Case 197: Improvement in Claudication and Penile Function... Study of Plasminogen Activator Inhibitor and Nitric Oxide Levels.

Born 5/16/25, this gentleman was referred for inclusion in a study on male potency that was initiated because many of our male boot patients have offered the information that their erectile capacity had improved during the course of their boot therapy for their various leg ailments. This patient had obesity, insulin-dependent diabetes, hyperlipidemia, a past history of smoking, chronic pulmonary disease, angina and claudication in addition to his impotency. His daily medication list included 78 units of NPH insulin, Elavil 25 mg at bedtime, Lanoxin 25 mg, Lipitor 10 mg, Lasix 20 mg and Klorcon 10 mEq. His leg pain interfered with sleep and daily activities. His walking capacity was limited to 1.5 lengths of our hall (the hall a 100 foot in length) before calf pain occurred and 3.5 length before the pain caused him to stop. With the use of the Regensteiner questionnaire (Regensteiner JG, Steiner JF, Panzer RJ and Hiatt WR: Evaluation of walking impairment by questionnaire in patients with peripheral arterial disease. J Vas Med and Biol 2:142-152, 1990), he estimated his walking distance score to be 0.247 and his walking speed score to be 0.565.

His ankle/arm indices were reduced at both ankles as were his pulse volume waveforms (the latter on the G scale where 1 cm = 0.5mmHg).

His Penile Brachial index was also reduced.

He was given 20 treatments with both the Long Circulator Boots and the new Penile Circulator cuff. During the treatments, both nitric oxide and plasminogen activator inhibitor levels were measured at Temple University in cooperation with Drs Mattiacci and Chen. The PAI-1 was detected by an ELISA assay that is specific for the free and latent forms. The PAI-1 that is bound to tissue plasminogen activator (tPA) is not meassured. Nitric oxide is rapidely converted to nitrate, it was estimated by measuring the sum of the nitrate and nitrite in the serum samples.

The usual levels of PAI-1 in the literature are in the 4-50 ng/ml range. Here our patient is in the low range at the start of his first treatment on day 1 and he increases progressively during the treatment and falls off slightly 30 minutes after the treatment is over. His levels rise considerably as his treatments continue. It is to be noted that the lowest pre-boot level was seen on the first day. The low value 30 minutes post booting on day 10 was thought to be collected in a wrong tube. The values at the end of the study were especially interesting; his response to booting was clearly heightened. These values are to be compared with another patient who was treated for impotence but did not have any other ailment.

Unlike our diabetic patient, this 64 year old man is healthy and plays squash regularly. His Changes in PAI-1 are in contrast to the above: His baseline values are higher and fall with boot treatment. Like the diabetic, however, a large increase was seen with treatment the last day of the study.

A rise in nitric oxide is seen with treatment initially. The values on day 4 through day 18 as above were obtained before and 30 minutes after the boot treatments. After 22 days of booting, the changes in nitric oxide with booting were minimal.

The squash player again has effects generally opposite to the diabetic patient. A fall in nitric oxide was seen with the treatment. However, like the diabetic patient, his values changes little during his treatment on the last day of his study.

The patient was walked up and down the hall outside our office before his first treatment to establish his walking capacity. He then was seated quietly on a treatment table for about 40 minutes before his baseline levels of nitric oxide and PAI-1 were drawn. He was asked to rest at least one half hour and fast on the days subsequent blood tests were drawn. In addition, he was to keep a diary of his activities. His diary was reviewed after he finished the study. We learned from his diary that he tested his walking capacity every day prior to his treatments. While he was made to rest a half hour after he entered our office, his walking may have altered his subsequent blood tests. His diary documented improvement in his leg comfort and function. After his first and second treatments, he reported no improvements. Before his 4th treatment, he walked 3 hall laps before he noted a slight stiffness in his leg and he went on to finish 4 laps. Before his 5th treatment, he noted both that he had forgotten to fast for his blood tests and that his usual stiffness and aching was gone from his legs. He received no treatments on the 6th day and noted that he had slept the night for the first time with no leg discomfort and was walking pretty well. On the 7th day, he noted he had another night sleep without discomfort and that he managed 3 good laps in the hall before experiencing tightness in the left calf and upper thigh.... On day 9, he noted that he went to a shopping mall and did losts of walking at an easy pace without experiencing any discomfort. On day 10, he found his hall walking easy until the 4th lap...On day 13, he noted his walking was continuing to improve, that he had a strange sensation in his left shin and in his toes, but that he noted no changes in his penile function...On day 15, he noted a warm and tingling sensation in his calf and shins and was conscious of new feeling in his toes and heel pad...On day 16, he found his hall walk comfortable and extended his activities to include walking, shopping and hitting a small bucket of golf balls, all with none of the usual leg discomforts... On day 17, he found that his pain during his hall walk was dropping from his hip to his upper outer thigh... Day 18 was another day without treatments. He reported doing a good deal of walking with no appreciated discomfort... On day 19, he noted he had a deep sleep through the night with no medications. He again was aware of a warm tingling feeling in the lower legs but no noticeable change in his penile area... On day 20, he noted that he was still aware of a tight feeling in his ankle area. He called his urologist for his follow-up nocturnal tumescence study but found the monitor was not to be available until his return from his coming vacation (he never did get his follow-up study done, but the squash player did and did well as seen below)... On day 22, he found he could walk the hall 6 times before he experienced upper thigh pain in his left leg that led him to stop walking. His Regensteiner Questionnaire had improved to 0.46 for distance and to 0.71 for speed (his lung disease precluded jogging or running). How did his vascular tests do?

