Unusual Causes of Stroke - Hypercoagulable States and their work-up

Unusual Causes of Stroke 

John EE. Greenlee Greenlee, M.D. M D 

University of Utah Health Sciences Center 

George Geo ge E. . Wahlen W e VAHSC V SC 

Salt Lake City, Utah

DDisclosure l 

• Associate Editor for Medlink 

• Consultant for “Best Doctors in 

America” 

• Reviewer for Merck Manual 

• CConsultant: lt t Perseid P id 

Pharmaceutical Company 

• Unlabeled use of product: 

p 

none

TTopics to CCover 

• Anticardiolipin antibody syndromes 

• Hereditary y factors associated with stroke 

– Factor V (Leiden) mutation 

– Protein C and Protein S deficiency 

– AAnti ti thrombin th bi III activity ti it 

– Lipoprotein a 

• Sickle cell disease and sickle cell trait 

• Cerebral vasospasm / stroke associated with 

methamphetamine p 

and cocaine abuse

Anticardiolipin Antibody Syndromes

Anticardiolipin Antibodies: History 

• 1952: Conley et al 

– “AA hemorrhagic disorder caused by circulating 

anticoagulant in patients with disseminated 

lupus p erythematosus” 

y 

– Usually no hemorrhagic complications unless 

hypothrombinemia or thrombocytopenia 

• Association with false-positive VDRL

Anticardiolipin Antibodies: History 

• 1964: Bowie: 

– Association of lupus p anticoagulant g and antibodies to 

cardiolipin with venous thrombosis 

• 1972: “lupus anticoagulant” 

• 1983: First anticardiolipin antibody test 

• Subsequent association of anticardiolipin 

antibodies and lupus anticoagulant with stroke and 

other conditions

Antiphospholipid Antibody 

Syndrome 

• Is a syndrome, not a specific disease entity 

– Defined (by committee) on the basis of both 

clinical and immunological parameters 

– The definition probably does not cover the full 

spectrum of disease 

• Is a disease blessed (or cursed) by eponyms 

– Hughes syndrome, Asherton syndrome, 

Sneddon syndrome


Syndrome 

Clinical 

• One or more episodes of 

confirmed thrombosis 

– Arteries 

– Veins 

– Small vessels 

• Pregnancy morbidity and 

ffetal ll loss 

Immunological 

• Serum anticardiolipin 

antibody of high titer 

– IgG or IgM isotype in blood 

– On 2 or more occasions, occasions at 

least 6 weeks apart 

• Prolonged 

antiphospholipid- 

ti h h li id 

dependent coagulation 

– Lupus anticoagulant


Syndrome 

• Clinical manifestations are multifaceted 

• Serological tests are problematical 

– Antigenic targets still not completely understood 

– Difficulties with standardization among laboratories 

• Animal models provide information, but no 

animal model as yet duplicates human disease

AAntiphospholipid h h l dA Antibodies b d 

• Can be found in 2-12% of normal individuals 

– Incidence increases with age g 

– May be transient (e.g. with infectious mononucleosis) 

• Not all are pathogenic 

– ACA type A antibodies bind to β2 glycoprotein 1 to 

procoagulant lipid surfaces and are thought to be 

pathogenic 

– ACA type B antibodies: do not bind and are not 

pathogenic p g


Syndromes 

• Primary antiphospholipid antibody 

syndrome 

• Antiphospholipid antibody syndrome 

associated with other conditions 

– SLE, rheumatoid arthritis, other autoimmune 

disorders

Antiphospholipid Antibodies: A 

Conceptual Challenge 

• Antiphospholipid antibodies 

– Anticardiolipin p ( (aCL) ) 

– Antibodies to β2 glycoprotein 1 (β2GP1) 

– Lupus p anticoagulant g ( (LA) ) 

– Others 

• These antibodies do not recognize g the same 

antigenic epitopes 

– Can be found together or independently



• IgG, IgM antibodies all most commonly 

studied 

– IgM sometimes considered an acute phase 

reactant unrelated to actual clinical pathology 

– IgA discounted (and not tested) in some studies 

• However However, cases exist with either IgM 

antibodies in isolation or IgA antibodies in 

isolation

Antibody Targets in Antiphospholipid 

Antibody Syndrome 

• Lupus anticoagulant 

• Cardiolipin(s) 

