ASA
81mgs. Then refused chemotherapy and splenectomy.
Case #2
Mrs WW
 In April 2010 she presented with her fifth stroke. Again
started on Plasmapheresis and steroids and continued on
ASA 81mgs. Again refused chemotherapy and
splenectomy.
 In May 2010 she presented with her sixth stroke. Again
started on Plasmapheresis and steroids and continued on
ASA 81mgs. Her ADAMTS 13 inhibitor levels were 6.8
(normal < 0.4) suggestive of a possible recurrence. This
time she agreed to be started on the Rituximab and an
elective splenectomy.
 She was discharged on May 17, 2010.
Will this be her last admission for a Stroke?
GOK
Case # 2 – MRI DWI Imaging
Feb 2003
Jul 2005
Apr 2010
Oct 2008
Feb 2009
May 2010
Hypercoaguability and Stroke
Final Summary
Connect the dots….
1. ASK the right questions in History.
2. LOOK for embolic strokes or venous strokes on
MRI Imaging.
3. CONFIRM presence or absence of PFO.
4. ORDER patient specific Hypercoaguable workup.
5. OBTAIN hematologist consultation BEFORE
initiating anticoagulation.
6. NEVER forget to address the usual stroke
causes.
7. PRAY for and with your patient.
Remember….
Site of Thrombosis Vs. Coagulation Defect
Abnormality
Arterial
Factor V Leiden
Prothrombin G20210A
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Hyperhomocysteinemia
LA/ aCL / aPL
+
+
Venous
+
+
+
+
+
+
+
Hypercoaguability and Stroke
The End
Thank You
Questions / Comments