Stroke Education Series - 2010 Phaniraj Iyengar MD Director Director Hypercoaguable states & Stroke

Stroke Education Series - 2010Stroke Education Series - 2010

Phaniraj Iyengar MDPhaniraj Iyengar MDDirectorDirector

Phaniraj Iyengar MDPhaniraj Iyengar MDDirectorDirector

Hypercoaguable states & StrokeHypercoaguable states & Stroke

DisclosureDisclosure

• I am on the speaker panel for Bristol Myers and Sanofi Aventis

• I am on the speaker panel for Bristol Myers and Sanofi Aventis

Discussion PointsDiscussion Points1. Introduction2. Hemostasis3. Thrombosis4. Neurologist workup philosophy5. Inherited hypercoaguable states6. Acquired hypercoaguable states 7. Case presentations (Two)8. Final summary

1. Introduction2. Hemostasis3. Thrombosis4. Neurologist workup philosophy5. Inherited hypercoaguable states6. Acquired hypercoaguable states 7. Case presentations (Two)8. Final summary

Hypercoaguable states & StrokeHypercoaguable 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.

• 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 StrokeHypercoaguability and Stroke

HemostasisHemostasis

IntroductionIntroduction

• 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.

• 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 ProcessThe Three main Steps

Hemostatic ProcessThe Three main Steps

1. Primary hemostasis Local vasoconstriction

& platelet plug formation.

2. Coagulation cascade.

3. Fibrinolysis

1. Primary hemostasis Local vasoconstriction

& platelet plug formation.

2. Coagulation cascade.

3. Fibrinolysis

HemostasisHemostasis

A very complex process!!!A very complex process!!!

Rube Goldberg MachinePencil Sharpener

Rube Goldberg MachinePencil 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 & AggregationFirst Step

Platelet Activation & AggregationFirst Step

Exposed endothelial surfaceExposed endothelial surface

Platelets exposed to collagenPlatelets exposed to collagen

Platelets are activatedPlatelets are activated

Release contents of cytoplasmic granulesRelease contents of cytoplasmic granules

Adenosine Diphosphate (ADP)Adenosine Diphosphate (ADP) Thromboxane (TxA2)Thromboxane (TxA2)Accelerates Platelet activationPlatelet aggregation

Accelerates Platelet activationPlatelet aggregation

VasoconstrictionIncreases ADP releasefrom Platelets

VasoconstrictionIncreases ADP releasefrom Platelets

Hemostatic ProcessCoagulation Cascade

Hemostatic ProcessCoagulation 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

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

Coagulation Cascade

TF =tissue factorPK = prekallikreinHK=high molecular kininogena = activated

Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

“Contact Activation” Tissue Factor + VIITissue Factor + VII

XIIIXIIIaa

XIIIXIII

Thrombin

XL-XL-Fibrin

PolymerFibrinogen Fibrin

Monomer

IX

XIXI

XIXIaa

IXa

XaVVaa

XIIXIIaaProthrombin

TF-VIITF-VIIaa

(Prothrombinase)

PLPL

PL, Ca2+

(Tenase)

VIIIVIIIaa

PL, Ca2+

XX

Intrinsic Pathway

PrekallikreinHMW

Kininogen

Extrinsic Pathway

Common Pathway

“TF Pathway”

Anticoagulation proteins: Protein C, Protein S, Antithrombin III, TFPI

Ca2+

Coagulation PathwaysCoagulation Pathways

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!

CoagulationSome facts to consider…

CoagulationSome facts to consider…


ThrombosisThrombosis

ThrombosisAn Eye OpenerThrombosisAn Eye Opener

Thrombosis Is

Clotting In

the Wrong Place

Thrombosis Is

Clotting In

the Wrong Place

IntroductionIntroduction• 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.

• 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 ThrombosisPathophysiology

Arterial ThrombosisPathophysiology

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.

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.

HypercoaguabilityHypercoaguability

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.

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 StrokeIs Challenging because of

Hypercoaguable Workup in StrokeIs 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.*

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.

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………Before ordering please……… Attempt to connect the dots by asking

the right questions especially in the context of History Presentation Imaging

Attempt to connect the dots by asking the right questions especially in the context of History Presentation Imaging

Because these tests are expensive!!!Because these tests are expensive!!!

