The aim of this article is to highlight the significance of these factors in stroke, to assess their

impact on long-term prognosis, and to outline an approach to the patient with stroke for
evaluation of hemostatic abnormalities. The specific factors discussed in this article include
factor V Leiden (ie, resistance to activated protein C [APC] ), deficiencies of proteins C and
S[2] and antithrombin III, sickle cell anemia, hyperhomocystinemia, antiphospholipid
syndrome (APS), hereditary disorders of fibrinolysis, and certain acquired conditions leading
to abnormal platelet function and hypercoagulable state.

Hematologic Risk Factors in Stroke

In general, patients with blood dyscrasias and stroke are prone to recurrent cerebrovascular
events. These patients are usually younger than stroke patients in the general population and
do not have the vascular risk factors. Known hematologic abnormalities are estimated to
account for about 4% of all strokes,[3, 4] but this proportion may be higher in younger people.

APC resistance and factor V Leiden

The most common inherited defect leading to venous thrombosis is hereditary resistance to
activated protein C (APC), which is caused by a mutation in factor V (factor V Leiden) and
that renders activated factor V unable to be cleaved by APC.[5, 6] . This occurs in 5-7% of the
normal population, 20% of patients with deep vein thrombosis (DVT), and 60% with
recurrent DVT.
No study has established a relationship between factor V Leiden and arterial strokes, thus the
incidence of this factor in patients with stroke is not known. In general, however, factor V
Leiden correlates more with venous mechanisms of thrombosis than arterial ones. Factor V
Leiden is suspected, therefore, to be associated with paradoxical emboli or with venous sinus
thrombosis more than with arterial mechanisms of stroke. The heterozygous state, unlike the
homozygous state, has not been shown to be a risk factor for recurrent venous
thromboembolism.

Deficiency of thrombin antagonists

Protein C, protein S, and antithrombin III (ATIII) deficiencies are all extremely rare, with a
frequency ranging from 1 per 1000 to 1 per 5000 in the general population. In a study by
Martinez et al, 10 of 60 patients (17%) had an acute ischemic stroke that was attributed to
deficiencies in protein C, protein S, or ATIII.[4]
Cerebral vein thrombosis is a more frequent presentation than arterial stroke. No clear-cut
association has been found between protein C or ATIII deficiency and arterial strokes,
although patients with low protein C levels at the time of acute stroke have poor outcomes.
However, 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).
Once a deficiency of protein C, protein S, or ATIII is identified, differentiating between
congenital and acquired cases is important.

Prothrombin gene mutation

Reports indicate that a G-to-A transition at nucleotide position 20210 (G20210A) in the
prothrombin gene is considered a risk factor for cerebral venous thrombosis.[7] The
heterozygous state, unlike the homozygous state, has not been shown to be a risk factor for
recurrent venous thromboembolism. This mutation has not been associated clearly with acute
ischemic strokes.

Hereditary abnormalities of fibrinolysis

Dysplasminogenemia is caused by genetic mutations that produce fibrinogen molecules that
form clots resistant to fibrinolysis or that bind with increased avidity to platelets to promote
thrombosis. This results in hypofibrinolysis by various mechanisms, including a decreased
level of circulating plasminogen, an abnormally functioning plasminogen, an increase in the
concentration of plasminogen activator inhibitor, or a decrease in the level of plasminogen
activator.
Although an association with stroke per se has yet to be described, these mutations thereby
increase the risk of venous and arterial thrombotic episodes, including stroke, and should be
considered in a young patient with stroke and a history of recurrent DVT.

Erythrocyte disorders
Although sickle cell disease itself does not alter hemostasis, it is believed to be a risk factor
for stroke by vascular damage. 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 plugging of microcirculation and cerebral veins has
also been noted.
The incidence of stroke in patients with hemoglobin SS is 10%; in those with hemoglobin
SC, it is 2-5%. The incidence of brain infarction peaks around age 10 years.
Other erythrocyte disorders, such as polycythemia vera, cause hyperviscosity-related
diminished cerebral blood flow.