• Beta(2)-glycoprotein 1 

• Phosphatidylserine 

• Prothrombin 

• Activated protein C 

• Tissue plasminogen 

activator 

• Plasmin 

• Annexin A2, A5 

• Protein Z 

• Other platelet and 

endothelial antigens 

• And more besides 

– Neurons 

– Astrocyes y



• Antigenic targets not completely understood 

– Some antibodies reported are likely 

epiphenomena 

– Some pathogenic antibodies may not be any of 

the above 

• Some patients may have none of these 

antibodies yet still have typical clinical 

manifestations (e.g. (e g Sneddon syndrome)

Anticardiolipin Antibody 

Syndromes: Pathogenesis 

Espinosa: Arthritis Research 2008

Antiphospholipid Antibodies: Major 

Effects 

• Platelet aggregation 

• Circulating fibrin-platelet aggregates 

• Circulating immune complex aggregates 

• Thrombus formation

Anticardiolipin Antibody 

Syndromes: Mechanisms of Injury 

• Vascular occlusion (Large or small vessel) 

– Arteries 

– Veins 

– Placental vessels 

• Platelet-fibrin emboli microvascular infarcts 

• Possibly a two-stage process 

– Anticardiolipin antibody-mediated injury may require 

prior vascular injury

Antiphospholipid Antibodies: 

Associated Systemic Diseases 

• Syndrome of recurrent fetal loss 

• Recurrent peripheral p p venous thrombosis 

• Cutaneous changes, esp. livedo reticularis 

• Systemic arterial thrombosis 

– Myocardial infarction / stent failure 

– Renal failure 

– Addison’s disease 

• Cardiac valvular abnormalities and marantic 

endocarditis e doca d t s

Antiphospholipid Antibody Syndrome: 

Described CNS Complications 

• Stroke 

• Transient ischemic attack 

• Amaurosis fugax 

• Cerebral venous sinus 

thrombosis 

• Ocular ischemia 

• Acute ischemic 

encephalopathy 

• Multi-infarct dementia 

– May involve micro-infarcts 

• Seizures 

• Cognitive impairment 

• Optic atrophy 

• Transverse myelopathy 

– Esp. sp. wwith t SSLE 

• Multiple-sclerosis-like 

disease 

• Ch Chorea 

• Migraine 

• Psychiatric y 

disturbances

Antiphospholipid Antibody Syndrome: 

Major Cerebrovascular Complications 

• Stroke / TIA 

• Cortical vein or venous sinus occlusion 

• Retinal venous or arterial occlusion 

• Progressive cognitive decline without 

obvious stroke

MMayer et t al l Clin Cli Neurol N l Neurosurge N 2010;112:602-8 

2010 112 602 8

SSneddon dd syndrome d 

• Antiphospholipid 

antibodies 


– Brain, spinal cord, or 

retinal events 

• Livedo reticularis

Catastrophic Antiphospholipid 

(Asherton’s) Syndrome 

• ~1% of cases 

• Widespread microvascular thromboses in 

the presence of antiphospholipid antibodies 

• High rate of mortality: 30 30-50% 50% 

• Considered an indication for 

immunosuppression 

– However, no good controlled trials 

– No proven immunosuppressive regimen

Antiphospholipid Antibody and 

Stroke: Physical Findings

Serological Diagnosis: 

Lupus Anticoagulant 

• Inhibit phospholipid-dependent coagulation 

reactions 

• Characteristics of test 

– Prolonged aPTT 

– Nt Not corrected tdb by mixing ii with ithnormal lplatelet-poor ltlt 

plasma 

– Shortening/correction of the prolonged coagulation 

time by excess phospholipids 

– Exclusion of other coagulopathies, eg, factor VIII 

inhibitor or heparin p

Serological Diagnosis: 

Anticardiolipin Antibody Titers 

IgG IgM IgA 

Normal 1-15 units 1-10 units 1-14 units 

LLow positive iti 16 16-40 40 units it 11 11-20 20 units it 15 15-40 40 units it 

Moderate positive 41-80 units 21-40 units 41-80 units 

High positive >80 units >40 units >80 units


Syndrome: Treatment 

• Antiplatelet therapy 

– Clearly ineffective in many patients 

• AAnticoagulation ti l ti 

• INR 2-3 

• INR 3-4 

• IImmunosuppressive i treatment 

– Prednisone 

– IVIgG / Plasma exchange 

– Cyclophosphamide (may not affect antibody titers) 

– Rituximab 

• Only y 

limited data from controlled trials

Treatment

Catastrophic Anticardiolipin 

Antibody Syndrome: Treatment 

Espinosa: Arthritis Research 2008

PPossible bl New N Treatments 

T

Anticardiolipin Antibody Syndrome: 

Unanswered Questions 

• To what extent should therapy be individualized? 

