Microplasmin Intravitreal Administration

in Patients with Vitreomacular Traction

Scheduled for Vitrectomy
The MIVI I Trial
Marc D. de Smet, MDCM, PhD,1 Arnd Gandorfer, MD,2 Peter Stalmans, MD, PhD,3 Marc Veckeneer, MD,4
Eric Feron, MD,4 Steve Pakola, MD,5 Anselm Kampik, MD, PhD2

Purpose: To evaluate the safety and preliminary efficacy of 4 doses and several exposure times of
intravitreal microplasmin given before pars plana vitrectomy for vitreomacular traction maculopathy.
Design: A multicenter, prospective, uncontrolled, dose-escalation, phase I/II clinical trial.
Participants: Sixty patients enrolled into 6 successive cohorts.
Intervention: A single intravitreal injection of microplasmin at 1 of 4 doses (25, 50, 75, or 125 ␮g in 100 ␮l)
administered either 1 to 2 hours, 24 hours, or 7 days before planned pars plana vitrectomy.
Main Outcome Measures: For safety, a complete ophthalmologic examination, fundus photography, fluo-
rescein angiography, Humphrey visual fields, and electrophysiology; for efficacy, posterior vitreous detachment
(PVD) induction as assessed by B-scan ultrasound and ease of PVD induction at the time of vitrectomy.
Results: The use of microplasmin led to a progressively higher incidence of PVD induction on ultrasonog-
raphy with increasing time exposure. A PVD before surgery was observed with 25 ␮g microplasmin in 0, 2, and
5 patients with increasing exposures (2 hours, 24 hours, 7 days). With increasing dose, a PVD before surgery was
observed by ultrasound as follows: 25 ␮g, 0; 50 ␮g, 1; 75 ␮g, 2; 125 ␮g, 3. However, at surgery, with a 125-␮g
dose, these patients had a discontinuous layer of vitreous present on the retinal surface resulting from the
induction of an anomalous PVD in the form of vitreoschisis. One retinal detachment developed shortly after
administration of microplasmin. Two developed after surgery. There were no other safety concerns.
Conclusions: Results from this initial clinical trial evaluating intravitreal microplasmin show the drug to be
well tolerated and capable of inducing a pharmacologic PVD in some patients. These results warrant evaluation
of microplasmin in larger, controlled trials.
Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.
Ophthalmology 2009;116:1349 –1355 © 2009 by the American Academy of Ophthalmology.

Traction at the vitreomacular interface is a major contribu-
tor to macular dysfunction.1 Fluid shifts generated by eye
movement exert tractional forces on the fovea that can lead
to the development or progression of macular holes or
cystoid macular edema.2,3 When this tractional vitreous is
relieved either spontaneously or by means of a surgical
intervention, resolution or significant improvement in vision
may occur.4,5 However, surgery can lead to localized macu-
lopathy,5,6 whereas incomplete vitreous separation can
cause disease progression.7,8 An enzyme that could facili-
tate peeling of the posterior hyaloid would help to minimize
surgically induced trauma and would provide a more uni-
form retinal surface.
Several enzymes have been tested as vitreolytic agents
in experimental models. These include hyaluronidase,
dispase, chondroitinase, plasmin, and microplasmin.9 –14
In patients, plasmin enzyme has received considerable
attention, and reported surgical series have shown prom-
ising results.15,16 Plasmin, a serine protease, hydrolyzes a
variety of glycoproteins, including laminin and fibronec-
tin, which are both present at the vitreoretinal interface,
and these are thought to play an important role in vitreo-
retinal attachment.17,18 Plasmin does not degrade colla-
gen type IV, a major component of the basement mem-
brane and the internal limiting membrane (ILM). Thus, it
potentially allows for the separation of the posterior
hyaloid without damaging the ILM or retina. Unfortu-
nately, plasmin enzyme is not yet available for clinical
use, despite being promoted for more than 10 years as a
promising vitreolytic agent. Several issues were raised
with regard to the production of an autologous product,
including stability, sterility, and biologic activity. Being
highly autolytic, plasmin enzyme requires activation im-
mediately before intraocular injection.19,20