Cost of Hypercoaguabilty workupCost of Hypercoaguabilty workup

Test Approximate Cost*

Natural anticoagulants

(antithrombin, protein C, protein S):

$450-750

Genetic tests

(factor V Leiden, prothrombin G20210A):

$600

Antiphospholipid antibodies: $1000-1500

Other (factor VIII, homocysteine): $200

TOTAL PANEL COST $2250-3050

* Duke Coagulation Laboratory


Neurologists Hypercoaguability Workup

philosophy

Neurologists Hypercoaguability Workup

philosophy

Workup of a suspected Hypercoaguable state causing Stroke

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%).

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%).

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.

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 EvaluationLaboratory EvaluationRISK 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


Evaluation for Causes of a Hypercoaguable State is

Complicated

Evaluation for Causes of a Hypercoaguable State is

Complicated

What the Mind Does Not Know, The Eye Does Not See

What the Mind Does Not Know, The Eye Does Not See

Factors leading to ThrombosisFactors leading to ThrombosisInherited 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

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

Acquired Risk Factors Age Malignancy Immobilization Trauma, Post-op Pregnancy Estrogen use Antiphospholipid Antibodies Long distance flights Hematologic Diseases

TTP

Inherited or Acquired Risk FactorsHyperhomocystenemiaElevated levels of Factor VIII, IX,XI


Inherited Hypercoaguable

States

Inherited Hypercoaguable

States

Inherited Hypercoaguable StatesInherited Hypercoaguable States

MUTATIONS

RARE Antithrombin III

deficiency. Protein C deficiency. Protein S deficiency

MUTATIONS

RARE Antithrombin III

deficiency. Protein C deficiency. Protein S deficiency

POLYMORPHISMS

COMMON Factor V Leiden. Prothrombin gene

polymorphism. Thermolabile MTHFR

variant.

POLYMORPHISMS

COMMON Factor V Leiden. Prothrombin gene

polymorphism. Thermolabile MTHFR

variant.

Inherited Hypercoaguable StatesInherited Hypercoaguable StatesDefect Incidence % of

Hypercoaguable States

Factor V Leiden 2 – 8 % 40-60%

Prothtombin Gene Mutation 1-2 % ?10%

Protein C deficiency 1: 200 5-10%

Protein S deficiency 1: 5,000 5-10%

Antithrombin III deficiency 1: 2- 5000 1-3%

Dysfibrinogenemia rare 1%

Inherited Hypercoaguable StatesPolymorphisms of coagulation proteins

Inherited Hypercoaguable StatesPolymorphisms 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).

• 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


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

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.

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.



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).

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).

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

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




Antithrombin deficiency


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.

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.

• 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.

• 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 Antithrombin deficiency

Inherited Hypercoaguable States Antithrombin deficiency


Prothrombin Gene Mutation


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

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

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).

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

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).

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

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

Vitamin K dependent plasma glycoprotein Functions by inactivating factors Va and

VIIIa Protein C activity is enhanced by Protein S Autosomal dominant inheritance

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.

Prevalence in normal population ~0.2-0.4% Present in ~3-4% of patients with venous


purpura fulminans. 50% of patients with protein C deficiency


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).

• 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

Inherited Hypercoaguable States Protein S

Vitamin K dependent anticoagulant Cofactor to protein C and enhances its

activity against factors Va and VIIIa.

Vitamin K dependent anticoagulant Cofactor to protein C and enhances its

activity against factors Va and VIIIa.

Prevalence in the normal population ~0.003% Present in ~2-3% of patients with venous


purpura fulminans. 50% of patients with protein S deficiency


Prevalence in the normal population ~0.003% Present in ~2-3% of patients with venous


purpura fulminans. 50% of patients with protein S deficiency



Protein S Deficiency


Protein S Deficiency

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).

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).


Protein S Deficiency and Stroke


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).

At this time, the data available DO NOT suggest any role between protein S deficiency and arterial thrombosis (stroke, heart attack).

Inherited Hypercoaguable States Protein S Deficiency and Stroke

Inherited Hypercoaguable States Protein S Deficiency and Stroke

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.

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.


Fibrinogen


Fibrinogen

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.

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.


Fibrinogen Polymorphisms and Stroke



Over time, more polymorphisms are likely to be discovered in the Fibrinogen gene that are related to stroke.

Over time, more polymorphisms are likely to be discovered in the Fibrinogen gene that are related to stroke.





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.

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.

Inherited Hypercoaguable States Polymorphisms of Platelet Proteins & CAD Inherited Hypercoaguable States

Polymorphisms of Platelet Proteins & CAD

1Wciss EJ et al. N Engl J Med 1996;334:1090-10942Carlsson LE at al. Stroke 1997;28:1392-1395

1Wciss EJ et al. N Engl J Med 1996;334:1090-10942Carlsson LE at al. Stroke 1997;28:1392-1395

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.