Acquired disorders associated with abnormal platelet function

Most of the microvascular occlusions of thrombotic thrombocytopenic purpura (TTP) are
secondary to multiple microvascular platelet-fibrin thrombi that involve small arteries and
capillaries. Most studies of coagulation and fibrin degradation products are normal, but
elevated plasma fibrinogen is often found.
Heparin-induced thrombocytopenia is a disorder in which patients develop antibodies against
heparin that are directed toward platelets, causing activation. Two types have been identified:
Type I develops 1-5 days after institution of heparin therapy and is a benign condition that
results in platelet aggregation. Type II develops 6-10 days after institution of heparin therapy
and is a risk factor for recurrent stroke.

Myeloproliferative disorders, particularly essential thrombocytosis and polycythemia vera,

place patients at higher risk of thrombotic events, including stroke. Atherosclerosis and
dysfunctional platelets, more than elevated platelet count, are believed to contribute to the
cerebral thrombotic events.
Paroxysmal nocturnal hemoglobinuria also causes cerebrovascular thrombotic events,
associated primarily with venous thrombosis.

Hyperhomocystinemia
Hyperhomocystinemia is associated with vasculopathy. Patients with stroke have
homocysteine levels 1.5 times those of age- and sex-matched controls. Prospective and casecontrol studies have found that the incidence of stroke increases with increasing
homocysteine levels. Thus, all young persons with unexplained stroke, especially those with
atherosclerosis, should have homocysteine levels checked. Unlike most prothrombotic states,
hyperhomocystinemia causes more arterial strokes than venous.
Individuals who are homozygous for cystathionine beta synthase deficiency develop
premature atherosclerosis and often experience a stroke early in life. Homozygous patients
clinically manifest a marfanoid habitus, lenticular dislocations, and other skeletal
abnormalities, in addition to strokes. These patients excrete homocysteine in the urine and
have 20-fold or greater elevations of homocysteine and related amino acids in the plasma.
However, patients who are heterozygous for cystathionine beta synthase deficiency can
develop a mild clinical picture.
A mutation in methylenetetrahydrofolate reductase (MTHFR) in the folate pathway has been
correlated with an increase in plasma homocysteine and may be a cardiovascular disease risk
factor. However, hyperhomocystinemia is more commonly acquired; the most common
acquired cause of hyperhomocystinemia is dietary deficiency of folate and vitamin B-12.
MTHFR C677T, homozygous TT, or A1298C are not risk factors for cerebral arterial or
venous thrombosis.
The range for a normal serum homocysteine is controversial, but levels greater than 14
mol/L, the highest quartile of homocysteine levels, significantly increase the risk of stroke.
Folate and vitamin B-12 levels should be checked, as evidence that folate and B-12
deficiencies can lead to elevated homocysteine levels is definite.
Older age and renal insufficiency can lead to elevated homocysteine levels, as can the use of
antiepileptic drugs such as phenytoin.

Autoantibody syndromes
Antiphospholipid syndrome (APS) (ie, presence of antiphospholipid [aPL] antibodies or
lupus anticoagulant [LA]) occurs in 10% of patients with acute ischemic stroke. This number
is higher in younger patients. Recognizing aPL antibodies is important, as they are associated
with a hypercoagulable state characterized by fetal loss, thrombocytopenia, and venous and
arterial thrombosis.
The 3 major types of clinically relevant aPL antibodies are anticardiolipin (aCL) antibodies,
LA, and anti2 -glycoprotein I (anti-2 GPI) antibodies. In a patient with APS, the

concordance of aCL and LA may be up to 70%. Up to 10% of patients with aPL antibodies
are positive solely for anti-2 GPI antibodies.
The mechanisms of thrombosis are heterogeneous and include cardiac valve lesions that
embolize, hypercoagulable states, and cerebral vascular endotheliopathy. They tend to
interfere in some way with normal endothelial cell functions via the protein C and protein S
anticoagulant pathway.
In 2006, the Sapporo Criteria for APS were updated.[8] Clinical criteria include vascular
thrombosis and pregnancy morbidity. The laboratory criteria on 2 or more occasions more
than 12 weeks apart include the following:

ACL antibodies (immunoglobulin [Ig] G or IgM; medium or high titer of >40

GPL/MPL or >99th percentile, where GPL is IgG phospholipid units and MPL is IgM
phospholipid units)

Anti 2 -glycoprotein I antibodies (IgG or IgM, >99th percentile)

LA

There is evidence that at least one lipoprotein, lipoprotein(a) (Lp(a)), is elevated in selected
populations with cerebrovascular disease. Many studies have shown elevated Lp(a) to be a
potent risk factor for stroke, especially in young individuals. However, a clear role for the
treatment of elevated Lp(a) in preventing strokes has yet to be established.