© 2009 by the American Academy of Ophthalmology ISSN 0161-6420/09/$–see front matter 1349
Published by Elsevier Inc. doi:10.1016/j.ophtha.2009.03.051
 Ophthalmology Volume 116, Number 7, July 2009
An alternative approach to the use of autologous plasmin
enzyme is to use a recombinant product. Study of plasmin’s
molecular structure reveals that it is composed of a small
catalytic domain close to the C-terminal end and a number
of binding domains called kringles, which help it to bind to
substrates but which are not essential for its function.21
Microplasmin (ThromboGenics NV, Leuven, Belgium), a
recombinant product, contains plasmin’s catalytic domain
and shares the catalytic properties of human plasmin.22 It is
highly characterized when supplied in a stabilized form,
which simplifies storage and administration. Tests con-
ducted in pig, cat, and human eyes have shown that it
consistently can produce a posterior vitreous separation,
leaving a smooth retinal surface at doses of approximately
125 ␮g.23,24 Preclinical toxicology studies were conducted
by the manufacturer before clinical evaluation. In several
animals models, including the rabbit, mini-pig, and monkey,
side effects were limited. Based on these results, approval
was obtained to conduct a first human trial in patients with
evidence of vitreomacular traction in whom surgery was
anticipated to test the safety of microplasmin both by dose
escalation and by increasing time of exposure.
Patients and Methods
In this phase IIa study aimed at assessing the safety of recombinant
microplasmin intravitreal administration and at obtaining an early
indication of possible efficacy, 60 patients were studied, divided
into 6 groups each containing 10 patients. In all patients, surgery
was performed at a predetermined time after the drug was injected
in mid vitreous. All patients were injected with microplasmin. The
study was designed to include 2 phases. In the first phase, a time
escalation phase, a fixed dose of microplasmin (25 ␮g in 100 ␮l)
was injected at specific times before surgery (1–2 hours, 24 hours,
7 days). In the second phase, dose escalation (50, 75, and 125 ␮g),
microplasmin was injected 24 hours before surgery. All patients
were 18 years or older. They had vitreomacular traction (diabetic
macular edema, vitreomacular traction syndrome) or stage II or III
macular hole of less than 6 months’ duration since the onset of
symptoms. Vitreomacular traction was demonstrated before sur-
gery in all study eyes using either optical coherence tomography
(OCT) or B-scan ultrasound. On OCT, the presence of a distinct
posterior hyaloid membrane inserting on the retinal surface with
some areas of separation between the retinal surface and the
membrane was considered evidence of macular traction. The B-
scan ultrasound results were considered positive if there was
evidence of vitreous strand insertion onto the macula on static and
dynamic imaging. All patients were required to give informed
consent. The study was approved by the institutional review boards
of all participating centers. The study adhered to the tenets of the
Declaration of Helsinki. The protocol is registered with clinicaltrials.
gov under the number 2005-07-21.
In addition to the inclusion criteria described previously, pa-
tients were considered candidates only if they did not meet the
criteria listed below. Although traction was required as an entry
criterion, evidence of fibrocellular proliferation on the ILM surface
based on clinical examination or OCT (white membrane on the
retinal surface) was a cause for exclusion. Patients were excluded
for poor media hampering visualization of the posterior pole or
for preventing adequate assessment by OCT. Patients also were
excluded from the study if they had a history in either eye
of rhegmatogenous detachment; proliferative vitreoretinopathy
(PVR), myopia beyond –5 diopters, or significant peripheral retinal
1350
degeneration in the study eye (such as lattice degeneration of more
than 1 clock hour); or if they had a history in the study eye of a