• How does one monitor treatment effect? 

• Should one begin treatment with platelet inhibitors? 

• If one needs to use warfarin, what INR? 

– Anticoagulation t coagu at o to INR N 3-4.5 3 .5 not ot shown s ow superior supe o in co controlled t o ed 

trials 

– INR of 3-4 increased risk of hemorrhage 

• At what point should one use immunosuppression? 

• Which immunosuppressive regimen should one use?

Hereditary Disorders of Coagulation

“He’s had a stroke. We need to order 

a hypercoagulable panel” 

-Neurology Neurology resident

Hereditary Abnormalities of Clotting 

Factors 

• Factor V Leiden 

• Prothrombin 20210A 

• Antithrombin III 

• Protein C deficiency 

• Protein S deficiency

Hereditary Abnormalities of Clotting 

Factors 

• Association with deep venous 

thrombophlebitis well established 

• Significant in cerebral vein / venous sinus 

thrombosis 

• Significance in arterial stroke not well 

established 

tblihd

Factor V Leiden and Deficiencies of 

Protein C, Protein S, Antithrombin III 


– Mutation of factor V 

– Prevents cleavage of factor V by activated 

protein C 

– Present in up to 9% of individuals 

– Important in venous occlusion 

• 20% of individuals with initial DVT 

• 60% of o individuals d v du s with w recurrent ecu e DVT V

Factor V Leiden and Deficiencies of 

Protein C, Protein S, Antithrombin III 

• Protein C, Protein S, Antithrombin III 

deficiencies 

– Less common than factor V Leiden 

– Association with DVT 

– Protein C and protein S deficiency: association 

with superficial thrombophlebitis

Inherited Thrombophilia and Stroke 

Risk 

Protein C Protein S Antithrombin III 

Asymptomatic controls 0.14-0.5% 0.1% 0.02-0.2% 

Unselected patients 3.2% 2.2% 1.1% 

with venous thrombosis 

Patients with familial 4.9% 5.1% 4.2% 

venous thrombosis: 4.2% 

Patients with 

ischemic stroke 

14% 1.4% 09% 0.9% 52% 5.2% 

Hankey et al: Stroke, 2001


Risk 

Factor V Leiden Prothrombin 20210A 

Asymptomatic controls 3%-6% 1-2% 

Unselected patients 19% 6.3%% 

with venous thrombosis 

Patients with familial 46% 18% 

venous thrombosis: 4.2% 

Patients with 

ischemic stroke 

46% 4.6% 37% 3.7% 

Hankey et al: Stroke, 2001


Risk: Lipoprotein a 

• Identified in some studies as an independent risk 

factor 

– Myocardial infarction 

– Atherothrombotic stroke in young adults 

• Elevated levels reported in 27% of children with 

stroke 

• Jones et al: associated with large large-artery artery 

atherosclerotic stroke 

– But not small artery occlusive stroke (Clinical 

Ch Chemistry. i t 2009 2009;55:1888-1890 

55 1888 1890

Lipoprotein a 

• Potentially useful for risk stratification in primary 

and secondary yp prevention 

– Significance in the individual less certain 

• Not proven if reduction in lipoprotein a decreases 

stroke risk 

– Lack of well-tolerated and effective agents 

• Not known whether lipoprotein a stroke risk can 

be addressed by treating other vascular risk factors

RRare Causes C of f Stroke S k 

• Factors VIII, IX, XI, XII 

• Antiphosphatidylethanolamine 

• (Plasinogen Inhibitor - 1) 

• (Tissue Plasminogen activator, antigen 

• Plasminogin g

Screening for Coagulopathies: 

Whom to Screen 

•

Screening for Coagulopathies: 

