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Abstract

There is growing research interest into the etiologies of cryptogenic stroke, in particular as it relates to hypercoagulable states. An elevation in serum levels of the procoagulant factor VIII is recognized as one such culprit of occult cerebral infarctions. It is the objective of the present review to summarize the molecular role of factor VIII in thrombogenesis and its clinical use in the diagnosis and prognosis of acute ischemic stroke. We also discuss the utility of screening for serum factor VIII levels among patients at risk for, or those who have experienced, ischemic stroke.

Keywords

stroke von Willebrand factor thrombosis hypercoagulability factor viii

Background

In the 1950s, investigators discovered that patients with prolonged bleeding time could be treated with the replacement of a particular clotting factor.¹ This factor was originally thought to be von Willebrand factor (vWF), but was later characterized as factor VIII (FVIII).² Electron microscopy confirmed that the procoagulant FVIII played a primary role in the adhesion of platelets to exposed subendothelium during times of injury, but this did not occur until the 1970s.³ Produced primarily in liver cells, FVIII circulates through the vasculature in its inactive form and is protected from proteolysis through its noncovalent interaction with vWF.^4,5 When injury occurs, it is activated by thrombin and dissociates from vWF, thereby activating the coagulation cascade.⁶ Despite the otherwise “dormant” state, the serum concentration of FVIII directly correlates with the occurrence of de novo and recurrent thrombotic events,^7,8 including acute ischemic stroke.^9

–12 The role of FVIII in the risk and pathogenesis of stroke is the subject of this review.

Although “stroke” comprises various cerebrovascular syndromes, the focus of our review will pertain to ischemic stroke subtypes, and therefore, any mention of stroke will denote an ischemic cerebrovascular event.

Molecular Role of Factor VIII in Thrombosis

Factor VIII, a 280 kDa glycoprotein expressed by the human X chromosome, plays a pivotal role in the propagation of clot formation in both the intrinsic and extrinsic coagulation pathways.^6,13,14 It is stabilized within the plasma by vWF. When bound together, this protein complex has a protective effect on the FVIII antigen (FVIII: ag) and permits appropriate binding and cleavage of FVIII with other components of the coagulation cascade during instances of vessel breakdown and hemorrhage.⁶ The FVIII: vWF complex also plays an important role in primary coagulation by mediating platelet attachment to damaged subendothelium.^3,5 Although FVIII is critical for proper coagulation, it has been increasingly shown to be associated with cardiovascular health outcomes when it is transcribed in excess or its activity level is amplified.

The role of FVIII in prothrombotic syndromes, such as myocardial infarction, deep vein thrombosis (DVT), and acute ischemic stroke was originally discovered by investigators who found that the absence of FVIII in hemophilic syndromes was associated with a reduced risk of coronary events.¹⁵ This same group would later demonstrate a strong association between elevated FVIII levels and nonmalignant DVT in a small case–control study.⁷ Other investigators described a higher risk of DVT recurrence in patients with elevated FVIII, quantified as a higher relative risk of 8% for every 10 IU/dL elevation in serum FVIII.⁸ The relationship between elevated FVIII and other thrombotic disorders such as myocardial infarction,¹⁶ pulmonary embolism,¹⁷ chronic thromboembolic pulmonary hypertension,¹⁸ and death from these disease states,¹⁹ has been well described, however, several of these relationships remain contested.^20

–23

The levels of FVIII appear to increase during the acute phase response,^24,25 implicating its role as a biomarker of systemic inflammation. Within the context of ischemic stroke, elevation of FVIII has been regarded as a result of the inflammation associated with the acute phase of stroke.^10,26 Newer data challenge this oversimplification of FVIII in the acute phase response and implicate an independent correlation between FVIII levels or activity and thrombosis.²⁷ In this study by O’Donnell et al in patients with thrombotic events, only half of the cases of persistently elevated FVIII levels can be attributed to elevations in vWF.²⁷ This is highly suggestive that FVIII, and not vWF, remains the driving force of these 2 markers behind thrombotic events. At our center, when analyzing the relationship between FVIII and vWF elevation and ischemic stroke outcomes, we observed that elevation of FVIII was significantly associated with elevated levels of C-reactive protein and erythrocyte sedimentation rate, irrespective of vWF level.²⁸

