Dose dependent suppression of mineralocorticoid metabolism by different heparin fractions

THROMBOSIS RESEARCH 66; 467-473,1992 0049-3646/92 $5.00 + .OO Printed in the USA. Copyright (c) i 992 Pergarnon Press Ltd. All rights reserved.

DOSE DEPENDENT

M. SIEBELS’,

SUPPRESSION

K. ANDRASSY’,

OF MINERALOCORTICOID FRACTIONS

P. VECSE13, H.P. SEELIG4,

METABOLISM

T.BACK’,

BY DIFFERENT

P. NAWROTH’,

HEPARIN

and E.WEBER3

Department Medicine’, Department of Neurology2, Department of Clinical Pharmacology3, University Hospital, 6900 Heidelberg and Institution of Immunology4, 7500 Karlsruhe, Germany

(Received 30.9.1991 accepted in revised form 10.12.1991 by Editor H. Graeff) (Received by Executive Editorial Office 20.3.1992) ABSTRACT One neglected side effect of heparin therapy is the inhibition of adrenal aldosterone production leading to occasionally life-threatening hyperkalaemia. This is only reported with (therapeutic) high doses (2 20.000 IU). The complex interplay of mineralocorticoid metabolites was studied in 29 subjects with unfractionated (UFH) and low molecular weight heparin (LMWH). Both heparins altered mineralocorticoid metabolism in a dose dependent manner. Whereas no effect was observed with UFH 2x5000 IU se/day or LMWH 2500 a FXa U sdday, higher doses significantly suppressed aldosterone and 18-hydroxycorticosterone production in plasma and urine. Three out of seven patients receiving UFH 3x7500 IV SC/day developed hyperkalaemia. This study shows the threshold dosage of UFH leading to suppression of mineralocorticoid metabolism in man and provides information that LMWH as well as UFH can suppress mineralocorticoid production. With respect to therapeutic implications it is important that LMWH at 2500 a FXa U se/d had no effect on mineralocorticoid metabolism in contrast to UFH at a dosage currently used for prevention of thromboembolism (3x5000 lu sdd).

INTRODUCTION

UFH is commonly used in order to prevent or to treat thromboembolism. While bleeding, thombocytopenia, osteoporosis and cutaneous hypersensitivity are well documented complications of heparin administration (1) the inhibition of aldosterone production (2) as an additional side-effect is neglected. This inhibition may cause life-threatening hyperkalaemia (3), especially if predisposing diseases affecting the adrenals are present or if Key words: Heparin, LMWH, Correspondence:

aldosterone, hyperkalaemia.

Prof. Dr. med. K. Andrassy Department of Medicine University Hospital Bergheimerstr. 56a 6900 Heidelberg, Germany 467

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468

Vol. 66, No. 5

drugs interfering with adrenal metabolism are given simultaneously (4). Only high doses of have been shown to block aldosterone production. LMWH has not yet been tested. available on low doses of UFH (<20.000 U) and LMWH we tested the effect of various heparins on mineralocorticoid metabolism and electrolytes. The first aim of the study was to determine the threshold of UFH and LMWH to mineralocorticoid The second metabolism.

metabolism. aim was to compare

equivalent

doses of UFH and

LMWH

with

UFH (~20.000 NJ) Since no data are low doses of both exert

an effect on

regard to aldosterone

Material and Methods Protocol After approval by the ethical committee of the faculty of Medicine (University of Heidelberg) the study was performed on 29 participants (16 male, 13 female). Renin and glucocorticoid production were stimulated by physical work or with furosemide (40 mg iv). Blood samples for measurement of basal adrenal metabolism were always taken at the same time (8:00 h, the nadir of daily cortisol-secretion), after 1 hour of recumbent posture. The study was organized according to the following groups:

TABLE 1 Organisation of groups

n=

mean age

median weight(kg)

(range/kg)

