Risk-factor profile in severe, generalized, obliterating vascular disease.

Abstract: A 74-year-old woman had a history over 25 years of endarterectomy of both renal arteries, iliac venous thrombosis, pulmonary embolism, left internal carotid artery endarterectomy, coronary angioplasty, aortocoronary bypass grafting, occlusion of the right axillary artery, lower-limb claudication due to common iliac artery aneurysm, external iliac artery stenosis, multiple femoral artery stenoses, bifurcational stent grafting, occlusion of the left brachial artery and the right external iliac artery, and stroke. Assessment of the risk-factor profile revealed an absence of classic risk factors but the presence of the factor V Leiden mutation, the methylenetetrahydrofolate reductase AI298C mutation, the HFE C282Y mutation, plasminogen activator inhibitor-1 gene mutation, the -455 G/A fibrinogen gene polymorphism, the [euro]3/[euro]4 apolipoprotein E -675 4G gene polymorphism, and hyperhomocysteinemia. This case shows that sever, generalized, occlusive vascular disease may be due to the combination of various genetic risk factors for atherosclerosis and venous thromboembolism.

Key Words: atherosclerosis, cerebral ischemia, coagulation, endovascular surgery, thromboembolism

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Obliterating vascular disease (OVD) is a major cause of morbidity and mortality in the industrialized world. OVD may affect either arteries (atherosclerosis/thrombosis; cerebral, coronary, and peripheral arterial occlusive disease) or the venous system (venous thromboembolism). (1) The development of OVD involves complex interactions between environmental and genetic risk factors. (2), (3) Abnormalities of hemostasis and lipid metabolism may play key roles in the pathogenesis of OVD. (4-6) In the following report, we evaluate the risk-factor profiles for both atherosclerosis/thrombosis and venous thromboembolism in a patient with sever, generalized OVD.

Discussion

There are a number of well-established, classic, major risk factors for OVD, such as advanced age, male sex, cigarette smoking, arterial hypertension, dyslipidemia, diabetes, insulin resistance, hyperinsulinemia, obesity, sedentary lifestyle, and stress. In addition, new risk factors have emerged and their roles in the pathogenesis of OVD are still controversial. (1) Various new causes for severe generalized OVD such as APC resistance; HHCE; and gene mutations of hemochromatosis (HFE), plasminogen activator inhibitor-1 (PAI-1), fibrinogen, and apolipoprotein E (apo E) remain possibilities, because classic, major, and some new risk factors could not be detected in the patient.

APC resistance is characterized by a poor anticoagulant response to APC, which is activated by thrombin and inhibits coagulation by cleaving and inactivating coagulation factors Va and VIIIa. APC resistance can be inherited or acquired and has a prevalence of 3 to 5% in the general population. The most common cause of inherited APC resistance is the factor V Leiden mutation, found only in Caucasians, with a prevalence in the general population of 1 to 15%. (7) The factor V Leiden mutation is a point mutation in the factor V gene that results in the substitution of arginine (R) at position 506 by glutamine (Q). (7-9) The factor V Leiden mutation induces a hypercoagulable state, with a lifelong increased risk of venous thromboembolism. The association of the factor V Leiden mutation with atherosclerosis/thrombosis is less clear. A review of all of the available data indicates that the factor V Leiden mutation may contribute to the development of atherosclerosis/thrombosis by acting synergistically with other major risk factors and may therefore increase the risk conferred by the classic risk factors. (2)

[FIGURE 1 OMITTED]