prior vitrectomy at any time, surgery or laser photocoagulation in
the previous 3 months, or an intravitreal injection in the previous
6 months. Patients with a history of uveitis, significant ocular
trauma, or glaucoma uncontrolled by ocular hypotensive agents in
the study eye were not allowed to participate. Poor health (life
expectancy of less than 6 months), uncontrolled hypertension or
hemoglobin A1C of more than 9%, and participation in another
investigational trial were additional reasons for exclusion.
Before the injection of microplasmin, each patient underwent a
baseline series examination consisting of a complete ophthalmo-
logic examination (Early Treatment Diabetic Retinopathy Study
best-corrected visual acuity, applanation tonometry, slit-lamp ex-
amination of the anterior segment with particular attention to
inflammation in the anterior chamber assessed using a scale from
0 to 4 for cells and flare modified from Hogan and Kimura,25
cataract score using the Lens Opacities Classification System III
scoring system, dilated fundus examination with a graded assess-
ment of vitreous haze),26 fundus photography, fluorescein angiog-
raphy (using the 7 fields from the Early Treatment Diabetic Ret-
inopathy Study), OCT (OCT3, Zeiss, Jena, Germany), B-scan
ultrasound, and electrophysiology (electroretinogram, visual evo-
ked potential, electroculogram).
Because the main objective of the study was to determine
safety, several additional ocular examinations were scheduled be-
fore surgery when logistically possible. In the third cohort, an
ophthalmologic examination was scheduled after injection, at 24
hours (⫾6 hours), 3 days (⫾1 day), and 7 days (⫾2 days). This
examination included a complete ophthalmologic examination as
described above, OCT, and B-scan ultrasonography. Surgery was
carried out using 20-gauge cannulas in all patients. The surgeon
was not blinded to the fact that patients had received an intraocular
injection of microplasmin. They also were not blinded to the dose
given. During the postoperative period, patients were seen on days
1 and 3, approximately day 7, day 14, day 28, and at 3 and 6
months. At each visit, a complete ophthalmologic examination was
to be carried out as was possible based on the ocular condition
(except for vision assessment in the immediate postoperative set-
ting in patients injected with a gas bubble). Optical coherence
tomography was performed from day 14 onward when possible.
Electrophysiologic tests were performed on days 7 and 28. If
results were abnormal on day 28, the tests were to be repeated at
subsequent visits until the results normalized. If vision at the
3-month visit dropped by 10 Early Treatment Diabetic Retinopa-
thy Study letters as compared with baseline, a fluorescein angio-
gram was scheduled to assess the macula more fully with a repeat
examination at 6 months.
Treatment was allocated on a sequential basis starting at the
lowest dose with the shortest exposure. For each treatment group,
after the allocation of the first patient, an observation period of 2
weeks after surgery was imposed to allow for observation of any
untoward events. The clinical data and reported adverse events (if
any) were reviewed by a safety committee consisting of 2 of the
investigators (MdS, AK), 1 independent ophthalmologist, and a
nonvoting company physician working for ThromboGenics, Ltd.
Continued enrollment was allowed when unanimous agreement
was obtained from the data safety committee. After enrolling the
last patient in a cohort, a second safety committee meeting was
organized to review the data, no earlier than 2 weeks after the last
surgery. The committee was asked to approve enrollment in the
following cohort for which an identical approach was used to
monitor safety.
The injection procedure was as follows. Frozen microplasmin
was thawed immediately before use and was diluted to the appro-
priate concentration with ice cold balanced salt solution plus
 de Smet et al 䡠 Microplasmin MIVI I Study