Evaluation of Patients With Blood Dyscrasias and Stroke

Patient characteristics and physical findings
Blood dyscrasias or hypercoagulability should be suspected in patients with ischemic stroke
who have the following characteristics:

Younger than 55 years with no obvious cause of stroke

History of multiple unexplained strokes

Previous history of venous thrombosis

Family history of thrombosis

Abnormalities on routine screening coagulation tests

In addition, antiphospholipid syndrome (APS) must be suspected in patients with history of

multiple miscarriages, dementia, optic neuropathy, and thrombocytopenia, as well as
lupuslike syndromes and "complicated migraine." Although strokes of all sorts are noted,
involvement of the cerebral cortex and subadjacent white matter by platelet-fibrin
microthrombi is most commonplace.

Few physical findings point toward the diagnosis of blood dyscrasias in stroke. Blood
dyscrasias more commonly predispose to thrombosis in the large arteries. Uncommonly,
blood dyscrasias may lead to lacunar stroke or cardioembolic stroke, as seen in APS.

Diagnosis
In patients diagnosed with blood dyscrasias, a search should be made for clinical findings of
thrombosis elsewhere, including venous thrombosis. In a few instances, antiphospholipid
syndrome (APS) is associated with Sneddon syndrome, which is manifested by livedo
reticularis and cerebrovascular disease.
Other conditions that should be considered when evaluating blood dyscrasias and stroke
include cardioembolic stroke; dissection syndromes; fibromuscular dysplasia; lacunar
syndromes; anterior circulation stroke; cerebral venous thrombosis; cerebellar, intracranial,
and subarachnoid hemorrhage; epidural and subdural hematomas; seizures and epilepsy;
atherosclerotic disease of the carotid artery; and transient ischemic attack.
Metabolic diseases have also been associated with stroke, including
hyperglycemia/hypoglycemia; syndrome of mitochondrial encephalomyopathy, lactic
acidosis, and strokelike episodes (MELAS); methylmalonic acidemia; and propionic
acidemia.

Coagulation Studies
Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are recommended
tests for all patients in whom a hypercoagulable state is suspected.
PT is used to diagnose deficiencies or inhibitors of factors I, II, V, VII, and X. It also is used
to monitor warfarin therapy and screen for vitamin K deficiency. PT results are usually
expressed in terms of a standardized international normalized ratio (INR).
APTT is used to diagnose deficiencies or inhibitors of factors VIII, IX, XI, and XII, as well as
to diagnose deficiency of von Willebrand factor. This study is also used to monitor heparin
therapy and as a screening test for lupus anticoagulant (LA).

Tests for Hypercoagulability

Additional testing is aimed at specific hypercoagulable states that may be suspected on the
basis of patient history and findings (see Evaluation of Patients With Blood Dyscrasia and
Stroke).

Thrombin time
Thrombin time is used to diagnose fibrinogen deficiencies, to detect heparin resistance, and
to monitor fibrinolytic therapy.

Antiphospholipid antibodies and lipoprotein(a) levels

Antiphospholipid antibodies of the immunoglobulin (Ig) G class and lupus anticoagulant

(LA) are tested in patients with or without clinical systemic lupus in whom
hypercoagulability is suspected. These patients include those with stroke who have a history
of thrombocytopenia, fetal loss, dementia, optic change, and recurrent venous thrombosis.
High levels of Lp(a) have been correlated with atherosclerosis of the cerebral and other
vasculature.

