Ординатура / Офтальмология / Английские материалы / Retinal Vascular Disease_Joussen, Gardner, Kirchhof_2007

ingly high rates of thrombophilic abnormalities in both cohorts with every plasma protein they looked for.

Glacet-Bernard et al. and Carbone et al. also reported the same APA prevalence whether the patients were younger or not than 50 years old. This raises the question as to whether the elevation in

21 III APA could be secondary to the thrombosis instead of being the culprit. Carbone et al. prospectively studied 68 patients with all types of ocular vascular occlusion with no mention made about age composition of the two control groups or sex composition of the three groups. They included six anterior ischemic optic neuropathies but those will not be discussed here since it is beyond the scope of this text. The rest of the patient group was composed of 46 RVOs, 14 RAOs and 2 combined RVO-RAOs. Seven patients had retinal vasculitis, ten had thrombocytopenia, five had repeated abortions and four had livedo reticularis. Those patients were compared to a group of 45 patients with ocular inflammatory diseases and another group of 49 “randomly selected healthy volunteers.” Of the 16 patients who tested positive for APA, four did so on later retesting. Two developed a stroke and four were amongst the seven “coincidental” retinal vasculitis patients. Of the three other vasculitis cases, one was ACA positive and two were ANA positive. Additionally, two of the 16 APA positives developed lupus-like disease. This cohort most likely does not represent our usual retinal vasculopathic patient.

Most of the English language papers on APA are detailed in Table 21.1.5. Lahey’s level of evidence II study did find an association between CVO and APA. When we reject data duplication, six level III studies did find an association between RVO and LA or ACA as nine did not. Many of them are scrutinized throughout this chapter.

We could not find any study looking exclusively at BVO. All studies grouped them with CVO under “venous retinal disease.” No distinction could be made in the results of each study looking at multiple types of vascular retinal occlusions, whether arterial or venous.

Most of the authors who have studied this topic have lumped together CVO, BVO, CAO and BAO and since the etiologies and pathogenesis likely differ, additional studies splitting out the various groups will be needed.

Based on the actual literature, mass screening for APA is definitively not recommended at this point for patients experiencing RVOD. Obvious evidence has been offered for the association of APS or SLE with RVOD [10], and APA should be looked for in patients presenting with a familial or personal history suggestive of such. Special conditions were the detection

of APA, which could be beneficial for counseling the patient or altering the course of the treatment and will be discussed in greater detail at the end of this chapter.

21.1.4Disorders of Coagulation and Anticoagulation

The human organism maintains a fine equilibrium between factors allowing the blood to circulate in its fluid form and others preventing us from bleeding to death should an accident occur. This complex balance is maintained through pro-coagulating factors closely monitored by anticoagulant proteins as described in Fig. 21.1.2. Inborn or acquired errors can happen in this well tuned cascade leading to prothrombotic states. We provide an overview of the main possible defects of the natural anticoagulants in the following section.

21.1.4.1Factor V Leiden and Activated Protein C Resistance

Protein C is a vitamin K dependent circulating zymogen. Once activated by the complex formed by thrombin and thrombomodulin, it becomes a natural anticoagulant which degrades activated factor V and VIII. Activated protein C resistance (aPCR) is seen when factor V or V III are resistant to degradation by aPC and keep their thrombotic properties for an extended period.

Causes of acquired aPCR include pregnancy, birth control pill use and the presence of lupus anticoagulant [65]. There is general agreement in the literature that 94 % of aPCR is caused by factor V Leiden (FVL) (named after the Dutch city where it was discovered). It is also called factor V R506Q and G1691A mutation of factor five for the following reasons. FVL comes from a single point mutation at nucleotide location 1691 when adenine is substituted for a guanine. The new codon created by this G1691A mutation causes the replacement of an arginine (R) by a glutamine

(Q) as the 506th amino acid of the protein backbone. This is where aPC normally cleaves factor five to inactivate it. The mutant factor V R506Q is then protected from degradation by aPC. It is inherited as an autosomal dominant trait. For general understanding, a homozygous mutation usually leads to a more severe prothrombotic phenotype than a heterozygous one.

Table 21.1.6 summarizes the findings of various researchers about FVL, aPCR and the possible relationship with retinal vascular disease. We find no level I evidence study.

Perhaps the strongest study summarized in Table 21.1.6 is that of Lahey and is described in the

Hcy section earlier in this chapter. He found no statistically significant difference in aPCR or FVL prevalence compared to the prevalence in well-matched controls.