Al 2x5000 A2 3x5000 A3 3x7500

UFH scfd+ UFH sdd UFH sdd

8 7 7

25 59 62

74 72 78

69-81 60-95 70-86

Bl 1x2500 B2 1 x5000

LMWH LMWH

8 7

25 53

74 75

69-81 68-84

sdd* se/d

*In group Al and Bl the same participants (students) were used. A wash-out period of 7 days was sufficient for all parameters to recover to baseline. Al and Bl served as basis for the consecutive studies. The lowest doses tested (i.e. group Al-2x5000 IE.Id UFH and group Bl-1x2500 a FXa U/d LMWH) are not established as effective anticoagulant therapy. Hence our ethical committee requested those dosages to be tested in volunteers. Higher doses of heparin (3x5000/3x7500 NJ/d UFH and 1x5000 a FXa U/d LMWH) are possibly associated with bleeding or other complications. Therefore we could not perform these experiments in volunteers according to the standard ot the ethical committee of the University of Heidelberg. A placebo group was not possible because in groups A2-A3 and 82 a clear necessity of heparin prophylaxis was given. In addition the results of mineralocorticoid metabolism in our patients before heparin therapy were (due to our exclusion criteria) identical to a healthy population (5). Because the possible complications of heparin therapy occur in the clinical situation we did not perform our study in volunteers, but rather in a carefully selected group of patients (mostly with neurological disorders, except stroke) with established criteria for heparin prophylaxis. Since several diseases and drugs are known to interfere with mineralocorticoid metabolism the following exclusion criteria were used: post operative state, hypertension, present or past hemostatic disorders, acute thromboembolism, allergy against heparin, dehydration, intake of spironolactone, steroids, beta-blocker, angiotensin converting enzyme-inhibitors or diuretics and also any invasive procedures during the study. Patients at risk to develop hyperkalaemia, diabetes mellitus or renal insufficiency were also excluded according to the guidelines of the ethical committee. Therefore from originally 52 participants, 23 were excluded. Heparin was administered by one investigator (MS) to prevent problems arising with different application techniques. All participants in the study received a standardized hospital diet.

Vol. 66, No. 5

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In all groups heparin was given for 4 days. LiqueminR (Roche, Crenzach, Germany) was used as UFH and FragminR (KABI, Erlangen, Germany) was used as LMWH (the units are calibrated against the 1 st. International LMWH standard). At days 0 and 4 the following parameters were analyzed in plasma: aldosterone, I& hydroxycorticosterone (180HB), cortisol (F), corticosterone (B) and renin, all determined as described (5-8). At days 0, 3 and 4 the following parameters were analyzed in urine: 180HB (9), aldosterone-18glucuronide (aldo-ER) (9), tetra-hydroaldosterone (TH-aldo) (9), cortisol (7), corticosterone (7), electrolytes and creatinine (24-hour collection). Serum and urine electrolytes, creatinine and blood count were measured by routine automated laboratory techniques. Antithrombin Ill was determined with an amidolytic method (S 2238 of KABI) (10). Anti-F-Xa activity was measured as inhibition of F-Xa with the chromogenic substrate S 2222 from KABI (11). Statistical analysis Significance

was tested by the t-test for paired samples, p< 0.05 was accepted.

RESULTS The effect of heparin

was measured as inhibition

of F Xa in all participants

significant change in antithrombin Ill during the study. Body weight, sex and age were comparable in the main groups studied.

(data not shown). Body weight

There was no

remained

constant

during the study. The different parameters reflecting mineralocorticoid metabolism followed the same pattern during heparin treatment: while the lowest concentration of UFH (2x5000 IU) and LMWH (lx2500 a FXa U) had no significant effect, a certain tendency to lower levels after 4 days of application on mineralocorticoid markers was noticed, increasing doses led to significant impairment of plasma aldosterone (Fig. 1) and 180HB (Fig. 2).

UFH

UFH 3x5000 NJ/d n=7

UFH 2x5000 IU/d n=8

LMWH

LMWH

3x7500 IU/d n=7

1 x2500 IU/d n=8

11x5000 N/d

p(O.00 1

I

0

0

p(o.001

n=7

I

p(o.02

ii Fig.1

Effect

of

heparin

(mean

+SD)

a,fter

on 4

4

basal plasma days

of

alcloeterone

application

Cevele

4 days

470

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i

n-8

n-7

n=7

n=8

LMWH 1x5000 NJ/d

LMWH 1 x2500 NJ/d

UFH 3x7500 NJ/d

UFH 3x5000 NJ/d al

n=7

p(O.002

p(O.002

p(O.OOrn

A-

I

I

_I-

1 4

Fig.2

\ I

-

4

0

Effect

of heparin

levels

(mean

i

-

-r

0

on banal plaema

-r

ti

4

0

0

18-hydroxgcorticoeterone

LSD) a$tar 4 day8 of applicati

After stimulation of the mineralocorticoid balance with 40 mg iv of furosemide (or by physical work) the same effect of heparin was observed (Table 2) as without stimulation, indicating that heparin did not increase stores of mineralocorticoids, which might be released after furosemide stimulation. Evaluation of renin levels demonstrated success of stimulation (p
TABLE 2 Effect of heparin (mean +SDj.

on stimulated

day:

plasma aldosterone,

aldosterone 4

0

- 18-hydroxycorticosterone

and - renin levels

18-OH-B 0

renin 4

0

4

Al UFH 2x5000 IU/d

18.4 27.8

1 2.6a +2.3

60.1 +I 9.3

55.5a f25.1

8.7 22.1

11.3 k4.8

A2 UFH 3x5000 NJ/d

14.3 f7.0

8.3d k4.0

75.8 k26.1

59.G k25.2

5.1 24.6

6.1 k6.5

A3 UFH 3x7500 Iu/d

15.8 26.2

9.6d +4.8

66.9 k27.2

43.ad *31 .a

7.1 56.6

8.0 +I 2.6

Bl LMWH 1 x2500 a FXa U/d

17.5 k3.8

13.0a +6.1

62.5 213.4

57.aa k19.7

a.7 f3.5

7.5 k3.6

B2 LMWH 1x5000 a FXa U/d

20.6 28.4

1 2.8b k6.8

63.8 +I 6.8

42.8d +a.9

3.9 k3.3

4.2 t3.2

(a: ns, b: ~~0.02,

c: p
Consistent with a block in mineralocorticoid metabolism caused by increasing doses of heparin, Figs. 3 and 4 show the effect of UFH and LMWH on the urine markers TH-aldo and 180HB which were decreased.