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.

Inherited Hypercoaguable States Platelet Protein Polymorphisms & Stroke Inherited Hypercoaguable States Platelet Protein Polymorphisms & Stroke

Gonzalez-ConejeroR et al. Blood 1998;92:2771-2776Gonzalez-ConejeroR et al. Blood 1998;92:2771-2776


Hyperhomocysteinemia


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

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

Homocysteine

Mutations,heterozygotic

1-2%Nutrition30-40%

Mutations,homozygotic

<<1%

Polymorphisms30-40%

Renalinsufficiency

Endothelialdysfunction

Venousthrombosis

CVD

PVD

CAD

Oxidativestress

Inherited Hypercoaguable States Hyperhomocysteinemia

Inherited Hypercoaguable States Hyperhomocysteinemia

Caused by two primary enzyme defects

1. Cystathionine Beta-Synthase (CBS)

2. Methylene-Tetra-Hydro-Folate Reductase (MTHFR),

Caused by two primary enzyme defects

1. Cystathionine Beta-Synthase (CBS)

2. Methylene-Tetra-Hydro-Folate Reductase (MTHFR),


Homocysteinemia


Homocysteinemia

1. Ocular manifestations – ectopia lentis

1. Ocular manifestations – ectopia lentis

Inherited HomocysteinemiaClinical Manifestations


2. Marfanoid appearance combined with CNS manifestations, like mental retardation



3. Musculo-skeletal manifestations - osteoporosis

3. Musculo-skeletal manifestations - osteoporosis



4. Vascular manifestations – vascular occlusions, thromboembolism



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.

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


Polymorphisms

Fasting tHcy levels up to 40 fold seen A vascular event occurs before the age of 30

in over 50% of untreated homozygotes.

Fasting tHcy levels up to 40 fold seen A vascular event occurs before the age of 30

in over 50% of untreated homozygotes.


Polymorphisms - Homozygotes


Polymorphisms - Homozygotes

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.

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.


Polymorphisms - Heterozygotes


Polymorphisms - Heterozygotes

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.

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 Homocysteinemia from MTHFR

Polymorphisms

Inherited Hypercoaguable States Homocysteinemia from MTHFR

Polymorphisms

MTHFR C677T, Homozygous TT or A1298C are NOT risk factors for cerebral arterial or venous thrombosis.

MTHFR C677T, Homozygous TT or A1298C are NOT risk factors for cerebral arterial or venous thrombosis.


MTHR Polymorphisms & Stroke Inherited Hypercoaguable States

MTHR Polymorphisms & 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.

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 and Stroke

Inherited Hypercoaguable States Homocysteinemia and Stroke

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.

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.

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.



Autosomal recessive genetic disease: β-globin gene (chromosome 11q) mutation

GAGGTG 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

Autosomal recessive genetic disease: β-globin gene (chromosome 11q) mutation

GAGGTG 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 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.

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.



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%.

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%.



Sickle Cell Disease


Acquired Hypercoaguable

States

Acquired Hypercoaguable

States


Antiphospholipid SyndromeAntiphospholipid Syndrome

Antiphospholipid SyndromeAntiphospholipid 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.

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

Antiphospholipid Syndrome Etiology

• Combination of genetic background and environmental factors: infection, trauma, drugs

- infections – molecular mimicry with B2GPI

• Combination of genetic background and environmental factors: infection, trauma, drugs

- infections – molecular mimicry with B2GPI

APS PathophysiologyAPS Pathophysiology

platelets

Coagulation cascade

Endothelial cells

Activate platelet

aggregation

Inhibit Protein C, Protein S,

thrombomodulin, antithrombin III

fibrinolysis

TF, adhesion molecules and

proinflammatory cytokines

Placental tissue

Trophoblastic cell growth,

apoptosis

IL-3

Complement system

aCLaCL

• 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

• 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

• 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 SyndromeClinical manifestations

Antiphospholipid SyndromeClinical manifestations

Antiphospholipid AntibodiesThree primary classes of AntibodiesAntiphospholipid 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 (2GPI) antibodies are

directed against a plasma protein that binds phospholipid with high affinity

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 (2GPI) antibodies are

directed against a plasma protein that binds phospholipid with high affinity

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.

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 SyndromeEpidemiology

Antiphospholipid SyndromeEpidemiology

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 SyndromeFrequency of APS antibodies in different

populations

Antiphospholipid SyndromeFrequency of APS antibodies in different

populations

Antiphospholipid Syndrome Risk of thrombosis in patients with APS

antibodies

Antiphospholipid Syndrome Risk of thrombosis in patients with APS

antibodies

Incidence of thrombosis: ~2-2.5%†. Coincident risk factors for thrombosis: up to 50%‡.

