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(Circulation. 1997;96:4380-4384.)
© 1997 American Heart Association, Inc.

Articles

Hydroxychloroquine Reverses Thrombogenic Properties of Antiphospholipid Antibodies in Mice

Michael H. Edwards, MD; Silvia Pierangeli, PhD; XiaoWei Liu, MD; John H. Barker, MD, PhD; Gary Anderson, PhD; ; E. Nigel Harris, MD

From the Division of Rheumatology, Department of Medicine (M.H.E.), the Department of Surgery (J.H.B.), and the Department of Physiology (G.A.), University of Louisville (Ky); and Morehouse School of Medicine (S.P., X.-W.L., E.N.H.), Atlanta, Ga.

Correspondence to Michael H. Edwards, MD, Medicine/Rheumatology, University of Louisville, Louisville, KY 40292.

	Abstract

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Background Previous studies have demonstrated that human monoclonal and polyclonal anticardiolipin antibodies have thrombogenic properties in vivo. Using such a model in which these antibodies have been shown to increase both the size of an induced thrombus and the duration of time in which such a clot lasts, we investigated whether hydroxychloroquine alters the dynamics of such thrombus formation.

Methods and Results Three groups of nine mice were injected with purified immunoglobulin G (IgG) from a patient with the antiphospholipid syndrome (IgG-APS) and then fed with hydroxychloroquine at various doses (100, 6, and 3 mg/kg body wt). Three control groups of mice were also studied, including mice injected with IgG-APS and then fed with placebo, as well as two other groups injected with IgG from normal human serum and fed either hydroxychloroquine or placebo. A standardized thrombogenic injury was subsequently induced in the femoral vein of each mouse and the area (size) of thrombus measured as well as the total period of time that thrombus was present. Mice treated with hydroxychloroquine and IgG-APS showed significantly smaller thrombi that persisted for a shorter period of time compared with animals treated with IgG-APS and placebo.

Conclusions Hydroxychloroquine significantly diminished both thrombus size and total time of thrombus formation in mice previously injected with IgG-APS.

Key Words: thrombus • antibodies • anticoagulants • drugs • hydroxychloroquine

	Introduction

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Recurrent venous and/or arterial thrombosis, pregnancy losses, thrombocytopenia, and the presence of high levels of either anticardiolipin antibodies or a positive lupus anticoagulant test have been found in patients with the antiphospholipid syndrome (APS).¹ Recurrent thrombosis is the most threatening feature of this hypercoagulable state. Generally, such patients are treated with oral anticoagulants such as warfarin for prolonged periods of time.^{2 3 4} Several reports have suggested that patients with a known hypercoagulable state are less prone to thrombosis when treated with hydroxychloroquine.^{5 6 7 8 9} These include a few retrospective studies that have found an association between the use of hydroxychloroquine and a reduction in the frequency of thrombotic events in patients with systemic lupus erythematosus.^{9 10 11}

Currently, warfarin is generally the long-term anticoagulant of choice for patients with known APS.^{3 4} If effective, hydroxychloroquine could be a much safer alternative to warfarin as prophylaxis against thrombosis in patients with this syndrome. However, convincing evidence that hydroxychloroquine can be effective (and the mechanism by which it might work) remains unclear.

We have recently devised a mouse model of APS in which human polyclonal and monoclonal anticardiolipin antibodies have been demonstrated to increase both the size of an induced thrombus and the duration of time that the clot persists.^{12 13 14}

This study was performed to determine whether administration of hydroxychloroquine to mice preimmunized with immunoglobulin G (IgG) from a patient with APS (IgG-APS) might result in reduction of thrombus formation. Further experiments were performed to determine whether the effects of hydroxychloroquine are dose dependent.

	Methods

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Animals
Normal male CD-1 (outbred) mice weighing 30 to 40 g were purchased from Charles River Laboratories. The animals were housed in the Animal Care (approved by the American Association for Accreditation of Laboratory Animal Care) facilities at the University of Louisville. Animals were handled by trained personnel according to Institutional Animal Care and Use Committee guidelines.

Hydroxychloroquine
Hydroxychloroquine sulfate (powder form) was kindly provided by Dr Charles Nicol (Sanofi-Winthrop Pharmaceuticals; New York, NY). Hydroxychloroquine suspensions were prepared in 1% tragacanth gum suspension (Sigma Chemical Co) at the desired concentration. Three concentrations of hydroxychloroquine were used in this study: 100, 6, and 3 mg/kg body wt.

Isolation of Immunoglobulin G From an APS Patient
IgG was isolated from the serum of a patient with the antiphospholipid syndrome (IgG-APS) with the use of DEAE ion exchange chromatography as described elsewhere.¹⁵ Purity was determined by SDS-PAGE (single band at 150 kD), and the absence of contamination with ß₂GP1 was ruled out by immunoblot with a rabbit anti-human ß₂GP1 antiserum. Protein concentration was determined by the method of Lowry. After adjustment of the protein concentration with a sterile saline solution, these preparations were filter-sterilized before injections. Similarly, IgG from normal healthy controls was obtained (IgG-NHS).

Determination of Hydroxychloroquine Levels in Mouse Blood
To ensure that hydroxychloroquine was being absorbed through the gastrointestinal tract and that significant blood levels could be achieved, 0.5 to 1.0 mL of whole blood was obtained from additional groups of mice 2 hours after being fed with a variable dose of the drug. All whole blood samples were sent to the Pharmacokinetics Drug Analysis Laboratory at North Dakota State University for determination of hydroxychloroquine concentrations as described elsewhere.¹⁶

Experimental Design
To achieve high serum levels of anticardiolipin antibodies in each mouse, intraperitoneal injections of IgG-APS or equivalent amounts of IgG-NHS were administered at times 0 and 48 hours, as described elsewhere.¹²

Kinetic experiments were initially performed to determine an appropriate time that oral hydroxychloroquine should be given. Because levels of hydroxychloroquine were found to reach a plateau within 1 to 2 hours after feeding (Figure), surgery, as described below, was performed 2 hours after oral administration of the drug. This was 72 hours after the first intraperitoneal injection of IgG.