There remains no concrete data implicating that acute inflammation induces transcriptional elements or promoters of the FVIII gene, thereby resulting in amplified production of this procoagulant antigen. One particular prospective study that assessed the effect of vitamin E on oxidative stress mechanisms demonstrated that FVIII increases in response to tissue hypoxia, thereby promoting thrombogenesis.²⁹ Compared to normal oxygen conditions (21% oxygen content), patients in the placebo arm of this trial who experienced significant hypoxia (12% oxygen content) experienced greater increases in FVIII levels (248 vs 171 ng/mL, P < .05) and activity (143% vs 97%, P < .05).²⁹ The clinical implications of this response in cerebrovascular disease are unclear although it seems plausible that hypoxic conditions may induce or perpetuate a thrombogenic state.

Presently, the quantification of FVIII can be made using one of the 2 distinct methods: determination of FVIII activity (FVIII: c) and FVIII: ag levels. Each serves a unique purpose and provides distinct clinical information although both have a positive correlation with each other and with thrombotic disease.²⁵ FVIII: c is typically measured using a standardized coagulation assay whereas an enzyme-linked immunosorbent assay is typically performed to quantify the amount of FVIII: ag present in sera. In the acute phase response, both FVIII: ag and FVIII: c have been shown to rise,³⁰ which we speculate may occur in a causal fashion whereby FVIII: ag production increases and effects a subsequent rise in function of the procoagulant.²⁴ This is could play a role in the risk of stroke and stroke progression, which we have seen in previous investigations.²⁸

Many studies on FVIII investigate either activity or antigen level, but few assess both simultaneously. Unfortunately, that may result in some confusion when comparing results between studies. In the present review, we will describe reported results according to the method utilized for FVIII quantification in order to alleviate any confusion between the methods of detection.

Factor VIII and Stroke

Incident Stroke

Although there are some conflicting results,^22,23 it is well established that FVIII levels and/or activity are associated with acute ischemic stroke risk. Historically, the first investigation to relate FVIII with ischemic stroke was published by Gaston et al in 1971.³¹ Since then, numerous investigations have been published demonstrating an association between higher FVIII: c or antigen levels and the incidence of stroke.^{9,11,12,32,33} In the largest prospective cohort to date, the Atherosclerosis Risk in Communities investigators confirmed the association between elevated FVIII and ischemic stroke.¹¹ In this study, the investigators followed nearly 15 000 patients without known cardiovascular disease for up to 9 years and characterized 191 ischemic stroke events. The adjusted relative risk for ischemic stroke in patients with the uppermost quartile of FVIII when compared to the lowermost quartile was calculated at 1.93 (95% confidence interval [CI] 1.2-3.1).¹¹

Stroke Etiology

Much of the data pertaining to FVIII and stroke with respect to etiology involve atherothrombotic strokes or strokes due to large vessel disease.^9,22,34 In one Chinese study, patients with carotid plaque on ultrasonography had a clinically, but not statistically, significantly elevated FVIII: c when compared to healthy controls (1.66 vs 1.43, P = .080).²² When adjusted for age and sex, patients with the highest tertile of FVIII had a higher odds of carotid plaque when compared to the lowest tertile of FVIII (odds ratio [OR] 3.35, 95% CI 1.28-8.75, P = .014). However, this association was statistically nonsignificant after adjustment for potential confounders (OR 2.65, 95% CI 0.94-7.49, P = .061). Similarly, another investigation by Catto et al with a larger sample demonstrated that FVIII levels were higher in patients with large vessel strokes when compared to patients with small vessel disease (2.43 vs 1.87 U/mL, P = .0001).⁹ In patients with transient ischemic attack, elevations in FVIII: ag have also been associated with carotid disease.³⁴ Although most studies to date have directly associated large vessel disease with FVIII, these conflicting results call for larger scale investigations.