The ankle/arm indices and the ankle pulse volume waveforms improved during the treatments in the diabetic patient. Note that one centimeter here represents 0.80mmgHg versus 0.50mmHg above.

The penile/arm index also improved in the diabetic patient. Note here that the upstroke of the PPG waveform is steeper compared to his baseline. The squash player likewise noted an improvement in his penile brachial index, rising from 0.51 to 0.63. His penile pulse volume was 0.16 mmHg before his first treatment, 0.19 mmHg after his first treatment and 0.22 mmHg after his last treatment. In his diary, he also recorded increases of 8.3% in the length of his erection and a 20% increase in the circumference of the base of his penis.

Comments: These patients are added to hopefully help our enlistment of more patients to this study and to encourage others to do similar studies. Clinically, both of the men benefited: the diabetic improved his walking distance and his sense of well-being. With his heart and lung disease, he was unlikely to gain a robust erectile capacity. The squash player lessened his Peyronie's disease and increased his penile size and function. Their differences in nitric oxide and PAI-1 were striking, however. These differences maybe due to the extremes they represented in cardiovascular fitness. Christen et al (see our Clotting library) found leg compressions in ten healthy volunteers produced no changes of t-PA or PAI-1 antigens. Comerota et al compared normal volunteers with postthrombotic patients. They found a striking elevation in fibrinolytic activity was noted at 180 minutes with all devices in both groups. However, baseline and stimulated fibrinolytic activity was attenuated in postthrombotic patients. They found an increase tPA-activity only in normal subjects, despite a decrease in plasma tPA-Ag, which was observed in both normal subjects and patients. PAI-1-Ag decreased in both normal subjects and patients with a marked reduction in PAI-1-Act in both normal subjects and patients. They concluded that stimulation of endogenous fibrinolytic activity occurs after IPC, both in normal subjects and postthrombotic patients; however, baseline and overall fibrinolytic response in postthrombotic patients is reduced. The mechanism of increased fibrinolytic activity, they thought, is likely because of a reduction in PAI-1, with a resulting increase of tPA activity. Gruden et al compared fibrinolysis in type-1 diabetics with and without microalbuminuria. They found increased levels of PA1-1, factor VII and fibrinogen in the patients with microalbuminuria. Our diabetic patient likely shared these characteristics. Jacobs et al studied fibrinolytic consequences of intermittent pneumatic compression again in normal volunteers. They obtained serial blood samples via femoral venous catheters. Catheter placement caused elevations in PAI-1 and tPA-PAI, which stabilized within 4 hours of catheter insertion. During leg compression, they found significant increases in fibrin degradation products, fibrinogen degradation products, and tPA-PAI and decreases in euglobulin lysis time and PAI-1, all of which quickly reverted to baseline on termination of compression. Kosir et al. studied fibrinolysis in postoperative patients receiving either heparin or compression boot therapy. t-PA antigen levels rose from baseline on POD 1 in both groups, with a return toward baseline by POD 7. The PAI-1 levels increased on POD 1 in both groups, but several fold more in the group on compression devices. The elevation in PAI-1 decreased by 50% in the compression group by POD 7, while values returned to normal in the heparin group. Both groups showed an enhanced fibrinolysis by elevation in t-PA antigen and D-dimer on POD 1, as expected when fibrinolysis occurs. Tarnay TJ et al demonstrated that intermittent calf compression increased fibrinolytic potential locally and this effect could be demonstrated systemically. The greater the volume of tissue compressed, the greater the response. Taken together these references suggest that the stimulus of pumping both legs would be adequate to produced large changes in fibrinolytic activity, that technique in obtaining the samples makes a difference, that different results might be obtained in normal people as opposed to those with advanced vascular disease and that PAI-1 might be a good test to follow. We obviously need more patients and it would be helpful to follow a test like the euglobulin lysis time to document actual fibrinolytic effects. Our variations in nitric acid may be decreased with a more steady diet... but to adhere to a steady diet over 4 weeks may be a lot to ask of patients. As it turned out, the introduction of Viagra killed our study; patients preferred the convenience of pill to a boot program.