(BSS⫹; Alcon, Fort Worth, TX). Using a 30-gauge needle, 0.1 ml

of the appropriate solution was injected through the pars plana into
the mid vitreous of the study eye. Time between reconstitution and
injection was kept to a strict minimum, always less than 15
minutes.
A secondary objective consisted of obtaining preliminary effi-
cacy data. For this purpose, preoperative sequential B-scan ultra-
sound and OCT examinations were used, as well as perioperative
observations. The surgeon was asked to assess the presence or
absence of a complete posterior vitreous detachment (PVD) at the
onset of surgery. If not present, the ease with which a PVD could
be induced was determined using a grading scale meant to assess
the degree and duration of mechanical manipulation required to
induce a PVD. In these cases, the surgeon applied suction with the
vitrector set at 40 mmHg for 30 seconds; if this did not result in a
complete PVD, suction at 80 mmHg was applied for an additional
30 seconds, followed by suction at 120 mmHg for a further 30
seconds. If a complete PVD still was not achieved, the surgeon
was allowed to proceed with his or her conventional techniques
and machine settings for complete vitreous removal, with or with-
out the use of instruments to separate the posterior hyaloid me-
chanically. Before including the first patient, surgeons were asked
to develop a certain proficiency in assessing PVD induction by
using this approach in at least 4 patients during routine surgery.
All data were recorded on case report forms and checked for
accuracy. Group comparisons were made using the Kruskal-Wallis
test. Statistics on the whole patient population were done with the
Wilcoxon rank-sum test or the Mann-Whitney U test where ap-
propriate. Rates for cataract development were compared with
historical series, as was the rate of spontaneous PVD.
Results
Sixty (23 male and 37 female) patients with an average age of 65
years (median, 66 years; range, 43– 83 years) were included in the
study. Gender distribution was equal in all cohorts except in
cohorts 5 and 6, where there was a predominance of women over
men (8 in cohort 5 and 8 in cohort 6). Twenty-six patients had a
macular hole (stage 1, n ⫽ 1; stage 2, n ⫽ 9; stage 3, n ⫽ 16);
diabetic macular edema was present in 13 patients; and in 21
patients, vitreomacular traction syndrome was not associated with
any other condition. Thirty-five of the 60 patients had evidence of
macular edema at the time of study entry. Demographic data and
group assignments are summarized in Table 1. Because of the
timing of enrollment of individual patients relative to the transition
between cohorts, 11 patients were included in group 5, and only 9
were in group 6. The study was completed successfully to 6
months by 58 patients. In 1 patient, a pancreatic carcinoma devel-
Figure 1. Graph showing the percentage of patients achieving a posterior
vitreous detachment (PVD) with increasing time exposure to microplas-
min (fixed dose 25 ␮g).
oped, and the patient could not complete all scheduled follow-ups.
The other patient withdrew from the study after a recurrent retinal
detachment developed.
The use of microplasmin leads to an apparent higher incidence
of spontaneous PVD with increasing exposure time (Fig 1). Spon-
taneous PVD was observed in 5 of the 10 patients treated with 25
␮g microplasmin 7 days before vitrectomy (cohort 3), the longest
exposure time evaluated in the study. In these patients, PVD
appeared between days 3 and 7. Increasing dose led to an increase
in the perceived number of patients achieving a PVD as assessed
by B-scan ultrasound before surgery (cohort 2, n ⫽ 0; cohort 4,
n ⫽ 1; cohort 5, n ⫽ 2; cohort 6, n ⫽ 3). For cohorts 4 and 5 (as
in cohorts 1 and 3), these same patients at surgery were believed
to have had a complete PVD. In cohort 6, the patients were found
to have had an incomplete dehiscence of the vitreous from the
optic nerve. Removal of the remaining thin layer of vitreous
required 80, 120, and 250 mmHg of suction, respectively, using
the vitrector. Staining with fluorescein dye in 2 patients confirmed
the existence of a thin discontinuous layer of vitreous adjacent
to the retinal surface. When engaged, it peeled off the retina (Fig 2,
available at http://aaojournal.org). Figure 3 shows that the induc-
tion of a PVD seemed to be easier at higher doses compared with
the 25-␮g dose. Taking account of an anomalous PVD in 3 patients
at the highest dose (Fig 3B) more clearly shows this association. In
all patients, a PVD could be induced.
Patients tolerated the intravitreal injection procedure well.
Some patients in cohorts 2 and 3 noted the development of floaters