Lately, cryptogenic stroke has gained attention as more hypercoagulable states are being related to unclear etiologies of ischemic stroke. In one case–control study of 150 patients by Karttunen et al, the investigators found that patients with cryptogenic stroke had a higher mean FVIII: c when compared to controls (124% vs 112%, P = .021).³³ In the adjusted model, the investigators associated elevated FVIII: c with higher odds of cryptogenic stroke (OR 3.59 95% CI 1.1-12.2, P = .041). These results warrant confirmation in larger, more generalizable samples in order to determine the presence and strength of the association between FVIII: c and cryptogenic stroke.

The relationship between cardioembolic stroke and FVIII has been investigated, but is less well described. Data from a Swedish case–control study of 100 patients suggest that elevated FVIII may be associated with stroke in patients with nonvalvular atrial fibrillation.³² In this investigation by Gustafsson et al, FVIII levels were confirmed using 2 unique clotting assays.³² In both methods, FVIII was found to be elevated in patients having stroke with nonvalvular atrial fibrillation when compared to either (1) patients with stroke in sinus rhythm or (2) healthy patients (without stroke or atrial fibrillation). Interestingly, these investigators also found that patients with nonvalvular atrial fibrillation who did not experience a prior stroke still had higher FVIII than (1) sinus rhythm patients with stroke and (2) healthy controls. These data are suggestive that elevated FVIII may be related to the presence of clot formation and dissolution in the fibrillating atrial walls, thereby posing a threat to the cerebrovascular system.

Paradoxical embolism, in which a venous thrombus embolizes from the venous circulation to the arterial circulation through an intracardiac shunt (classically a patent foramen ovale), may also be more common in patients with elevated FVIII given their higher risk of DVT.^7,8 This mechanism has been proposed in 1 case–control cohort of patients with cryptogenic stroke,³⁵ but a causal relationship has yet to be demonstrated in this patient population.

Small vessel disease seems to bear little, if any, relation to FVIII. One study by Knottnerus et al attempted to clarify an association between small vessel disease and FVIII.³⁶ These investigators found that FVIII: c was not significantly different between patients with isolated lacunes when compared to symptomatic lacunes, as well as extensive white matter lesions (consistent with small vessel ischemic disease) when compared to asymptomatic lacunes who lacked extensive white matter lesions (109% ± 25% vs 113% ± 25% vs 115% ± 26%).³⁶

Stroke Severity

In our center’s experience, we have been unable to detect an independent association between elevated FVIII: c and baseline stroke severity, as measured by the National Institutes of Health Stroke Scale (NIHSS) score.¹⁰ However, we found that combined elevations of FVIII and vWF were associated with worse neurologic outcome (defined as discharge modified Rankin Scale score > 2).²⁸ There also appeared to be a clinically significant association between FVIII and vWF levels and inpatient complications (such as infection), neurologic deterioration (defined as an increase in NIHSS score of 2 or more within a 24-hour period³⁷), and recurrent thrombotic events following acute ischemic stroke.²⁸

Risk of Elevated FVIII

Limited evidence is available currently regarding what characteristics predispose patients to elevated FVIII. The levels of FVIII have some association with the acute phase response, but they have also been independently elevated in patients without other elevations in biomarkers traditionally expressed during acute inflammation. Some studies have suggested a familial relationship³⁸ and blood type relationship.³⁹ One genetic study involving over 50 000 patients identified a single nucleotide polymorphism in the ABO locus (rs505922) that was associated with FVIII levels and ultimately risk of stroke.⁴⁰ Individuals with non-O blood types (particularly AB blood type) appear to be more likely to have elevated levels of FVIII as compared to those with O-type. There also appears to be an association between elevated FVIII and age and gender, with older patients, blacks, and women at higher risk for this phenomenon.^{9,39,41
–43}

Pediatric Considerations

Although there are occasional case reports to the contrary,⁴⁴ the association between FVIII and incident stroke has not been confirmed in children with stroke.^45,46 This may be due to sample size issues or the differing etiologies of pediatric ischemic stroke.

Table 1 depicts 11 key studies from 1987 to present that have investigated the association between FVIII and acute ischemic stroke.

Table 1.