Whom to Screen 

• Lupus anticoagulant 

• Anticardiolipin antibody 

• Protein C, S, antithrombin III 

• Lipoprotein a 


– Functional assay for activated protein C 

resistance

Sickle Cell Disease and Trait

SSickle kl Cell C ll Hemoglobin H l b 

• Point mutation: valine 

for glutamic acid 

– Position 6, 

hemoglobin B chain 

• If homozygous: sickle 

cell disease: 

– Hemoglobin SS 

• If heterozygous: sickle 

cell trait 

– HHemoglobin l bi SA

SSickle kl Cell C ll Hemoglobin H l b 

Hydrophobic region on 

hemoglobin g B chain 

 

Agglutination gg of B chains 

 

Sickling

SSickle kl Cell C ll Trait T and dD Disease 

• Sickle cell trait 

– Approximately 2 million individuals in U.S.A. U S A 

• Sickle cell disease 

– EEstimated ti t d72 72,000 000i individuals di id l 

– 1 in 500 African Americans 

– Only l about b 30% of fi individuals di id l have h 

symptomatic disease

Sickle Cell Disease 

• Presentation early in life 

• Hemolytic anemia 

• “Vaso-occlusive crises” 

– Extremities, bones, and viscera (e.g. spleen) 

• Bacterial infections 

• Acute chest syndrome: pulmonary edema, 

etc.

SStroke k in Sickle S kl Cell C ll Disease D 

• Prevalence: 0.5-1% per 

year 

– 11% by 20 years of age 

– Compared to 2.5/100,000 

for children w/o sickle cell 

disease 

• May be overt or silent 

– Not usually preceded by 

TIA 

– May follow acute chest 

syndrome


• Usually ischemic (70-80% 

of cases) 

• Usually thrombotic 

• Intimal hyperplasia 

arterial t i lstenosis t i 

– Possible roles for decreased 

protein p C/S, , other factors 

• Rarely due to fat 

embolism 

Silva: Stroke 2009


• Usually anterior 

circulation 

– Distal ICA 

– Proximal ACA 

– Proximal MCA 

• Usually distal to posterior 

communicating i i artery 

Silva: Stroke 2009

Stroke in Sickle Cell Disease: Other 

Presentations 

• PRES 

• Moyamoya disease 

• Cerebral hemorrhage 

– Older patients 

– Aneurysm rupture 

– Moyamoya vessels 

– Veins

Sickle Cell Trait: MRI in Children 

SSteen et al, l Radiology R di l 2003; 2003 228:208–215 

228 208 215

Sickle Cell Disease and Trait: 

Diagnosis 

• Consider hemoglobinopathy in African-American 

(or Mediterranean) patients with stroke 

– HHemoglobin l bi electrophoresis 

l t h i 

• CT / CTA, MR / MRA 

• Angiography 

– Especially in hemorrhage, to exclude vascular 

malformation 

– Safe if hemoglobin S < 30% of total hemoglobin 

• TCD: major role in assessing need for and 

response to therapy in children

SSickle kl Cell C ll Disease: D Treatment T 

• Most experience is with stroke in children 

• TPA: no controlled studies, very yfew case reports p 

• Major treatment in children blood transfusion plus 

hydration 

– Efficacy of simple transfusion versus exchange not 

established 

– Exchange g possibly p ymore effective acutely yand 

in 

decreasing likelihood of stroke (Hulbert 2006) 

– Goal (children) to reduce hemoglobin S to

SSickle kl Cell C ll Disease: D STOP Trials T l 

STOP 1 

• TCD as major monitoring 

tool 

– TCD velocities of 200 

cm/sec. known to indicate 

high stroke risk 

• Children with TCD mean 

blood flow velocities of 

200 cm/second 

randomized to either 

– Regular blood transfusions 

– No transfusion. 

• 90% reduction d ti in i first fi t 

stroke with transfusion. 