Protein C, protein S, and ATIII activity

Protein C activity is used to screen for protein C deficiency or to diagnose protein C
deficiency secondary to dysproteinemia. To confirm protein C deficiency and to differentiate
it from dysproteinemia, the protein C antigen is measured. Protein C deficiency is noted in
liver disease, disseminated intravascular coagulation (DIC), vitamin K deficiency, and
warfarin therapy.
Protein S activity is used to screen for protein S deficiency or to diagnose the presence of a
dysfunctional protein. To confirm protein S deficiency and to differentiate it from
dysproteinemia, the protein S antigen is measured. Protein S deficiency is noted following
acute thrombotic events; in liver disease, DIC, vitamin K deficiency, warfarin therapy, lasparaginase therapy, and pregnancy; and with oral contraceptive use.
Antithrombin III (ATIII) activity is used to screen for ATIII deficiency or to diagnose
dysfunctional ATIII. To confirm antithrombin III deficiency and to differentiate it from
dysproteinemia, the ATIII antigen is measured. Antithrombin III deficiency is noted following
acute thrombotic events or surgery; in liver disease, nephrotic syndrome, DIC, heparin
therapy, l-asparaginase therapy, and pregnancy; and with oral contraceptive use.

APC resistance and factor V Leiden assays

Resistance to activated protein C (APC) is the most common inherited risk factor for
thrombosis and may be tested on plasma from patients on heparin or warfarin. A value < 2.2
indicates a high likelihood of APC resistance, and DNA-based testing for factor V Leiden
should be then performed.
More than 95% of patients with resistance to APC have the Arg506Gln mutation defect,
which is readily identifiable by DNA amplification and analysis. Testing for factor V Leiden
is not confirmation that APC resistance is expressed.

Homocysteine levels
Fasting homocysteine level is measured most commonly by high-performance liquid
chromatography (HPLC) with fluorescence detection. Hyperhomocystinemia is associated
with arterial and venous thrombosis and is to be distinguished from autosomal recessive
homocystinuria. Elevated homocysteine levels are encountered in the elderly; in patients with
nutritional deficiency of vitamin B-6, B-12, or folate; and in renal insufficiency and other
disorders.

Hemoglobin electrophoresis

Hemoglobin electrophoresis enables detection of hemoglobin SS and SC. The test should be
ordered in black individuals and others whose ethnicity puts them at particular risk of sickle
cell anemia.

Magnetic Resonance Studies

Magnetic resonance imaging (MRI) of the brain (T1-, T2-, and diffusion-weighted images
[DWIs]) may be helpful in assessing suspected stroke or stroke risk. Magnetic resonance
venography may be useful if cerebral venous thrombosis is suspected.

Angiography
Obtain a cerebral angiogram if noninvasive tests yield inconclusive results. Magnetic
resonance angiography (MRA) or computed tomography angiography (CTA) may be helpful
in cases of arterial stroke.

Ultrasonography
Transcranial Doppler ultrasonography is used to assess stroke risk in patients with sickle cell
anemia.[9, 10] This imaging modality is most useful in children, as it allows detection of
increases in mean blood velocities within the circle of Willis and middle cerebral artery as the
arteriopathy of sickle cell disease develops. Transcranial Doppler ultrasonography is also
helpful in the assessment of intracranial arterial stenosis or occlusion.
Consider carotid ultrasonography if extracranial stenosis or occlusion is suspected.

Medical Treatment of Blood Dyscrasias

Treatment of blood dyscrasias that may cause stroke remains controversial. The risks and
benefits of treatment must be considered in the context of the number of episodes of
thrombosis. In patients who are not treated with anticoagulants, prophylaxis should be
considered during times of high risk, such as pregnancy, immobilization, or the postoperative
period.

General, evidence-based recommendations

The recent evidence-based guidelines have made recommendations on topics that are relevant
to stroke/transient ischemic attack (TIA) patients with hypercoagulable state, as follows[11] :

Patients with arterial ischemic stroke or TIA with an established inherited

thrombophilia should be evaluated for deep vein thrombosis (DVT), which is an
indication for short- or long-term anticoagulant therapy depending on the clinical and
hematologic circumstances (Class I; level of Evidence A).

Patients should be fully evaluated for alternative mechanisms of stroke. In the absence
of venous thrombosis in patients with arterial stroke or TIA and a proven

thrombophilia, either anticoagulant or antiplatelet therapy is reasonable (Class IIa;

level of Evidence C).