Summary of Studies Investigating the Association Between Factor VIII and Ischemic Stroke in Adults.^a

Investigators	Study Design	Study Size	Major Findings
Landi et al¹²	Case–control	115 adults	Higher FVIII activity was detected in patients with stroke compared to age-matched controls.
Gustafsson et al³²	Case–control	100 adults	In patients with nonvalvular atrial fibrillation, higher mean FVIII was found in patients with a prior stroke vs those with no prior stroke (1.92 vs 1.37 IU/mL, P < .001).
Pan et al²²	Retrospective cohort	147 adults	In a regression model adjusted for age and sex, patients in the highest tertile of elevated FVIII activity had a greater odds of carotid atherosclerosis compared to patients with the lowest tertile (OR 3.4, 95% CI 1.3-8.8), but there was no relationship between FVIII and stroke.
Catto et al⁹	Retrospective cohort	392 adults	Patients with stroke had elevated FVIII antigen levels initially (2.20 U/mL) and 3 months after the ischemic stroke event (1.90 U/mL) compared with a healthy reference population (1.49 U/mL, P = 0.0001 for both comparisons).
Folsom et al¹¹	Prospective cohort	>15 000 adults	Adjusted relative risk of ischemic stroke for patients with elevated FVIII compared to normal FVIII is 1.93 (95% CI 1.2-3.1).
Karttunen et al^33, ^a	Case–control	150 adults	FVIII activity is higher in patients with cryptogenic ischemic stroke (124% vs 112%, P = .021), and elevations in FVIII (highest vs lowest quartile) were associated with increased odds of cryptogenic ischemic stroke in an adjusted model (OR 3.6, 95% CI 1.1-12.2).
Karttunen et al^35, ^a	Case–control	209 adults	Prothrombotic states (including FVIII elevations) were independently associated with cryptogenic stroke in patients with PFO (OR 2.8, 95% CI 1.2-6.5); however, this effect was driven largely by the relationship between factor V Leiden and prothrombin G20210A mutations with stroke.
Smith et al²³	Prospective cohort	>2000 adults	High FVIII level (>118 IU/dL) is not associated with an increased risk of incident stroke compared to low FVIII level (<84 IU/dL; adjusted HR 1.1, 95% CI 0.6-2.0).
Knottnerus et al³⁶	Retrospective cohort	149 adults	FVIII activity is not significantly different between patients with large vs small lacunar infarctions (109% vs 113%, P = NS).
Williams et al⁴⁰	Retrospective cohort	∼63 900 adults	The single nucleotide polymorphism rs505922 (associated with ABO blood groups) is associated with FVIII activity (P = 1.2 × 10^–36), and this polymorphism is significantly associated with large-vessel (P = .001) and cardioembolic stroke (P < .001) subtypes.
Chang et al^10, ^b	Retrospective cohort	116 adults	Elevated FVIII activity is related to more severe neurologic deficits at presentation (NIHSS 5 vs. 2) and higher rate of neurologic deterioration during hospitalization (21.4% vs. 9.4%).
Samai et al^28, ^b	Retrospective cohort	148 adults	Elevated FVIII activity is independently related to greater discharge disability (mRS > 2, OR 2.9, 95% CI 1.2-7.1), neurologic deterioration (OR 3.2, 95% CI 1.2-8.7), and recurrent thromboses (OR 4.2, 95% CI 1.6-11.3).

Abbreviations: FVIII, factor VIII; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; PFO, patent foramen ovale; HR, hazard ratio; CI, confidence interval; NS, not significant.

^aOnly studies including 100 or more patients are described here.

^bThese two investigations involve patients from the same cohort.

^cThese two investigations involve patients from the same cohort.