HHCE has attracted much recent interest as a potential risk factor for OVD. (10), (11) It is of special interest that, with the administration of B vitamins, there is a safe and inexpensive therapeutic option for treating this risk factor. HHCE is present in up to 5% of the general population but in 50% of the patients with OVD. (10), (11) HHCE is associated with advanced age; postmenopausal state; male sex; smoking; alcoholism; physical inactivity; a methionine-rich diet; vitamin B deficiency; renal insufficiency; lymphatic leukemia; psoriasis; treatment with methotrexate, carbamazepine, or phenytoin; and genetically determined defects in enzymes involved in homocysteine metabolism, such as cystathionine [beta]-synthetase (catalyzes homocysteine to cysteine, vitamin [B.sub.6] dependent) and 5,10-methylenetetrahydrofolate reductase (MTHFR) (methylates homocysteine to methionine, vitamin [B.sub.12] dependent). (10) Homocysteine directly damages the endothelium (injury, dysfunction, and growth inhibition), stimulates smooth-muscle-cell proliferation, increases the generation of prothrombin and thrombin, enhances low-density lipoprotein peroxidation, and increases platelet aggregation. Other possible mechanisms for HHCE-mediated atherogenesis include altered methylation of DNA, altered cell-membrane regulatory proteins, decreased bioavailability of nitric oxide, increased elastolysis and collagen accumulation, over-stimulation of N-methyl-D-aspartate receptors, and excessive adhesion of monocytes and neutrophils to endothelium. (10) HHCE appears to be only a weak risk factor for venous thromboembolism. (12), (13) On the other hand, several studies have demonstrated a consistent association between HHCE and atherosclerosis/thrombosis. (11), (14) Whether HHCE is causative or only an enhancing risk factor is unknown. Genetic causes for HHCE are various polymorphisms in the MTHFR gene. Among these, the C677T and A1298C polymorphisms have been studied extensively as possible genetic determinants of increased risk for OVD, but a meta-analysis of 13 studies failed to support the association between genotype and phenotype. (15) Whether HHCE in the patient was only a reaction to recurrent thromboembolic events and did not extend back for 25 years remains speculative.

Apart from APC resistance and HHCE, the patient showed heterozygosity for the HFE C282Y mutation, which is associated with increased serum levels of iron. As the development of atherosclerosis is assumed to be multifactorial, iron may play a role by promoting oxygen radical formation and lipid peroxidation, (16) but studies have shown no clear evidence to prove that this HFE mutation is associated with increased risk of atherosclerosis/thrombosis. Studies that investigated the association of HFE and factor V Leiden regarding venous thromboembolism found that the hemochromatosis mutation did not emerge as an additional risk factor for venous thromboembolism in patients carrying the factor V Leiden mutation. (17)

Elevated concentrations of PAI-1, the major inhibitor of tissue plasminogen activator (t-PA), are fairly consistently associated with increased risk of vascular disease. The gene for PAI-1 shows several polymorphic loci, including the 4G/5G insertion/deletion -675 base pairs from the start site of the promotor, related to the plasma PAI-1 concentration. Adjacent to the 4G/5G site, a triglyceride-responsive region has been identified, (18) with the highest levels of PAI-1 in 4G/4G subjects with elevated triglyceride levels. (19), (20) Additional risk for OVD was assumed to be rather low for the patient despite the homozygous state for 4G because of normal PAI-1 and triglyceride levels.

Among the components of the coagulation system, an elevated fibrinogen level has been most consistently associated with OVD. (21) Within the fibrinogen gene cluster, a number of polymorphisms have been studied with respect to plasma fibrinogen levels, in particular the -455G/A [beta]-fibrinogen polymorphism. Plasma fibrinogen levels have been reported to be higher in subjects homozygous for the -455A allele, (22) but associations between disease and genotype have been inconsistent. (23) Fibrinogen levels interact with other risk factors, mainly smoking and hypertension, but because the patient had always been a nonsmoker showing normal levels of fibrinogen, the heterozygous -455G/A polymorphism was not regarded as the main cause of OVD. Because they are acute-phase reactants, elevated levels of fibrinogen and highly sensitive C reactive protein (CRP) could be expected in the patient, reflecting the degree of inflammatory reaction that accompanies atherosclerosis/thrombosis. (24) Why both parameters were within normal range in a patient suffering from such severe OVD remains speculative.