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Vol. 66, No. 5

UFH

UFH

UFH

2x5000 IU/d n=8

3x5000 IU/d n-7

LMWH

3x7500 IU/d n=7

p(O.05

471

1 x2500

LMWH

NJ/d n-8

5000

p(O.05

p(O.05

L

Ii

0

4

Fig.3

0

heparin

Effect

of

(mean

+SD)

I

II

n=8

t

4

on urine

0

0

4

4

tetra-hyd+ozyaktoetgne

dags

lweb

after 4 daye of application

UFH 3x5000 IU/d

UFH 3x7500 NJ/d

n=7

LMWH x2500

n=7

p(O.002

PP.0

LMWH

N/d

I x5000

n=8

NJ/d

n=7

1

I

p(O.001

I

12 4 --

I

f 1

NJ/d n=7

I--

1 -.

I -.

O-

7

0

-

Fig.4 Effect (mean Serum

potassium

-

4

levels did

7

4

0

of heparin

SD)

after

not change

-

7

0

on urine

0

-

‘T-

4

IB-hydrozycorticoeterone

0

i

-

i

4 days

levels

4 daya of application significantly

in the different

groups;

however,

417 patients

in the

3x7500IU group showed a rise in potassium from 3.7 mmol/l (range 3.4-4.0) on day 0 to 4.5 mmol/l (range 3.9-5.0) on day 4. Neither plasma nor urine B and F were affected by heparin with all doses, indicating that heparin does not block 11 -hydoxylase. The data indicate that the threshold differs with respect to the different heparins used: for UFH the threshold was 3x5000 IU, whereas for LMWH no effect was seen with 1x2500 a FXa U. 1x2500 a FXa U LMWH, which is sufficient for prevention of thromboembolism (12), does not affect mineralocorticoid metabolism, whereas the lowest dose of UFH (3x5000 IU) affects mineralocorticoid metabolism on all levels (plasma, urine, unstimulated and stimulated) tested in this study.

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Discussion Since the sixties (13) it is known that heparin interferes with adrenal metabolism. Animal experiments demonstrated that this inhibition was dependent on dosage and time (14). The maximum of inhibition was reached at 4-5 days after heparin application and it lasted up to 7 days until the inhibitory effect was lost, as evaluated by investigation in man (15). The adrenal zona glomerulosa is the target area of heparin. Steroidgenesis at the l&hydroxylase step is suppressed (4). This suppression is demonstrable in primary as well as in secondary hyperaldosteronism (15,16). Given over a period of several years heparin causes an atrophy of the zona glomerulosa (3). The consequent hypoaldosteronism may result in hyperkalaemia in patients predisposed to impairment of adrenal aldosterone production. Such a predisposition is likely in patients suffering from diabetes mellitus or renal insufficiency. Hypoaldosteronism is also observed in patients receiving drugs interfering with mineralocorticoid metabolism, i.e. potassium-sparing diuretics, non-steroidal anti-inflammatory drugs or ACE inhibitors. Regarding the increased use of ACE inhibitors it is of note that the concomitant use of heparin as a possible cause of hyperkalemia has not been mentioned hitherto among precautions or warnings of these drugs. It is easily understandable that the elderly are particularly prone to this complication. It is remarkable that in those patients receiving 3x7500 IU UFH/day, 4 out of 7 developed a distinct rise in serum potassium levels. Up to now, the critical heparin dosage resulting in electrolyte imbalance in man was unknown. Only one study (17) claimed UFH to provoke hypoaldosteronism in a dosage of 2x5000 IU/day. However, the methods used in that study are insufficient, because steroid markers other than aldosterone were not measured and the values obtained for plasma and urine aldosterone in volunteers do not correspond with other studies (12). According to our study a critical UFH dosage of 15.000 IU/day in patients with normal body weight leads to hypoaldosteronism. Hypoaldosteronism is also seen when LMWH is administered, but only in doses used for high risk patients (> 5000 a FXa U/day). With a usual dosage of 2500 a FXa U/day for the prevention of thromboembolism thisside effect is not observed. The basal steroid levels in group Al and Bl are lower than in the other groups. This could be explained by the differences in age (Table 1). However, these differences do not affect the conclusions based on Figs. l4, since the stimulated values confirm the effect of heparin on the baseline levels of steroid metabolites (Table 2). No difference in the mechanism of aldosterone inhibition by UFH or LMWH was found; however, at doses sufficient for prevention of thromboembolism only UFH, but not LMWH, suppressed aldosterone. This might be another argument for the preference of LMWH over UFH as a thrombosis prophylactic agent.

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Enke Verlag 1975.

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