Future Directions

Utility of Screening

The association between FVIII and stroke raises the question, should we screen for FVIII levels in patients with stroke, or at least patients at risk of stroke? This has been raised before,⁴⁷ but current guidelines do not recommend for or against the serologic testing of FVIII levels for routine stroke evaluation.⁴⁸

At the time of publication, the authors of the present article argue against the routine screening of FVIII levels in patients with stroke or at risk of stroke because we lack the data to justify testing. We know that elevated FVIII levels are seen in more than 1 in 10 asymptomatic individuals⁷ and have been associated with women, blacks, and the elderly patients.⁴³ This knowledge may ultimately aid in establishing potential predictors of this laboratory anomaly. However, this has not been prospectively investigated for utility. Whether the routine testing of this clotting factor in asymptomatic or symptomatic patients is cost-effective also remains to be answered in clinical studies. Its evaluation must comply with the following elements associated with any screening tool used in clinical management: (1) economic feasibility for testing (low cost with high impact), (2) reliability/reproducibility, and (3) minimal risk to the patient. One can argue that both the FVIII: c and FVIII: Ag meet the standard of low risk associated with serum sampling, however the lower prevalence of FVIII elevations in the general population may not render it an entirely useful screening tool (low impact given possible low probability of positive testing).

Once a patient is found to have elevated FVIII, the clinician may also be left more puzzled than when he or she had initially begun the evaluation—in part due to no known treatment and no known clinical result of such treatment. Presently, we have no guidelines for the treatment of elevated FVIII in humans. Furthermore, we have no data to support that these patients would improve from pharmacologic intervention. We have already demonstrated a higher proportion of neurologic deterioration in patients with elevated FVIII who suffer ischemic stroke,²⁸ but whether any targeted intervention to reduce FVIII may reduce the risk of neurologic deterioration is unknown.

Conclusions

In conclusion, FVIII levels appear to be associated with both ischemic stroke and outcome following ischemic stroke. This has been demonstrated in stroke of large vessel, cardioembolic, and cryptogenic etiologies. Epidemiologic studies have shown that asymptomatic community dwelling adults with elevated FVIII levels are at twice the risk of ischemic stroke when compared to patients with normal or low FVIII. FVIII is known to be elevated in older patients, blacks, and women. Currently, guidelines do not recommend the routine screening of FVIII in patients with stroke, despite its potential role in prognostication and association with subsequent thrombotic events. Future investigations are called upon to identify whether the measurement of FVIII is justifiable as a screening tool for prognosis or treatment in adult patients who have suffered ischemic stroke.

Footnotes

Author’s Note

This manuscript has not been the subject of any previous oral or poster presentation. Dr. Boehme is supported by NINDS NIH T32 NS007153-31. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS or the NIH. The remaining authors represent no other sources of funding. All authors report no competing financial interests exist.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Dr. Boehme is supported by NINDS NIH T32 NS007153-31. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS or the NIH.

References

Nilsson

Blomback

. Willebrand's disease in sweden; its pathogenesis and treatment. Acta Med Scand. 1959;164:263–278.

Cornu

Larrieu

Caen

Bernard

. Transfusion studies in von willebrand's disease: Effect on bleeding time and factor viii. Br J Haematol. 1963;9:189–202.

Sakariassen

Bolhuis

Sixma

. Human blood platelet adhesion to artery subendothelium is mediated by factor viii-von willebrand factor bound to the subendothelium. Nature. 1979;279(5714):636–638.

Weiss

Hoyer

. Von willebrand factor: Dissociation from antihemophilic factor procoagulant activity. Science. 1973;182(4117):1149–1151.

Weiss

Sussman

Hoyer

. Stabilization of factor viii in plasma by the von willebrand factor. Studies on posttransfusion and dissociated factor viii and in patients with von willebrand's disease. J Clin Invest. 1977;60(2):390–404.

Lenting

van Mourik

Mertens

. The life cycle of coagulation factor viii in view of its structure and function. Blood. 1998;92(11):3983–3996.

Koster

Blann

Briet

Vandenbroucke

Rosendaal

. Role of clotting factor viii in effect of von willebrand factor on occurrence of deep-vein thrombosis. Lancet. 1995;345(8943):152–155.

Kyrle

Minar

Hirschl

. High plasma levels of factor viii and the risk of recurrent venous thromboembolism. N Engl J Med. 2000;343(7):457–462.