The geographical prevalence of the FVL carrier rates has been shown to widely vary from 0 % in African countries, to 6 % in the USA population and up to 15 % in Greek Cypriots [48]. The FVL carrier rate is estimated at 0.6 – 2.9 % in southern Europe, compared to 3.4 – 7.9 % in northern European countries [18]. In their German population, which has a 7 % prevalence of FVL in their healthy individuals [52], Greiner et al. investigated 76 patients with any retinal vascular disease who had an inpatient evaluation (see next paragraph) for aPCR and other plasma proteins. Eighty-one percent of the cases had at least one, 37 % had 2 and 11 % had three of the major risk factors. Sixteen percent of the RVO patients had a previous history of DVT. They found 29 % of their CVO and 19 % of their BVO subjects to have aPCR. One hundred percent of their 17 cases of aPCR were due to the presence of FVL. They found the same anomaly in 19 % of their group control with deep vein thrombosis. They did have one patient with CAO and two with BAO testing positive for aPCR/ FVL. This is a very small number of cases and with this type of control group, it is impossible to establish if the results could have been due to chance only.

The same authors later reported a larger study. We may be mistaken, but on close reading of the two papers, it appears that the second larger paper

included some or all patients from their first publication, causing a second reporting of some of the same data. For instance, 10 of their 13 CVO patients positive for FVL in their second study were from the first one discussed above. One hundred percent of their aPCR was proven to be secondary to FVL in the second study as well. Unfortunately, in their second study also, the presence of major risk factors was not accounted for in the control group but 11 of 13 of their CVOs had at least one. There could easily be important imbalances in features not recorded or not reported and it is for reasons such as this that we consider this work as supplying level III evidence. They did find an association between CVO and aPCR/FVL but no such conclusions could be made with BRVO. The three RAO patients were discussed above with their first paper and the second did not offer additional cases. We do not dismiss their findings but do not offer them as conclusive.

Ciardella et al. conducted a very puzzling study in which they first evaluated the prevalence of aPCR with the old technique of standard partial thromboplastin time (PPT). This technique calculates the ratio of a PPT performed with a fixed amount of aPC added to the plasma tested, divided by a PPT performed only with the plasma. They found 45 % of their 84 RVO patients having a ratio 2.1 (considered positive) compared with 9 % of the control group. They then compared this old technique with a more specific and sensitive newer aPCR assay on 40 of their RVO patients. This time they found 58 % of

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21 III

III Pathology, Clinical Course and Treatment of Retinal Vascular Diseases

Table 21.1.6. Studies assessing FVL’s and aPCR’s possible relationship with RVOD

DVT: deep vein thrombosis; CAD: coronary heart disease; Prospective: not matched

*Prospective study matched for sex and age

**Prospective study matched for sex, age hypertension, and hypercholesterolemia

***Numbers following each specific RVOD represent the number of patients in each category of event

them to have aPCR using the old ratio compared with 10 % if the newer assay was used. The same tactic was used with nine controls and three tested 2.1 with the old technique compared to one with the new one. They concluded the first generation commercial test for aPCR is not a useful screening test. They did not find an association between aPCR/ FVL and RVO.

Several of the other studies reviewed regarding aPCR showed an obvious lack of appropriate control populations. Williamson and coworkers found a 12.5 % prevalence of aPCR using the first generation assay. This was higher than the 5 % of a historical group control from Scotland. They concluded an association between CVO and aPCR but did not, as well as in the following study from Larsson, confirm their aPCR by the almost universal FVL. As Larsson points out himself: “aPCR assays sometimes yield conflicting results when conducted on the same blood sample twice” [16]. Larsson and Williamson were the first ones to find a positive association between aPCR and CVO and are quoted frequently throughout the literature. Let us not forget they only used a functional aPCR assay, which is associated with some preanalytical and technical issues potentially affecting its accuracy [30]. Furthermore, Larrson et al. did not include a control group in their retrospective study and found 8 out of 31 patients (26 %) with aPCR in a population where the normal incidence of aPCR is around 10 – 11 %. All those patients with aPCR were less than 45 years of age, thus explaining the 36 % prevalence they calculated when getting rid of the older patients with CVO in their study. Gottlieb and Hodgkins also did not use a control group. Interestingly enough, Hodgkins who only used patients without major risk factors concluded there was no association of CVO with aPCR as Larsson, who did not use a sample free of major risk factors, concluded the opposite. In Gottlieb’s study, which did not find a relationship, the only patient with FVL had a past history of thrombosis, as did 16 % of Larrson’s CVO patients. Larsson et al. in a separate study on patients over 50 years old did not find an association between aPCR and CVO. Those last studies discussed are good examples to explain the lack of consensus in the literature on this topic.