For patients with spontaneous cerebral venous thrombosis and/or a history of

recurrent thrombotic events and an inherited thrombophilia, long-term anticoagulation
is probably indicated (Class IIa; level of Evidence C)

For patients with cryptogenic ischemic stroke or TIA in whom an APL antibody is
detected, antiplatelet therapy is reasonable (Class IIa; level of Evidence B).

For patients with ischemic stroke or TIA who meet the criteria for the APL antibody
syndrome, oral anticoagulation with a target international normalized ration (INR) of
2-3 is reasonable (Class IIa; level of Evidence B).

For adults with sickle cell disease and ischemic stroke or TIA, the general treatment
recommendations cited above are reasonable with regard to control of risk factors and
the use of antiplatelet agents (Class IIa; level of Evidence B).

Additional therapies that may be considered to prevent recurrent cerebral ischemic

events in patients with sickle cell disease include regular blood transfusions to reduce
hemoglobin S to less than 30-50% of total hemoglobin, hydroxyurea, or bypass
surgery in cases of advanced occlusive disease (Class IIb; level of Evidence C).

Although folate supplementation reduces levels of homocysteine and may be

considered for patients with ischemic stroke and hyperhomocysteinemia (Class
IIb;level of Evidence B), no evidence suggests that reducing homocysteine levels
prevents stroke recurrence.

Anticoagulation is probably effective for patients with acute central venous

thrombosis (Class IIa; level of Evidence B).

In the absence of trial data to define the optimal duration of anticoagulation for acute
central venous thrombosis, it is reasonable to administer anticoagulation for at least 3
months, followed by antiplatelet therapy (Class IIa; level of Evidence C).

For pregnant women with ischemic stroke or TIA and high-risk thromboembolic
conditions such as hypercoagulable state, the following options may be considered:
adjusted-dose unfractionated heparin (UFH) throughout pregnancy, for example, a
subcutaneous dose every 12 hours with monitoring of activated partial thromboplastin
time; adjusted-dose low molecular weight heparin (LMWH) with monitoring of antifactor Xa throughout pregnancy; or UFH or LMWH until week 13, followed by
warfarin until the middle of the third trimester and reinstatement of UFH or LMWH
until delivery (Class IIb; level of Evidence C).

For women who have had ischemic stroke or TIA, postmenopausal hormone therapy
(with estrogen with or without a progestin) is not recommended (Class III; level of
Evidence A).

Consultations
Hematologic consultation may be requested when the clinical diagnosis is uncertain, when
abnormal test results require clarification, and when recommendations on the management of
the blood dyscrasia is needed.

Anticoagulation
Patients with hypercoagulable states such as activated protein C (APC) resistance; protein C,
protein S, or antithrombin III (ATIII) deficiencies; or antiphospholipid syndrome (APS) are
treated with anticoagulants for stroke prophylaxis, especially if deep vein thrombosis (DVT)
is present or recurrent thrombotic events have occurred. The anticoagulation regimen usually
is started with intravenous (IV) heparin, maintaining the activated partial thromboplastin time
(aPTT) at 2-3 times normal, until an oral anticoagulant (ie, warfarin) is able to achieve a
therapeutic prothrombin time (PT) (international normalized ratio [INR]).
In protein C and S deficiencies, starting heparin before warfarin is imperative to avoid
warfarin-induced skin necrosis. The level of anticoagulation in terms of PT (INR) required
for stroke prophylaxis is uncertain. In the treatment of APS, a retrospective study reported
that an INR of 3.0-3.5 was more effective than the routinely used INR of 2.0-3.0[12] ; however,
2 prospective studies showed that an INR of 2.0-3.0 is sufficient in APS.[13, 14] A sizable
fraction of neurologists avoid treating patients with stroke with a heparin bolus, as this is
thought to increase the risk of intracranial bleed.
Results of the Antiphospholipid Antibodies in Stroke Study (APASS) demonstrated that there
was no difference between aspirin and warfarin for treatment of patients with anticardiolipin
(aCL) antibodies or lupus anticoagulant (LA).[15] It is important to emphasize that APASS did
not look specifically at APS. However, it was noted that the risk of recurrent thrombosis was
increased in patients who had both aCL antibodies and LA. In addition, patients enrolled in
APASS had low aCL antibody titers and a low INR, and the study was criticized for these
limitations.
Thus, in deciding whether patients need to be treated with warfarin, their LA status and hightiter aCL antibodies should also be borne in mind, and high-intensity anticoagulation (target
INR > 3.0) should be considered in appropriate patients. A clinical trial with defined APS and
high titers of aCL antibodies and LA with high-intensity regimen of warfarin would probably
answer the issue.
Currently, 3 new oral anticoagulants are available: Dabigatran (oral thrombin inhibitor),
rivaroxaban (factor X inhibitor), and apixaban (factor X inhibitor). These agents are FDA
approved to prevent thromboembolic events, including stroke/TIA in patients with atrial
fibrillation. Their role in the prevention of stroke/TIA in patients with hypercoagulable state
is yet to be determined.