Table 1. Patient Demographics and Associated Vitreomacular Pathologic Features

Cohort 1* Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6

Gender, male:female 5:5 4:6 5:5 5:5 3:8 1:8
Age (yrs)
Mean (range) 63 (44–79) 65 (55–72) 65 (55–77) 66 (43–83) 65 (50–73) 63 (54–77)
DME 1 5 4 1 2 0
VMTS 4 3 5 5 6 5
Macular hole 5 2 1 4 3 4
Stage I:II:III 0:1:4 0:1:1 0:1:4 0:1:3 0:2:4 1:1:2

DME ⫽ diabetic macular edema; VMTS ⫽ vitreomacular traction syndrome.

*Cohort 1, 25 ␮g 1–2 hour; cohort 2, 25 ␮g 24 hours; cohort 3, 25 ␮g 7 days; cohort 4, 50 ␮g 24 hours; cohort 5, 75 ␮g 24 hours; cohort 6, 125 ␮g 24
hours.

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 Ophthalmology Volume 116, Number 7, July 2009
Figure 3. Graph showing the percentage of patients achieving a posterior
vitreous detachment (PVD) with increasing dose of microplasmin (given
24 hours before surgery). A, Data are presented as reported in the surgical
file. B, Data are presented taking into account the B-scan ultrasonography
findings. If a posterior vitreous detachment was present on ultrasound, the
patient was reported as not requiring any suction.
in the first few hours and up to 2 days after the injection of
microplasmin. In 1 patient, photopsias developed 6 hours after a
25-␮g dose of microplasmin. On his day 1 postinjection visit, a
small tear close to the vitreous base was noted in the 10-o’clock
meridian associated with a retinal detachment in the supertemporal
quadrant involving the macula. At surgery a few hours later, the
vitreous was found still to be attached firmly to the retinal surface.
An incomplete PVD was present extending only to the arcade, with
residual attachment to the optic nerve. The site of microplasmin
injection had been in the inferotemporal quadrant. A week later,
the patient sustained a redetachment with a 4-clock hour tear
inferiorly along the vitreous base. The detachment was repaired
successfully with silicone oil.
With the induction of a PVD at surgery, small peripheral retinal
tears were created in 7 patients (cohorts 2, 3, 5, and 6, n ⫽ 1;
cohort 4, n ⫽ 3). Six of these were noted on depressed examination
of the peripheral retina and were treated with either cryocoagula-
tion or laser. In 1 patient, a localized detachment developed while
inducing the PVD. This also was easily repaired using standard
surgical procedures without recurrence (cohort 5). A retinal de-
tachment occurred 1 month into the postoperative period in a
1352
patient from cohort 1 in whom proliferative vitreoretinopathy had
developed. A mild vitreous hemorrhage not obscuring the posterior
pole developed after surgery in 4 patients, each in a different
cohort. In no patient did intraocular inflammation develop related
to the injection of microplasmin. Mild anterior segment inflam-
mation was reported to have developed in 1 patient 1 month after
surgery in both eyes. The patient recovered without sequelae.
A transient rise in intraocular pressure was reported in the
initial postoperative period in 14 patients. These transient pressure
increases responded to pressure-lowering medications or discon-
tinuation of steroid drops. The median duration was 12 days
(range, 2–91 days). There was no pressure rise observed in cohort
3 (the cohort with a 7-day interval between microplasmin injection
and surgery) before surgery. A composite graph shows the distri-
bution and timing of the individual reported cases (Fig 4). Visual
field changes were found on static perimetry in 1 patient from
group 4 who had been injected with silicone oil for the treatment
of a macular hole. There was a generalized depression of the visual
field without the development of an arcuate scotoma. This partially
recovered over time. The depression was attributed to the use of
silicone oil. Glaucoma was diagnosed in another patient during the
6-month follow-up.
Visual acuity was monitored after intraocular injections and in
the postoperative period. The findings are summarized in Figure 5.
There was a general trend toward improved vision after injection
in cohort 3, and after surgery in all groups, but this was not
statistically significant at any time point (Table 2, available at
http://aaojournal.org). On OCT, a decrease in macular thickness
was noted in all patients. Macular thickness was compared be-
tween patients achieving a vitreous detachment after microplasmin
injection but before surgery (10 patients) with those requiring a
surgical induction (50 patients; Fig 6). There was no difference in
macular thickness between these 2 groups at day 180. The decrease
in thickness was more rapid in patients having achieved a spon-
taneous PVD as compared with those patients who required a
surgical peel, but was not statistically significant. In the spontane-