Catto

Carter

Barrett

Bamford

Rice

Grant

. Von willebrand factor and factor viii: C in acute cerebrovascular disease. Relationship to stroke subtype and mortality. Thromb Haemost. 1997;77(6):1104–1108.

10.

Chang

Albright

Boehme

. Factor viii in the setting of acute ischemic stroke among patients with suspected hypercoagulable state. Clin Appl Thromb Hemost. 2014;20(2):124–128.

11.

Folsom

Rosamond

Shahar

. Prospective study of markers of hemostatic function with risk of ischemic stroke. The atherosclerosis risk in communities (aric) study investigators. Circulation. 1999;100(7):736–742.

12.

Landi

D’Angelo

Boccardi

. Hypercoagulability in acute stroke: Prognostic significance. Neurology. 1987;37(10):1667–1671.

13.

Furie

. Molecular and cellular biology of blood coagulation. N Engl J Med. 1992;326(12):800–806.

14.

Vehar

Keyt

Eaton

. Structure of human factor viii. Nature. 1984;312(5992):337–342.

15.

Rosendaal

Briet

Stibbe

. Haemophilia protects against ischaemic heart disease: A study of risk factors. Br J Haematol. 1990;75(4):525–530.

16.

Doggen

Rosendaal

Meijers

. Levels of intrinsic coagulation factors and the risk of myocardial infarction among men: opposite and synergistic effects of factors xi and xii. Blood. 2006;108(13):4045–4051.

17.

Erkekol

Ulu

Numanoglu

Akar

. High plasma levels of factor viii: an important risk factor for isolated pulmonary embolism. Respirology. 2006;11(1):70–74.

18.

Bonderman

Turecek

Jakowitsch

. High prevalence of elevated clotting factor viii in chronic thromboembolic pulmonary hypertension. Thromb Haemost. 2003;90(3):372–376.

19.

Haines

Howarth

North

. Haemostatic variables and the outcome of myocardial infarction. Thromb Haemost. 1983;50(4):800–803.

20.

Hamsten

de Faire

Walldius

. Plasminogen activator inhibitor in plasma: Risk factor for recurrent myocardial infarction. Lancet. 1987;2(8549):3–9.

21.

Thompson

Kienast

Pyke

Haverkate

van de Loo

. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European concerted action on thrombosis and disabilities angina pectoris study group. N Engl J Med. 1995;332(10):635–641.

22.

Pan

Bai

Chen

Chiu

. Associations between carotid atherosclerosis and high factor viii activity, dyslipidemia, and hypertension. Stroke. 1997;28(1):88–94.

23.

Smith

Patterson

Yarnell

Rumley

Ben-Shlomo

Lowe

. Which hemostatic markers add to the predictive value of conventional risk factors for coronary heart disease and ischemic stroke? The caerphilly study. Circulation. 2005;112(20):3080–3087.

24.

Ceciliani

Giordano

Spagnolo

. The systemic reaction during inflammation: The acute-phase proteins. Protein Peptide Lett. 2002;9(3):211–223.

25.

O’Donnell

Tuddenham

Manning

Kemball-Cook

Johnson

Laffan

. High prevalence of elevated factor viii levels in patients referred for thrombophilia screening: Role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost. 1997;77(5):825–828.

26.

Lasek-Bal

Puz

Kazibutowska

. Elevated factor viii level and stroke in patients without traditional risk factors associated with cardiovascular diseases. Neuropsychiatr Dis Treat. 2013;9:847–852.

27.

O’Donnell

Mumford

Manning

Laffan

. Elevation of fviii: C in venous thromboembolism is persistent and independent of the acute phase response. Thromb Haemost. 2000;83(1):10–13.

28.

Samai

Monlezun

Shaban

. Von willebrand factor drives the association between elevated factor viii and poor outcomes in patients with ischemic stroke. Stroke. 2014;45(9):2789–2791.

29.

Wang

Cheng

Yen

Lou

Liu

. Vitamin e suppresses enhancement of factor viii-dependent thrombin generation by systemic hypoxia. Stroke. 2009;40(2):656–659.

30.

Kamphuisen

Eikenboom

Vos

. Increased levels of factor viii and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions. Thromb Haemost. 1999;81(5):680–683.