Use of Antiplatelet Agents, Blood Transfusions, and

Hydroxyurea

Patients with sickle cell anemia and stroke are treated with antiplatelet agents such as aspirin.
The roles of other antiplatelet agents, such as ticlopidine (Ticlid) and clopidogrel (Plavix), or
combination therapy with aspirin and dipyridamole (Persantine), specifically in prevention of
strokes that result from blood dyscrasias, have not been evaluated.
Other methods of treatment that are advocated are blood transfusion and hydroxyurea[16] . The
role of bone marrow transplantation is, at best, experimental.[17]

Vitamin Supplementation
Hyperhomocystinemia is treated with vitamin supplementation, usually folic acid and
sometimes pyridoxine (vitamin B-6) and vitamin B-12, as well. Although the Vitamin in
Stroke Prevention (VISP) trial results did not show any significant benefit of treatment with
high doses of folic acid, pyridoxine, and vitamin B-12 in reducing adverse vascular outcomes
in patients with nondisabling strokes and elevated homocysteine (relative to low doses of
these vitamins), it did show that there was a persistent and graded association between total
homocysteine and outcomes, irrespective of the treatment group.[18] A larger study with high
baseline homocysteine levels and longer follow-up may help resolve the issue.

Dietary Issues
Hyperhomocystinemia has been attributed to dietary deficiency of vitamin B-6, vitamin B-12,
or folic acid, especially in older patients with poor nutritional intake.
Patients with hypercoagulable states that may cause stroke typically take the oral
anticoagulant warfarin. For these patients, monitoring vitamin K in the diet is important, as it
may alter the efficacy of warfarin.

Outpatient Monitoring
Patients being treated with an oral anticoagulant must be monitored with outpatient blood
testing for prothrombin time (PT) (international normalized ratio [INR]). Initially, PT (INR)
should be tested frequently to determine the maintenance dose (ie, daily to twice a week);
once a regular maintenance dose is determined, PT (INR) may be checked monthly.

Special Considerations
Supratherapeutic oral anticoagulation without monitoring can lead to intracranial and
extracranial hemorrhage. Common reasons for such a state include overdosage, interaction
with other drugs, and variation in dietary vitamin K. Subtherapeutic anticoagulation can lead
to ischemic stroke. These potential pitfalls need to be discussed with the patient before
initiating anticoagulation.
Another pitfall is starting a patient with a known history of a life-threatening bleeding
disorder and a hypercoagulable state on either an antiplatelet agent or an anticoagulant.
Treatment must be individualized for each patient, and the benefits of any treatment must
outweigh the risks.

During an acute thrombotic event, certain coagulation parameters may display acquired
deficiencies (protein S and antithrombin III [ATIII]). In addition, patients on warfarin can
have low protein C and protein S values, whereas patients on heparin have low ATIII values.
Other conditions known to affect coagulation parameters are liver disease (proteins C and S
and ATIII), estrogens, pregnancy, and inflammatory disease (protein S).
Because each hereditary coagulation factor deficiency encompasses more than 100 mutations,
genetic testing typically is not indicated in clinical practice.
Patients with cerebral amyloid angiopathy are at increased risk of intracranial hemorrhage
while on warfarin, even when levels are within the normal therapeutic range. Caution is
advised in considering warfarin for these patients. Magnetic resonance imaging (MRI)
sequences such as gradient echo (GRE) are useful tools to detect multiple bleeds, a feature
suggestive of amyloid angiopathy.
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