ous PVD group, the macula was somewhat thicker at baseline,
possibly explaining a more rapid decrease in thickness. The 5
patients in cohort 3 who achieved a preoperative PVD also dem-
onstrated a more rapid reduction in macular thickness, but did not
start off with a thicker macula than the other patients in their
cohort (Fig 7, available at http://aaojournal.org). However, these
differences, as for the group analysis, were not statistically signif-
icant. Improvements in macular thickness also were accompanied
by reduced leakage on fluorescein angiography (in those patients
with baseline fluorescein leakage), and a statistically significant
decrease in the number of patients with macular edema was noted
at day 90 (12 fewer patients) and at day 180 (15 fewer patients
from baseline; P ⫽ 0.007).
Lens Opacities Classification System III scores were recorded
at each visit in patients who were phakic (47 eyes). Changes were
observed after surgery, in particular progression of nuclear opacity
and color. No significant progressions in cortical or subcapsular
cataracts were observed (Fig 8, available at http://aaojournal.org).
There were no incidences of iridodonesis induced by the injection
of microplasmin in the study population.
Changes in electroretinograms were transient and were consis-
tent with random variations. There were no clinically significant
abnormalities at the final day 28 assessment (Fig 9). Visual evoked
potentials were compared between baseline and day 28 in 56
patients (1 missing in cohorts 3 and 4, 2 missing in cohort 5).
There were no consistent changes noted across groups. There were
no changes on the electroculogram between the preinjection eval-
uation and day 28 after surgery. No visual field changes were
observed between day 28 and the baseline examination.
 de Smet et al 䡠 Microplasmin MIVI I Study
Figure 4. Composite graph showing the intraocular pressures in patients reported to have a raised intraocular pressure at any time during the follow-up.
Discussion
This phase IIa study is the first reporting the use of recom-
binant microplasmin for intravitreal injection in human pa-
tients. Its major aim was to determine the safety of this
compound and to obtain preliminary data on efficacy. The
trial was initiated at a subtherapeutic dose based on preclin-
ical evaluations.14,23,24 Even at this low dose, with increas-
ing time, a higher proportion of patients achieved a spon-
taneous vitreous detachment. The highest number of
spontaneous PVDs was seen in patients with the longest
exposure (Fig 1). Some patients within a few hours of
injection noted an increase in floaters, but usually men-
tioned that this effect was transient. Few noted any signif-
icant change in vision, and none reported discomfort from
the injection procedure. For those patients not achieving a
PVD, increasing the suction in a stepwise fashion gave an
Figure 5. Graph showing the combined average of the Early Treatment
Diabetic Retinopathy Study (ETDRS) vision score at each data monitor-
ing time point after injection (PI) and after surgery (PO). (Error bars
correspond to the standard deviation.) D ⫽ day.
indication that a PVD was easier to induce as the exposure
time to microplasmin was extended.
Increasing the dose of microplasmin seems to facilitate
the separation of the posterior hyaloid, particularly when
assessed by using B-scan ultrasonography. B-scan ultra-
sound images obtained before surgery suggested that a
posterior hyaloid separation had occurred in 3 patients re-
ceiving the highest dose of microplasmin. In these patients,
higher suction levels were necessary to aspirate the vitreous
remaining on the retinal surface, although no residual pos-
terior hyaloid was seen (Fig 2, available at http://aaojournal.
Figure 6. Graph showing the mean macular thickness measurements from
optical coherence tomography (OCT) for all patients with or without a
spontaneous posterior vitreous detachment (PVD) at various data moni-
toring time points. (Error bars correspond to standard deviation.) D ⫽ day;
PO ⫽ after surgery. No pre-opreative PVD; Sponteneous PVD.
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 Ophthalmology Volume 116, Number 7, July 2009
Figure 9. Bar graph showing the composite electroretinogram changes in
millivolts (mV) for all patients combined at baseline versus day 7 and day
30 after surgery.
org). Because the discrepancy between the ultrasound find-
ings and the surgical findings with regard to the PVD were
present only for the highest microplasmin concentration, the
authors decided to present the results in Figure 3 as gener-
ated from the surgical record (Fig 3A) and to factor in
pre-existing PVDs as seen on B scan ultrasound prior to
surgery (Fig 3B). Of note, some of the remaining patients in