31.

Gaston

Brooks

Blumenthal

Miller

. A study of blood coagulation following an acute stroke. Stroke. 1971;2(1):81–87.

32.

Gustafsson

Blomback

Britton

Hamsten

Svensson

. Coagulation factors and the increased risk of stroke in nonvalvular atrial fibrillation. Stroke. 1990;21(1):47–51.

33.

Karttunen

Alfthan

Hiltunen

. Risk factors for cryptogenic ischaemic stroke. Eur J Neurol. 2002;9(6):625–632.

34.

Schneidau

Harrison

Hurst

Wilkes

Meade

. Arterial disease risk factors and angiographic evidence of atheroma of the carotid artery. Stroke. 1989;20(11):1466–1471.

35.

Karttunen

Hiltunen

Rasi

Vahtera

Hillbom

. Factor v leiden and prothrombin gene mutation may predispose to paradoxical embolism in subjects with patent foramen ovale. Blood Coagul Fibrinolysis. 2003;14(3):261–268.

36.

Knottnerus

Govers-Riemslag

Hamulyak

. Endothelial activation in lacunar stroke subtypes. Stroke. 2010;41(8):1617–1622.

37.

Siegler

Boehme

Kumar

Gillette

Albright

Martin-Schild

. What change in the national institutes of health stroke scale should define neurologic deterioration in acute ischemic stroke? J Stroke Cerebrovasc Dis. 2013;22(5):675–682.

38.

Bank

Libourel

Middeldorp

. Elevated levels of fviii: C within families are associated with an increased risk for venous and arterial thrombosis. Thromb Haemost. 2005;3(1):79–84.

39.

Orstavik

Magnus

Reisner

Berg

Graham

Nance

. Factor viii and factor ix in a twin population. Evidence for a major effect of abo locus on factor viii level. Am J Hum Genet. 1985;37(1):89–101.

40.

Williams

Carter

Hysi

. Ischemic stroke is associated with the abo locus: The euroclot study. Ann Neurol. 2013;73(1):16–31.

41.

Jeremic

Weisert

Gedde-Dahl

. Factor viii (ahg) levels in 1016 regular blood donors. The effects of age, sex, and abo blood groups. Scand J Clin Lab Invest. 1976;36(5):461–466.

42.

Shima

Fujimura

Nishiyama

. Abo blood group genotype and plasma von willebrand factor in normal individuals. Vox Sanguinis. 1995;68(4):236–240.

43.

Conlan

Folsom

Finch

. Associations of factor viii and von willebrand factor with age, race, sex, and risk factors for atherosclerosis. The atherosclerosis risk in communities (aric) study. Thromb Haemost. 1993;70(3):380–385.

44.

Rauch

Girisch

Hertzberg

Klinge

Hofbeck

. Persistent high factor viii: C in a child with ischemic stroke. Thromb Res. 2003;111(1-2):51–54.

45.

Duran

Biner

Demir

Celtik

Karasalihoglu

. Factor v leiden mutation and other thrombophilia markers in childhood ischemic stroke. Clin Appl Thromb Hemost. 2005;11(1):83–88.

46.

Sirachainan

Boonyatarp

Kadegasem

. High factor viii and von willebrand factor levels are not risk factors of cryptogenic arterial ischemic stroke in Thai children. J Child Neurol. 2015;30(8):1057–1059. doi: 10.1177/0883073814541475.

47.

Kamphuisen

Eikenboom

Bertina

. Elevated factor viii levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol. 2001;21(5):731–738.

48.

Jauch

Saver

Adams

Jr . Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the american heart association/american stroke association. Stroke. 2013;44(3):870–947.

Factoring in Factor VIII With Acute Ischemic Stroke

Abstract

Keywords

Background

Molecular Role of Factor VIII in Thrombosis

Factor VIII and Stroke

Incident Stroke

Stroke Etiology

Stroke Severity

Risk of Elevated FVIII

Pediatric Considerations

Future Directions

Utility of Screening

Conclusions

Footnotes

Author’s Note

Declaration of Conflicting Interests

Funding

References