Incidence of thrombosis: ~2-2.5%†. Coincident risk factors for thrombosis: up to 50%‡.

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)**

Lupus (1997) 6: 467. ** Lupus (1998) 7: 15.† Am J Med (1996) 100: 530. ‡ J Rheumatol (2004) 31: 1560.

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.

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 AntibodiesDetection & 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.

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.



Primary APS If the patient HAS NO known underlying

autoimmune disorder.

Secondary APS If the patient HAS an underlying

autoimmune disorder, such as SLE.

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 SyndromeClassification


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.

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 SyndromeDiagnosis - Clinical Criteria

Antiphospholipid SyndromeDiagnosis - 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

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


• 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 (anti-B2GPI), IgG or IgM >20 units for both, present on at least 2 occasions, at least 12 wks apart

• 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 (anti-B2GPI), IgG or IgM >20 units for both, present on at least 2 occasions, at least 12 wks apart

Antiphospholipid SyndromeDiagnosis - Laboratory Criteria

Antiphospholipid SyndromeDiagnosis - Laboratory Criteria



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.

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.

Antiphospholipid SyndromeDiagnosis

Antiphospholipid SyndromeDiagnosis


Antiphospholipid Syndrome and Stroke

Antiphospholipid Syndrome and Stroke

• 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.

• 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.

Antiphospholipid Syndrome & StrokeIncidence

Antiphospholipid Syndrome & StrokeIncidence

1Montalban J et al. Stroke 1991;22:750-7532Levine SR et al. JAMA 2004;291:576-584

1Montalban J et al. Stroke 1991;22:750-7532Levine SR et al. JAMA 2004;291:576-584

Antiphospholipid Syndrome & StrokeAPASS Study 2004

Antiphospholipid Syndrome & StrokeAPASS 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.

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 StudyOutcomes

APASS StudyOutcomes

Warfarin Aspirin0

10

20

30

aPL +aPL -

Treatment Group

Pro

porti

on w

ithE

vent

at 2

Yea

rs

APASS Investigators, JAMA, 2004; 291: 576.

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.

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.

Antiphospholipid Syndrome & StrokeAPASS Study 2004 - Caveats

Antiphospholipid Syndrome & StrokeAPASS Study 2004 - Caveats


TreatmentTreatment

• 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).

• 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 SyndromeACCP Guidelines

Antiphospholipid SyndromeACCP Guidelines

• 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).

• 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 SyndromeEvidence for Treatment Recommendations

Antiphospholipid SyndromeEvidence for Treatment Recommendations

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.

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.

Antiphospholipid Syndrome Treatment of aPL positive patients

Antiphospholipid Syndrome Treatment of aPL positive patients

1RHWM Derkson et al. Lupus 2010 19. 470-4741RHWM Derkson et al. Lupus 2010 19. 470-474


Thrombotic Thrombocytopenic Purpura

(TTP)

Thrombotic Thrombocytopenic Purpura

(TTP)

TTPHistoryTTP

History

• In 1924, Dr.Eli Moschcowitz described a 16- year old girl with abrupt onset of petechiae, pallor, followed by paralysis, coma, and death.

• Autopsy showed ‘hyaline’ thrombi occluding terminal arterioles and capillaries.

• In 1924, Dr.Eli Moschcowitz described a 16- year old girl with abrupt onset of petechiae, pallor, followed by paralysis, coma, and death.

• Autopsy showed ‘hyaline’ thrombi occluding terminal arterioles and capillaries.

TTPPresentation

TTPPresentation

Clinical findings1. Fever2. Neurologic changes3. Renal impairment

Laboratory findings4. Microangiopathic hemolytic anemia (Hb <

10g/dl)5. Thrombocytopenia (Platelets < 20,000/µl)

Clinical findings1. Fever2. Neurologic changes3. Renal impairment

Laboratory findings4. Microangiopathic hemolytic anemia (Hb <

10g/dl)5. Thrombocytopenia (Platelets < 20,000/µl)

Classic PentadAll 5 criteria present

Classic PentadAll 5 criteria present

TTPClinical Presentation

TTPClinical 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.

• 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.

TTPPathogenesis

TTPPathogenesis

Deficiency of VWF- cleaving protease Termed ADAMTS13 Corresponding gene : chromosome 9q34.