cohort 6 also required more suction to pull off the posterior
hyaloid, whereas the remaining vitreous was easily re-
moved. This behavior of the vitreous and its interface with
the retina was different than had been observed at lower
concentrations of microplasmina and suggested that vitreos-
chisis had occurred close to the retinal surface.27,28 For the
remaining concentrations, as with prolonged exposure, less
suction seems to be needed to obtain a PVD because the
concentration of microplasmin is increased.
In 1 patient with a macular hole, a retinal detachment
developed after study drug but before vitrectomy. This detach-
ment was associated temporally with the injection of micro-
plasmin. The incidence of iatrogenic retinal breaks in 7 patients
seems high, yet is in the range of published incidences for
noncannulated surgery (11% vs. 7%–14%).29 –33 In routine
practice, the case mix would include only a subset of patients
requiring so-called full PVD induction. In the current study,
patients were required to have an intact posterior hyaloid
before enrollment. In this subpopulation of patients, there is an
increased risk of developing a peripheral tear, particularly in
the lower quadrants.29 Therefore, caution is warranted when
considering pharmacologic induction of PVD. Appropriate
dose selection and perhaps longer exposure times to the drug
before surgery may minimize this risk. The highest incidence
was noted in cases where exposure was limited to 2 hours.
No increased inflammation was noted with the adminis-
tration of microplasmin, in contrast to autologous plasmin,
with which mild inflammation did develop in some pa-
tients.16 Microplasmin did not have apparent untoward ef-
fects on the lens. There was no incidence of iridodonesis,
and in no patient did a rapidly progressive cataract develop.
In keeping with studies on cataract formation after vitrec-
tomy, progression was observed mainly in nuclear sclerosis
and color.34,35 There was no significant progression in either
1354
cortical or subcapsular cataracts. Changes noted with elec-
trophysiology and visual fields were attributed to the effects
of surgery and not to the administration of microplasmin.
Certain limitations of the study should be pointed out. It
is a nonrandomized study and lacks controls. This prevents
comparing the rate of PVD induction in a controlled patient
population with the patients injected with microplasmin.
The PVD assessment is subjective in nature and is prone to
bias both from the effect of a learning curve (in applying the
stepwise suction) and from the hope of a positive effect.
Although this should have been reduced by having surgeons
practice the technique in at least 4 patients before enrolling
the first patient, it was probably not completely avoided.
Suction also might have been interpreted differently at each
site, because surgeons were not required to validate their
assessment against a specific standard.
In summary, in these first 60 patients studied, microplas-
min seems to have a promising activity profile. These ob-
servations suggest that a combination between an effective
dose and appropriate exposure time before surgery can
facilitate the development of a drug-induced PVD and fa-
cilitate its removal during surgery. Randomized studies with
appropriate controls are required to delineate further the
dose-response relationship of this drug in terms of PVD
induction.
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Footnotes and Financial Disclosures
Originally received: June 12, 2008.
Final revision: March 25, 2009.
Accepted: March 27, 2009.
Available online: May 17, 2009. Manuscript no. 2008-718.
1
Department of Ophthalmology, ZNA Middelheim Campus, Antwerp,
Belgium, and Department of Ophthalmology, University of Amsterdam,
Amsterdam, The Netherlands.
2
Department of Ophthalmology, Maximilians University Munich, Mu-
nich, Germany.
3
Department of Ophthalmology, University of Leuven, Leuven, Belgium.
4
Oogziekenhuis Rotterdam, Rotterdam, The Netherlands.
Microplasmin induced vitreolysis in porcine eyes. Invest
Ophthalmol Vis Sci 2003;44:Abstract 3050.
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5
ThromboGenics, Inc., New York, New York.
Financial Disclosure(s):
The author(s) have made the following disclosure(s):
Marc D. de Smet - consultant, patent holder, financial support
Arnd Gandorfer - consultant, financial support
Steve Pakola - employee, patent holder
Anselm Kampik - consultant, financial support
Supported by ThromboGenics, Inc., New York, New York.
Correspondence:
Marc D. de Smet, Lindendreef 1, Antwerp 2020, Belgium. E-mail:
mddesmet1@mac.com.
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 Ophthalmology Volume 116, Number 7, July 2009