Among the most powerful established risk factors for atherosclerosis/thrombosis are hypercholesterolemia and dyslipidemia with all their different causes, including a number of mutations in genes involved in the lipid metabolism. One lipoprotein that plays a basic role in the degradation of particles rich in cholesterol and triglycerides is apo E, which is able to bind to low-density lipoprotein (LDL) receptors, but also to chylomicron remnants. The apo E gene is polymorphic, resulting in three common alleles ([epsilon]2, [epsilon]3, [epsilon]4), among which the [epsilon]4 allele has been associated with elevated levels of serum cholesterol and LDL. (4) There is evidence that the [epsilon]4 allele is associated with early carotid atherosclerosis, (4) ischemic stroke (6) and, in a meta-analysis of 14 studies, coronary heart disease in both men and women. (25) There are numerous studies, however, that did not find these associations, particularly in women. Because the patient was a woman with normal serum levels of cholesterol, LDL, high-density lipoproteins, and triglycerides, it is rather unlikely that her OVD was caused by the heterozygous [epsilon]3/[epsilon]4 state. One study demonstrated that the [epsilon]4 allele, in combination with the AA genotype of the [beta]-fibrinogen -455 G/A polymorphism, is common in the large-vessel atherosclerosis subtype of cerebrovascular disease, (5) but data refer only to the compound homozygous state of these two polymorphisms.

Overall, generalized OVD in the patient could not be attributed to the presence of a single risk factor. Possibly, it was the combination of various genetic risk factors that was responsible for severe OVD in the described patient. These genetic abnormalities may have enhanced each other's pathogenic effects. However, only data are available regarding gene-gene interactions. Occasional unrecognized dyslipidemia might have contributed to the development of OVD. Arterial hypertension was excluded as a cause of atherosclerosis/thrombosis, because the patient's blood pressure had been in the normal range since 1975. Furthermore, there might have been so far unrecognized factors that enhanced the effect of the described genetic abnormalities. Although it was considered, anticoagulation therapy was not restarted because of the previous side effects the patient had suffered when she was taking phenprocoumon and because she had normal serum homocysteine values while she was taking vitamin B therapy. Cerebrospinal fluid abnormalities were attributed to the previous stroke. No pathologic examinations on specimens removed at arthrotomy or endarterectomy were carried out to determine if the disease was clearly atherothrombotic or simply atheromatous.

Conclusion

This case shows that severe, generalized OVD with multiple cerebral, coronary, and peripheral, arterial, and venous thromboembolic events necessitating recurrent revascularization procedures may be either due to the combination of various genetic risk factors or due to causes still unknown. Administration of antiplatelet agents and vitamin B may be helpful in preventing future thromboembolic events.

I Always behave like a duck--keep calm and unruffled on the surface but paddle like the devil underneath.

--Lord Barbizon

Table 1. Results of blood chemistry tests (a)

Component                           Reference
                                     values

Serum glucose (mg/dl)               <110
Insulin ([micro]U/ml)               3-17
Cholesterol (mg/dl)                 [less than or equal to]200
Triglycerides (mg/dl)               [less than or equal to]175
HDL (mg/dl)                         [greater than or equal to]35
LDL (mg/dl)                         [less than or equal to]160
Lipoprotein a (mg/dl)               [less than or equal to]30
TSH ([micro]U/ml)                   0.35-5.5
Serum iron ([micro]g/ml)            60-150
HsCRP (mg/L)                        [less than or equal to]6.0
Homocysteine 1 ([micro]mol/L) (c)   [less than or equal to]12 (women)
Homocysteine 2 ([micro]mol/L) (c)   [less than or equal to]12 (women)
Homocysteine 3 ([micro]mol/L) (c)   [less than or equal to]12 (women)
Homocysteine 4 ([micro]mol/L) (c)   [less than or equal to]12 (women)

Component                           Result

Serum glucose (mg/dl)                92
Insulin ([micro]U/ml)               2.6 (b)
Cholesterol (mg/dl)                 157
Triglycerides (mg/dl)               124
HDL (mg/dl)                          53
LDL (mg/dl)                         145
Lipoprotein a (mg/dl)                35 (b)
TSH ([micro]U/ml)                  0.13 (b)
Serum iron ([micro]g/ml)             43 (b)
HsCRP (mg/L)                        5.3
Homocysteine 1 ([micro]mol/L) (c)  18.5 (b)
Homocysteine 2 ([micro]mol/L) (c)  20.7 (b)
Homocysteine 3 ([micro]mol/L) (c)  16.6 (b)
Homocysteine 4 ([micro]mol/L) (c)  10.2

(a) HDL, high-density lipoprotein; LDL, low-density lipoprotein; TSH,
thyroid-stimulating hormone: HsCRP, highly sensitive C-reactive protein.
(b) Abnormal result.
(c) Blood samples for determination of total homocysteine levels were
obtained after a 12-hour fast and were centrifuged and frozen to
-70[degrees]C immediately after blood drawing.