STOP2 

• Discontinuing 

transfusions after 30 

months or more 

reversion reversion to abnormal 

TCD values and stroke

Sickle Cell Disease: Other 

Treatments 

• Hydroxyurea 

– Increases hemoglobin g F 

– Diminishes painful crises 

– Role in stroke not known 

• Stem cell transplantation 

• Aspirin or other platelet inhibitors: 

recommended by some clinicians, no 

controlled data

Sickle Cell Disease: Surgical 

Treatment 

• EC/IC bypass 

• Encephaloduroarteriosynangiosis 

YYoon et al l AJR 2000

Complications of Sickle Cell Trait 

• Probable 

– Venous thromboembolic events, fetal loss, neonatal 

ddeaths, h and dpreeclampsia l i 

• Possible 

– Acute chest syndrome syndrome, asymptomatic bacteriuria, bacteriuria 

anemia in pregnancy 

• Insufficient evidence: 

– Retinopathy, cholelithiasis, priapism, leg ulcers, liver 

necrosis, avascular necrosis of the femoral head, stroke 

Tsaras et al Am J Med 2009;122:507-12

Stroke in Sickle Cell Disease and 

Trait: Possible Risk Factors 

• Exertion / dehydration 

– Usually associated with collapse and sudden 

death (rare) 

• High altitude 

• Sleep apnea

Reversible Cerebral Vasospasm 

Stroke Following Substance Abuse


Syndrome 

• Severe headaches 

– With or without other 

neurological symptoms 

• Characteristic 

angiographic findings 

– “String of beads” 

• Spontaneous 

resolution in 1-3 

months 

Ducros et al Brain 2007;130:3091-3101


Syndrome: Not a New Condition 

• 1978: “Isolated benign cerebral vasculitis” asc litis” 

• 1985: “Benign acute cerebral vasculopathy” 

• 1984: Migrainous vasospasm” 

• 1988: “Call-Fleming Syndrome” 

• 1993: “Migraine angiitis 

• 1995: “Drug-induced Drug induced angiopathy angiopathy” 

• 1999: “CNS pseudovasculitis” 

• 1999: “Postpartum angiopathy” 

• 1999: “Thunderclap Thunderclap headache with reversible vasospasm 

• 2001: “Benign angiopathy of the central nervous system 

• 2003: “Primary thunderclap headache 

• 2005 2005: “Drug-induced “D id dangiopathy” i h”


Syndrome: Precipitating Factors 

• Postpartum states 

• Exposure to drugs, drugs alcohol, alcohol medications, 

medications 

blood products 

• Ct Catecholamine-secreting hl i ti tumors t 

• Other conditions


Syndrome: Associated Agents 

• Illicit drugs 

– Cannabis, , cocaine, , ecstasy, y, amphetamines, p , LSD 

• Binge alcohol drinking (usually in combination 

with use of vasoactive substances 

• SSRIs 

• Nasal decongestants g 

– Phenylpropanolamine, pseudoephrine, ephedrine


Syndrome: Associated Agents 

• Ergotamine agents 

– Ergotamine tartrate, tartrate methergine methergine, bromocriptine, 

bromocriptine 

lisuride, sumatriptan, isomethoptine 

• Misc Misc. agents: 

– Tacrolimus, cyclophosphamide, erythropoietin, 

IVIgG IVIgG, interferon alpha, alpha blood transfusions transfusions, 

nicotine patches, oral contraceptives, other 

hormonal treatments


Syndrome: Associated Conditions 

• Hypercalcemia 

• Porphyria 

• Spinal subdural hematoma 

• Postcarotid endarterectomy 

• Neurosurgical procedures 

• Cervical artery dissection 

• Unruptured cerebral saccular aneurysm 

• Cerebral artery dysplasia


Syndrome: Precipitating Factors 

• Spontaneous: 37% 

• Peripartum: 12% 

– During spinal anesthesia using epinephrine 

– Early postpartum (4-11 days) 

• Associated with use of vasoactive substances: 

62% 

– May involve use of more than one agent 

Ducros et al Brain 2007;130:3091-3101 

2007;130:3091 3101


Syndrome: Symptoms 

• Hallmark: recurrent thunderclap headache 

over a few days y to 2 weeks 

– Only symptom in 76% of cases 

– Can be single instead of repeating 

• Focal neurological deficits or seizures in 

24% of cases 

– Transient: esp. visual 

– Persistent


Syndrome: Vascular Imaging 

• Vasospasm on MRA or angiography 

• Increased velocity on TCD 

– Including patients with normal MRA) 