Glueck et al. were one of the first groups to publish their findings and are also often quoted in support of the positive associations for FVL and lupus anticoagulant with CVO. Three of their 17 CVO patients were heterozygous for FVL. Out of their 17 patients, 6 were on antihypertensive medications, two had diabetes and one smoked more than a pack of cigarettes per day. Twenty-four percent of the patients had a past history of deep vein thrombosis, 18 % had previous

avascular necrosis and 18 % had bilateral CVOs. On the other hand, the controls were 194 healthy children and 40 healthy adults that came from a separate study. The mean age of the patients was 52 compared to a mean age of 37 years old for the control group. These discrepancies and the small number of

patients cast doubt on the significance of the find-

ings. III 21 The study by Albisinni et al. is the last of the five

who did find a positive association between RVO and “genetic abnormalities.” To do so, they had to pool their prothrombin and factor V mutations together as well as analyzing their CVO and BVO as a whole. Out of 36 patients with RVO, 3 had FVL, 2 had the G20210A mutation of prothrombin and one had both mutations. Of those six patients, three had a familial history of thrombosis. The retrospective design of this study and the small number of people enrolled in it, limits the ability of readers to base decision making on this report.

Salomon [51] et al. found FVL in two BAOs and one CAO out of a group of 21 RAOs but the difference in FVL did not reach statistical significance. As discussed earlier, Greiner found three RAO cases FVL positive and other case reports exist [57]. Again, this leaves us with tenuous evidence of aPCR/FVL being a putative factor for RAO.

Almost all English language studies were reviewed. Without including data duplication, five level III evidence studies found an association between CVO and aPCR and/or FVL. No such conclusions could be made with BRVO. Eighteen level III evidence studies found no such association and they are detailed in Table 21.1.6.

In general, the studies are flawed by their retrospective design, small number of patients and lack of or poor group control. Most of the studies finding an association are mismatching cases and controls or not isolating confounding factors. They are divided concerning their conclusions but most of them, including the better-designed ones, tend to deny any associations between CVO and aPCR or FVL but do not absolutely rule them out.

Since most of the 1 – 7 % of individuals with the mutant allele for FVL remain asymptomatic, other factors have to account for their venous occlusive disease, and determination of aPCR and FVL levels does not appear at this time as being a necessary part of the regular investigation for patients with CRVO or BRVO. Special conditions where the detection of aPCR or FVL could be beneficial for counseling the patient or altering the course of the treatment will be discussed in greater detail at the end of this chapter.

21.1.4.2Natural Anticoagulant Deficiency: Protein C, S and Antithrombin III

Protein C’s function was discussed in the introduction to aPCR and has a normal level of activity of 60 – 70 % up to 140 %. Its deficiency has an auto-

21 III somal recessive inheritance mode. Homozygotes

lacking the expression of protein C have activity levels of less than 1 % and usually present with a thrombosis episode in their first few days of life. Heterozygotes have an activity level around 50 % and usually remain asymptomatic for their first few decades [14]. Protein S is also a vitamin K dependent and it acts as a cofactor accelerating the effect of protein C. ATIII

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III 21

bin mutation and was discussed in the aPCR/FVL section. All the other level III studies are included in Table 21.1.11 and none of them indicates an association of prothrombin G20210A mutation with any type of RVOD.

21.1.4.4 Lipoprotein A

Lipoprotein Lp(a) is an atherogenic, hypofibrinolytic, cholesterol carrying lipoprotein that may inhibit the conversion of plasminogen to plasmin [24]. Values above 300 mg/ml are associated with an increased risk of occlusive arterial disease [7]. Table 21.1.12 details studies looking at its possible association with RVOD. Marcucci (discussed in the FVL section of this chapter) found that in the absence of hypercholesterolemia, an increased Lp(a) level over 300 mg/dl was not associated with an increased risk of CRVO, while if the patient had hypercholesterolemia, the odds ratio was 2.4. Glueck (discussed previously) also found a correlation

between low-density-lipoprotein-cholesterol levels and Lp(a).

Bandello et al. carried out a well-matched cohort on 40 CVO patients. They could only find a statistically significant difference between their 12 cases and their 4 controls with elevated Lp(a) levels when using the Rosenbaum but not the Mann-Whitney test. Two other level III evidence studies are detailed in Table 21.1.12. In these, Lip found a positive association of Lp(a) in RVO patients as Sagripanti did not find such association for RAO.

The clinical significance of finding an increase of Lp(a) as well as the management of this anomaly remains to be addressed.