Table 2. Results of coagulation tests (a)

                                         Reference
Component                                 values    Result

Fibrinogen (mg/dl)                        200-400    237
Factor VII (%)                             70-120    119
Factor VIIIc (%)                           60-160    135
Factor IX (%)                              70-130    129
Factor XI (%)                              70-130    114
Factor XII (%)                             70-120    126 (b)
Antithrombin III (%)                       70-120     82
Protein C (%)                              70-140    128
Protein S activity (%)                     70-125     77
Protein S antigen (%)                      70-140    103
APC ratio, undiluted                         >2.2    2.0 (b)
APC ratio, diluted                           >2.0    1.7 (b)
Plasminogen (%)                            70-160     94
PAI-1 (U/ml)                                5-15     6.0
PTT-LA                                   Negative  Negative
DRVVT                                    Negative  Negative
[[beta].sub.2] glycoprotein-1 antibody.  Negative  Negative

(a) APC, Activated protein C; PAI-1, plasminogen activator inhibitor-1;
PTT-LA, lupus anticoagulant-sensitive activated partial thromboplastin
time; DRVVT, diluted Russell viper venom time.

(b) Abnormal result.

Table 3. Genetic findings in the presented patient (a)

Mutation                                      Status

Factor V Leiden G1691A                  Heterozygote
Factor V HR2                            Wild type
MTHFR C677T                             Wild type
MTHFR A1298C                            Heterozygote
Prothrombin G20210A                     Wild type
HFE C282Y                               Heterozygote
PAI-1-675 4G/5G                         4G/4G
HPA-1 a/b                               Wild type
Factor XIII Val34Leu                    Wild type
Fibrinogen-455-G/A                      Heterozygote
Apo B R3500Q                            Wild type
Apo E [epsilon]2/[epsilon]3/[epsilon]4  [epsilon]3/[epsilon]4

(a) MTHFR, methylenetetrahydrofolate reductase: HFE, hemochromatosis;
PAI-1, plasminogen activator inhibitor: glycoprotein IIIa; HPA, human
platelet antigen: Apo, apolipoprotein.

Acknowledgment

We thank Vienna Lab Labordiagnostika GmbH for the determination of genetic obliterating vascular disease risk factors by means of a new strip assay using reverse-hybridization analysis.

From the Department of Neurology, the Department of Laboratory Medicine, and the Department of Medicine, Krankenanstalt Rudolfstiftung, Vienna, Austria.

Reprint requests to Josef Finsterer, MD, PhD, Postfach 348, 1180 Vienna, Austria. Email: [e-mail]

Accepted April 3, 2002.

Copyright [c] 2004 by The Southern Medical Association 0038-4348/04/9701-0087

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RELATED ARTICLE: Key Points

* If classic risk factors for obliterating vascular disease are absent, genotyping of new risk factors may disclose the cause.

* Severe obliterating vascular disease may have not just one but many causes.

* Administration of antiplatelet agents and vitamin B may prevent further thromboembolic events in patients with new risk factors.