• MMultifocal l if lsegmental l vasoconstriction i i on 

catheter angiogram 

– Including patients with normal MRA or TCD 

• Cervical (esp. vertebral) artery dissection


Syndrome: Brain imaging 

• Subarachnoid 

hemorrhage g 


• PRES 

Ducros et al Brain 2007;130:3091-3101

Bartinsky, AJNR 2008;29:447-55


Syndrome: Treatment 

• D/C vasoactive medications 

• Nimodipine: no controlled data 

– Intra-arterial 

– IIntravenous t 

– Oral 

• Milrinone 

• Intravenous prostacycline


Syndrome: Outcome 

• Resolution in most patients 

• Persistent headache in some patients 

• Persistent neurological deficits 

• Post-stroke epilepsy

Stroke Following Substance Abuse

Stroke Following Substance Abuse 

• Substance abuse not a new problem 

– Early y1900s: approximately pp y1/400 

Americans were 

addicted to opiates 

– Use of cocaine and stimulant amines widespread 

• In some ways difficult to assess 

– Not all drug abusers tell the truth 

– Idiid Individuals l use different diff names for f different diff drugs d 

– Tainted or adulterated compounds are common

Stroke Following Substance Abuse 

• May be caused by 

– The actual drug 

– Other agents in the drug 

mixture 

– Adulterants (talc, etc) 

– Drug-associated endocarditis 

or other infections

Illicit Drugs Associated with Stroke

Cocaine 

• Usually cause stroke in minutes to hours after use 

– Rarely ydelayed y up pto 

one week 

• Cocaine hydrochloride 

– 80% of strokes are hemorrhagic 

– Roughly 50% are associated with aneurysm or AVM 

• Alkaloidal cocaine 

– 50% of strokes are hemorrhagic 

– 50% are ischemic

CCocaine: MMechanisms h of f Injury I 

• Abrupt hypertension 

• Cocaine-induced coagulation g 

– Can result in moyamoya 

syndrome 

• Vasospasm 

– Vascular endothelin-1 

– Can involve vasa vasora of 

larger arteries mural necrosis 

aneurysm or rupture 

Konzen et al. Stroke 1995;26:1114- 

• Vasculitis 1118

CCocaine-Induced I d dHHemorrhage h 

• More likely in African-American 

individuals 

• As compared to cocaine-negative controls 

– Higher admission blood pressures 

– Si Significantly ifi l more subcortical b i l hemorrhages 

h h 

– Higher rates of intraventricular hemorrhage 

– Worse functional outcome 

– 3 times more likely to die 

Martin Schild et al Stroke. 2010;41:680-4

CCocaine-induced d dVVasculitis l 

• Usually small vessels 

– Not seen on 

angiography 

• Can be progressive 

• Successfully treated 

with corticosteroids in 

a ffew 

cases 

Fredericks Stroke 1991

Methamphetamine and Related 

Drugs 

• Cause hemorrhage, stroke, necrotizing 

vasculitis similar to cocaine 

• Onset of stroke usually soon after use (like 

cocaine) 

– But onset may be delayed up to 3 weeks or 

longer

Stroke Associated with Stimulant 

Amines: Treatment 

• Very little controlled data 

• Control of blood pressure 

– Aggressive in intracerebral hemorrhage 

• TPA: Martin Schild et al. Stroke 2009 

– 29 patients with cocaine-induced stroke vs controls 

– No difference in outcome 

• Essentially no other controlled studies with TPA 

in stroke after cocaine or methamphetamine

TTreatment: APASS Trial T l 

• Subset of the WARSS trial 

• 1770 patients 

– 1050 (59”%) APL negative 

– 720 (41%) APL positive 

• No increase in stroke rate in APL + patients (22.2% vs 21.8%) 

– Patients with both APL and LA: 31.8% even rate) vs patients negative for 

both (24% event rate) 

• No difference between aspirin and warfarin 

• NOT necessarily applicable to patients with known APLS syndrome 

• Unanswered questions q concerning gstroke in the yyoung, g, repeated p 

strokes, and Sneddon syndrome

SSickle kl Cell C ll Disease D 

• Affects ~30% of 

individuals with 

hhemoglobin l bi SS 

• Variable presentation: 

may depend in part on 

haplotype 

– 3 major haplotypes (Benin, 

Senegal Senegal, and Bantu) 