21.1.4.5 Other Factors

Several other different plasma protein anomalies have been investigated. Plasminogen activator inhib- itor-1 4G/5G polymorphism, anomalies in factor VII, VIII or XII or von Willebrand are reported. Some of

the different articles covering those topics are detailed in Table 21.1.13. Once again in our opinion, the same conclusions as with Lp(a) should apply. We need more solid data to allow the detection of those investigational plasma protein anomalies in such a way it will make an evidence based difference in the patient’s management.

21.1.5 Conclusions

Periodic visits to an internist or family practitioner are appropriate for middle aged and older adults, and patients with retinal vascular disease who do not see a primary care physician should consider doing so. Patients presenting with ocular vascular occlusive disease should have an evaluation of their intraocular pressure since glaucoma is a risk factor for some of these conditions and may be seen as a complication during follow-up. The family physician will assess blood pressure and should rule out the presence of diabetes mellitus. Adults seeing primary care physicians likely will have an assessment of serum lipids and cholesterol. Although no level one evidence exists, when these common risk factors have been eliminated in young patients, Hcy, APA, FVL and perhaps ATIII, protein C and S might be looked at especially in cases of bilateral disease, positive family history or previous thrombotic disorders.

If a risk factor for retinal vascular occlusion is identified, the next question of course is what, if anything, should be done about it. The goals of treatment should be to reduce the likelihood of a future ocular occurrence as well as to reduce the chance of systemic thrombotic events. To date, there have not been any trials showing that management of a clot- ting-related protein alters the risk of a future retinal vascular event. We can only assume that if there is

evidence that thrombotic disease in general is reduced by such management, that the chance of future eye disease might be reduced as well.

There is good data for some of the conditions discussed in this chapter that future systemic disease can be discovered and early management instituted in selected groups of patients. It is beyond the scope of this chapter, which is written by ophthalmologists and presumably for ophthalmologists, to review the basic medicine and to teach hematology. This is why we strongly believe that the medical management, if any, needs to be recommended by appropriate specialists such as hematologists or perhaps internists. We will simply mention some examples and offer some comments about the systemic management but our review of this topic barely scratches the surface.

In this next section, we will discuss the implications of finding a positive result for each respective plasma protein anomaly. From a more general perspective, thrombosis prophylaxis could be contemplated more aggressively in surgical or prolonged immobilization settings. A stronger recommendation can be made regarding modifiable vasculopathic risk factors such as avoidance of smoking oral or contraceptive use. Vandenbroucke and coworkers [61] studied 155 women aged 15 – 49 years with deep vein thrombosis (DVT) and compared them to 169 controls. Women using oral contraceptives had a fourfold increase in the risk of DVT. They had a sevenfold increase if they were carriers of aPCR. The study demonstrated a 30-fold increase in the risk of thrombosis if a young woman with aPCR was using the birth control pill.

It is unknown if aPCR/FVL positive patients with RVOD or systemic thrombosis should be anticoagulated and, if so, at what dose and for how long. A calculation of the benefit to risk ratio of warfarin with a

target international normalized ratio (INR) of 2.5 does not support the use of long-term therapy in all patients with the factor V Leiden mutation following a first pulmonary embolism or DVT [6].

Khamashta and colleagues [36], writing in the

New England Journal of Medicine, teach that thrombosis is the main complication of the antiphospho- 21 III lipid syndrome and compare high intensity anticoagulation with warfarin (to achieve an INR of 3 or more) with or without low dose aspirin to low intensity anticoagulation (INR < 3) and report that high intensity treatment is needed for optimal risk reduction. Basically, lifelong intensive anticoagulation would be needed. Over the years, a severe adverse event related to treatment will almost be a certainty and whether this risk is reasonable theoretically to reduce the chance of a second ocular event we believe is quite questionable. The risk benefit ratio ought to be determined by the systemic issues and we would give much less weight to the ocular issues. We believe the decision whether patients with retinal vascular disease should be anticoagulated should be left to the hematology consultant for the systemic management

of their disease.

Unlike the management of antiphospholipid syndrome, which to us seems to involve significant ongoing risks, hyperhomocysteinemia may be reduced with small doses of folic acid [13, 21]. Although we doubt most ophthalmologists should be prescribing these things for their patients, we assume the long term risks of folic acid should be less than anticoagulation with coumadin and aspirin and if recommended by the consulting hematologists, should be considered based on less certain data than we would want to have than for the treatment of the antiphospholipid syndrome.

Lastly, the ophthalmologist ordering tests for AT III, protein C and S should expect an extremely low yield of positive results coming back. Whether those deficiencies are associated with RVOD in adults has yet to be established. If by any chance a patient would show such deficiency, the management of the systemic components of the disease should be addressed by referral to a specialist familiarized with this type of disorder.

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