RELATED ARTICLE: Case Report

The patient was a 74-year-old, nonsmoking, nonalcoholic woman who tested negative for human immunodeficiency virus (HIV) infection. The family history was negative for OVD. She had suffered from arterial hypertension since 1972. In 1975, she was found to have bilateral renal artery stenosis, which caused arterial hypertension. This was successfully treated with bilateral endarterectomy. Postoperatively, a left-sided iliac venous thrombosis occurred, necessitating thrombectomy. She simultaneously experienced a right-sided pulmonary embolism, which resolved without therapy. After these events, anticoagulation therapy with phenprocoumon was initiated and continued until 1978, when gastrointestinal bleeding caused by a duodenal ulcer necessitated several blood transfusions, selective proximal vagotomy, and splenectomy. She no longer required antihypertensive medication after her renal artery surgery. Because of a therapy-resistant gastric ulcer that she had developed in 1981, she underwent a Billroth I gastrectomy in 1982. In 1988, she had a transient ischemic attack with short-lived, right-sided hemiparesis. The causative high-grade stenosis of the left internal carotid artery was successfully treated with endarterectomy. Despite undergoing percutaneous transluminal coronary angioplasty twice in 1992 because of recurrent anginal chest pain, she needed aortocoronary bypass grafting in 1993. In 1995, she experienced acute occlusion of the right axillary artery and was treated with thromboembolectomy. Angiography was performed in April 1999 because of the patient's increasing lower-limb claudication (Fontaine Classification IIb-III) since 1998, which revealed aneurysms of both renal arteries and the right common iliac artery, high-grade stenosis of the right external iliac artery, and multiple stenoses of the right superficial femoral artery. As a consequence, endoluminal implantation of a bifurcational stent graft (Vanguard; Boston Scientific Corp., Natick, MA) was performed in September 1999, after the right external iliac artery had been dilated and the internal iliac artery had been therapeutically occluded in June 1999. In July 1999, she experienced sudden hypesthesia of the right side of the face that persisted for 3 weeks. Reevaluation disclosed a 60 to 70% stenosis of the right internal carotid artery. Despite stenting, claudication of the lower limbs recurred, accompanied by claudication of the left upper limb. Angiography in April 2000 revealed occlusion of the right common iliac artery and the left brachial artery and multiple high-grade stenoses of the brachiocephalic trunk, the right subclavian artery, the right vertebral artery, and the right common carotid artery. In May 2000, a Wall stent was implanted into the stent of the right common iliac artery. Nine days later, rupture of the left brachial artery occurred during angioplasty and was treated with open, extraluminal stent implantation. Eleven days later, a few minutes after displacement of a left-sided jugular-vein catheter, the patient developed acute impaired consciousness, slurred speech, left-sided hemiparesis, and hemihypesthesia. After a patent foramen ovale was excluded by echocardiography and transcranial Doppler sonography, the patient was transferred to the neurology department.

At admission, the patient presented with somnolence, stiff neck, agitation, absent gag reflex, deviation of the tongue to the left, exaggerated deep tendon reflexes with left-sided predominance, left-sided hemiparesis (Medical Research Council grade 4), and hemihypesthesia. Computed tomographic (CT) scan of the brain showed slight, diffuse cerebral atrophy, periventricular demyelination, and multiple lacunar lesions in the white matter, subcortically, cortically, and in the right thalamus. A CT scan of the brain on the seventh hospital day showed a small, hypodense lesion in the right posterior border zone, which was interpreted as representing a recent small stroke (Fig. 1). Cerebral magnetic resonance imaging excluded a brainstem infarction (Fig. 1). Blood pressure was 129/67 mm Hg and remained normal throughout her hospitalization.

Fasting serum levels of glucose, insulin, lipids, iron, and thyroid-stimulating hormone were normal, as were urine protein levels (Table 1). There was no evidence of vasculitis. Cerebrospinal fluid investigations showed a protein level of 140 mg/dl (normal, 15-45 mg/dl); lactate level of 3.1 mmol/L (normal, 1.2-2.1 mmol/L); and pleocytosis of 27/3 cells (normal, -12/3 cells), all of which were attributed to the recent stroke. Routine coagulation assays revealed values in normal range. Screening for thrombophilia, performed 3 and 5 weeks after the acute cerebrovascular event, showed activated protein C (APC) resistance and hyperhomocysteinemia (HHCE) (Table 2). The results of genotyping of various risk factors for OVD are given in Table 3.

Despite normal levels of vitamin [B.sub.6], vitamin [B.sub.12], and folic acid, B vitamin therapy was begun, in addition to treatment with molsidomine and clopidogrel bisulfate. Under this regimen, the acute neurologic abnormalities completely resolved within 3 weeks, and the homocysteine level decreased to normal range. Although it was considered, oral anticoagulation therapy was not restarted because the patient had previously suffered side effects while taking phenprocoumon and because her homocysteine values were normal after vitamin B supplementation therapy. During a 12-month follow-up period, no additional vaso-occlusive events occurred.

Josef Finsterer, MD, PHD, Astrid Dossenbach-Glaninger, MD, Walter Krugluger, MD, Claudia Stollberger, MD, and Piere Hopmeier, MD, PHD