Deficiency of VWF- cleaving protease Termed ADAMTS13 Corresponding gene : chromosome 9q34.

TTPPathogenesis – ADAMTS13


CUBS MP CysDD Spacer11 22 33 44 55 66 77 88 CUB

Metalloprotease

Disintegrin

Thrombospondin 1

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

Discovered in 1996 by Tsai and by Furlan

Requires Ca2+ and Zn2+ ions

Cleaves VWF between Tyr1605 - Met1606

Activated by shear stress, mild denaturants

Proteolysis by ADAMTS13Cleaves VWF Tyr1605-Met1606 INCREASE causes VWD (type 2A)DECREASE causes TTP



TTPPrimary TTP

TTPPrimary TTP

1. Familial recurrent TTP: Constitutional deficiency of VWF

1. Familial recurrent TTP: Constitutional deficiency of VWF

TTPSecondary TTP

TTPSecondary 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.

• 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 19982Bennett et al N Engl J Med 2000

1Bennett et al Ann Inter Med 19982Bennett et al N Engl J Med 2000

TTPSecondary TTP

TTPSecondary TTP

• Pregnancy and post-partum.• Allogenic bone marrow transplant.• Autoimmune disorders (SLE,scleroderma)• HIV infection.

• Pregnancy and post-partum.• Allogenic bone marrow transplant.• Autoimmune disorders (SLE,scleroderma)• HIV infection.

TTPDiagnosis – There is no Gold Standard

TTPDiagnosis – 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

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

TTPDiagnosis

TTPDiagnosis

• 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.

• 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.

TTPDifferential Diagnosis

TTPDifferential Diagnosis

• Disseminated intravascular coagulation.

• Sepsis: cytomegalovirus, rocky mountain spotted fever, meningococcemia.

• Preeclampsia/eclampsia, HELLP.

• Disseminated malignancy.

• Hemolytic-uremic syndrome

• Evans syndrome

• Malignant hypertension.

• Disseminated intravascular coagulation.

• Sepsis: cytomegalovirus, rocky mountain spotted fever, meningococcemia.

• Preeclampsia/eclampsia, HELLP.

• Disseminated malignancy.

• Hemolytic-uremic syndrome

• Evans syndrome

• Malignant hypertension.

TTPTreatment

TTPTreatment

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.

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.

TTPResponse To Treatment

TTPResponse 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

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

TTPDuration of treatment.

TTPDuration 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.

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.

TTPTreatment

TTPTreatment

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.

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

1Gordon et al , 1987; 2Harkness et al 1981

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

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

TTPTreatment

TTPTreatment

TTPOther Treatment Options

TTPOther Treatment Options

Antiplatelet Therapy Steroids Splenectomy (Crowther et al, 1996) Chemotherapy: Cytoxan, Vincristine,

Rituxan, CHOP. High- dose IV IgG Protein A immunoadsorption columns.

Antiplatelet Therapy Steroids Splenectomy (Crowther et al, 1996) Chemotherapy: Cytoxan, Vincristine,

Rituxan, CHOP. High- dose IV IgG Protein A immunoadsorption columns.

TTPFollow-up and outcome

TTPFollow-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 ?)

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 ?)


Case Presentations

Case #1

Case Presentations

Case #1

Case #1Case #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.

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 #1Case #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.

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



Case Presentations

Case #2

Case Presentations

Case #2

Case #2Case #2Mrs 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.

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 #2Case #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.

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 #2Case #2Mrs 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.

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.



Case # 2 – MRI DWI ImagingCase # 2 – MRI DWI Imaging

Oct 2008Oct 2008 Feb 2009Feb 2009

Apr 2010Apr 2010 May 2010May 2010

Feb 2003Feb 2003 Jul 2005Jul 2005


Final SummaryFinal Summary

Connect the dots….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.

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

Remember….Site of Thrombosis Vs. Coagulation Defect

Abnormality Arterial VenousFactor V Leiden - +

Prothrombin G20210A - +

Antithrombin deficiency - +

Protein C deficiency - +

Protein S deficiency - +

Hyperhomocysteinemia + +

LA/ aCL / aPL + +

Abnormality Arterial VenousFactor V Leiden - +

Prothrombin G20210A - +

Antithrombin deficiency - +

Protein C deficiency - +

Protein S deficiency - +

Hyperhomocysteinemia + +

LA/ aCL / aPL + +


The End

Thank You

Questions / Comments

The End

Thank You

Questions / Comments

Documents

Stroke Education Series - 2010 Phaniraj Iyengar MD Director Director Hypercoaguable states & Stroke