Table 2. Best Corrected Early Treatment Diabetic Retinopathy Study Visual Acuity Score at Various Time Points Post Injection of
Microplasmin (Standard deviation in parenthesis)

25 ␮g 25 ␮g 25 ␮g 50 ␮g 75 ␮g 125 ␮g
1–2 hrs 24 hrs 7 days 24 hrs 24 hrs 24 hrs
Baseline 51 (⫾ 19) 55 (⫾ 13) 46 (⫾ 21) 56 (⫾ 14) 47 (⫾ 15) 51 (⫾ 16)
PI D1 53 (⫾ 12) 42 (⫾ 18) 51 (⫾ 11) 47 (⫾ 12) 49 (⫾ 16)
PI D3 49 (⫾ 22)
PI D7 48 (⫾ 24)
PO D7 57 (⫾ 14) 52 (⫾ 11) 34 (⫾ 28) 54 (⫾ 14) 37 (⫾ 24) 46 (⫾ 17)
PO D14 47 (⫾ 22) 52 (⫾ 12) 48 (⫾ 17) 56 (⫾ 16) 42 (⫾ 23) 51 (⫾ 13)
PO D28 55 (⫾ 19) 55 (⫾ 13) 56 (⫾ 9) 57 (⫾ 15) 44 (⫾ 21) 61 (⫾ 12)
PO D90 60 (⫾ 15) 58 (⫾ 15) 61 (⫾ 8) 66 (⫾ 11) 53 (⫾ 26) 61 (⫾ 7)
PO D180 60 (⫾ 13) 58 (⫾ 18) 57 (⫾ 13) 61 (⫾ 16) 46 (⫾ 21) 64 (⫾ 11)

ETDRS ⫽ Early Treatment Diabetic Retinopathy Study; PI ⫽ post injection; PO ⫽ Post surgery; D ⫽ day; hrs ⫽ hours.

Figure 7. Graph showing the mean macular thickness measurements from

optical coherence tomography for patients in cohort 3 with or without a
spontaneous posterior vitreous detachment (PVD) at various data moni-
Figure 2. Image of fluorescein-stained vitreous on the retinal surface after toring time points. (Error bars correspond to standard deviation.) D ⫽ day;
injection of 125 ␮g microplasmin intravitreally 24 hours before surgery. PO ⫽ after surgery.

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 de Smet et al 䡠 Microplasmin MIVI I Study

Figure 8. Bar graph showing the average Lens Opacities Classification System (LOCS) III scores per data monitoring point after injection (PI) and after
surgery (PO). D ⫽ day.

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