– Bantu most severe, Senegal 

least severe

SSickle kl Cell C ll Disease D 

• Affects ~30% of patients with hemoglobin 

SSA

Th The Cl Clotting Cascade C d 

Fibrin 

polymers 

Fibrin 

monomers 

Thrombin 

Fibrinogen

TTreatment: APASS Trial T l 

• Subset of the WARSS trial 

• 1770 patients 

– 1050 (59%) APL negative 

– 720 (41%) APL positive 

• No increase in stroke rate in APL + patients (22.2% vs 

21 21.8%) 8%) 

– Patients with both APL and LA: 31.8% even rate) vs patients 

negative for both (24% event rate) 

• No difference between aspirin p and warfarin 

• NOT conducted in patients with known APL syndrome 

– Unanswered questions concerning stroke in the young, repeated 

strokes, and Sneddon syndrome

Antiphospholipid Antibodies and 

Stroke 

• Strong association with stroke in the young 

– Brey et al: LA or aPL in 21/46 patients

• Encephalopathy and biopsy-proven cerebrovascular inflammatory changes in a cocaine abuser. 

• Diez-Tejedor E, Frank A, Gutierrez M, Barreiro P. 

• Department of Neurology (Stroke Unit), Hospital Universitario La Paz, Universidad Autonoma de 

Madrid, Paseo de la Castellana, 261, Madrid, Spain. 

• Ab Abstract t t 

• Cocaine abuse is a well known cause of cerebrovascular complications. An inflammatory 

vasculopathy hypothesis has been proposed, but the medical literature has only reported a few 

pathological confirmations. We report a case with a biopsy demonstrating cerebral inflammatory 

vascular changes that are associated with cocaine abuse. A 21-year-old male, a twice weekly cocaine 

abuser abuser, developed encephalopathy encephalopathy, apraxia and left hemiparesis with hemisensory loss during the 

first week after his last cocaine intake; postural tremor and dystonia appeared later. Laboratory data 

were unrevealing. Cerebral angiography showed a lack of vascularization in the left precentral and 

central arterial groups. A corticomeningeal cerebral biopsy demonstrated perivascular cell collection 

and transmural lymphomonocytic infiltration of the small cortical vessels. All symptoms improved 

with corticosteroid treatment, but 4 years later, the patient returned with a worsening of his 

encephalopathy and a severe memory impairment, impairment emotional lability and apraxia. apraxia A cerebral 

magnetic resonance image (MRI) showed subcortical and periventricular lesions suggesting ischemic 

damage in small-size vessel areas as well as cortical atrophy. This new case supports the existence of 

an encephalopathy associated with vascular inflammatory changes in a cocaine abuser, although 

more clinical and experimental data are necessary to define its physiopathology. 

• PMID: 10210820 [PubMed [ - as supplied pp by y publisher] p ]

FFredericks d i k et t al l Stroke St k 1991;22;1437-1439 

1991 22 1437 1439

• Check TPA-pubmed 

CCocaine-induced d dstroke k

CCocaine-induced d dstroke k 

Konzen et al. Stroke 1995;26:1114 1995;26:1114-1118 1118

IgA Anticardiolipin Antibodies: 

Samarkos et al 2006 

• IgA anti-cardiolipin antibodies in 40% of 

patients with primary antiphospholipid 

antibody syndrome (PAPS) 

– IgA anti- anti- β2 glycoprotein 1 in 25.7% 25 7% of 

patients with PAPS 

• Only anti-cardiolipin antibodies correlated 

with disease 

– Those to β2 glycoprotein 1 correlated less well


Study Number of silent Total number Prevalence Confidence 

cerebral infarcts of patients Interval 

CSSCD 58 266 21.8% 16.8-26.8 

French cohort 23 155 15% 9.4-20.6 

London cohort 16 64 25% 14.4-35.6 

Cumulative total 97 485 20% 16.4-23.6 

Overt Strokes Silent Cerebral Infarcts 

Frequency < age 14% 9% 22% 

Average g age g of onset 7.7 years y Prior to age g 6 

TCD Abnormal Not necessarily abnormal 

velocity 

CCSD: Cooperative Study for Sickle Cell Disease Buchanan: Hematology 2004

Unusual Causes of Stroke - Hypercoagulable States and their work-up

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?