View larger version (13K): [in this window] [in a new window]   Figure 1. Pharmacokinetics of hydroxychloroquine in mice. Mice were administered orally 100 mg/kg body wt hydroxychloroquine in 1% gum tracaganth suspension, and samples of blood were drawn at the indicated times (two mice per group). The values of hydroxychloroquine in nanograms per milliliter blood represent the mean of two determinations.

Four groups of mice were studied, each group consisting of nine animals. Group A was injected intraperitoneally with IgG-APS and fed with hydroxychloroquine (100, 6, or 3 mg/kg body wt); group B was injected intraperitoneally with IgG-APS and fed with placebo (1% tragacanth gum suspension); group C was injected intraperitoneally with IgG-NHS and fed with hydroxychloroquine, and group D was injected with IgG-NHS and fed with placebo.

Determination of Anticardiolipin Antibody Levels by ELISA
Human anticardiolipin antibody levels in immunized mice were determined with an ELISA assay as described elsewhere.^{12 13 17} Alkaline phosphatase anti-human IgG sera were used as secondary antibodies in the ELISA system. The color reaction was stopped when a positive control (of 100 GPL units) reached 1.0 OD units (20 to 30 minutes). The levels of anticardiolipin antibodies were determined in GPL units by extrapolation of a curve constructed with calibrators (Louisville APL Diagnostics, Inc).

Surgical Procedure and Measurement of the Dynamics of In Vivo Thrombus Formation
To determine the dynamics of thrombus formation, we used a modification of the surgical procedure described previously.^{12 13 14 18} This procedure enables continuous and quantitative measurements of a standardized, focally induced, nonocclusive mural thrombus in a surgically exposed mouse femoral vein.

Using sodium pentobarbital (60 mg/kg IP) as anesthetic, a longitudinal incision was made in the right groin of the CD-1 mice. A standardized thrombogenic injury was produced in the vein with a standard pinch injury, as described elsewhere.^{12 13 18} A transilluminator was used to visualize the vein, and a stereoscopic operating microscope, equipped with a closed-circuit video system and a recorder, was used to visualize and observe the induced thrombus.

Measurements were made of the total period of time (minutes) that thrombus was present. Thrombus area was also measured (µm²). Three to five thrombi were induced in each animal, and mean thrombus area and time were computed for each group. The person (X.-W.L.) performing the surgery and measurements was blinded as to what treatment had been given to each animal.

Statistical Analysis
One-way ANOVA was used to compare the means of thrombus sizes and times of thrombus duration for the four groups. Tukey's honest significant difference was used for post hoc analysis of the means. Data were checked for normality with the Kolmogorov-Smirnov test. The null hypothesis of normality was not rejected.

	Results

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Effect of High-Dose Hydroxychloroquine on the Dynamics of Thrombus Formation
In the first series of experiments, a high dose of hydroxychloroquine (100 mg/kg body wt) was administered to mice previously injected with either IgG-APS or with IgG-NHS (group A and group C). Placebo was administered to control animals (groups B and D).

The animals in groups A and B, injected with IgG-APS, had high levels of anticardiolipin antibodies immediately before the surgical experiments. Mean levels of anticardiolipin antibodies in mice from both groups was >100 GPL units. Animals in groups C and D, injected with IgG-NHS, did not have detectable levels of anticardiolipin antibodies. Animals treated with hydroxychloroquine (groups A and C) had high levels of the drug in their blood at 2 hours after ingestion (Fig 1), whereas animals from groups B and D, both given placebo, showed levels <10 ng/mL (data not shown).

Animals treated with IgG-APS and placebo produced significantly larger thrombi that also persisted longer than animals treated with IgG-NHS and placebo, indicating that the IgG-APS enhanced thrombus formation, as shown previously¹² (Table 1). Thrombus size and the time that thrombus persisted in animals treated with IgG-APS and hydroxychloroquine (group A) were significantly reduced compared with animals treated with IgG-APS and placebo (group B). There was no significant difference in thrombus size and thrombus duration between IgG-NHS mice treated with hydroxychloroquine versus placebo (groups C and D). In addition, values obtained with IgG-APS–hydroxychloroquine–treated animals (group A) were not significantly different from IgG-NHS–hydroxychloroquine–treated animals (group C) (Table 1). These results indicate that a high dose of hydroxychloroquine prevented the enhanced thrombus formation associated with IgG anticardiolipin antibodies.

View this table: [in this window] [in a new window]   Table 1. Dynamics of Thrombus Formation in Mice Treated With High Doses of Hydroxychloroquine and IgG-APS

Effect of Different Doses of Hydroxychloroquine on the Dynamics of Thrombus Formation
In a second series of experiments, animals were injected with IgG-APS or IgG-NHS as before, but treated with lower doses of hydroxychloroquine (6 and 3 mg/kg). At 2 hours after administration of the drug, whole blood levels of hydroxychloroquine in mice treated with 6 mg/kg were 230 ng/mL, whereas in mice treated with 3 mg/kg, levels were 50 ng/mL. As shown in Table 2, hydroxychloroquine given at doses of 6 mg/kg to IgG-APS–injected mice was equally effective in reducing thrombus size and the time that thrombus persisted compared with mice treated with 100 mg/kg hydroxychloroquine as described above. However, with the 3 mg/kg dose of hydroxychloroquine, thrombus sizes were significantly larger compared with groups treated with 6 and 100 mg/kg of the drug, though still smaller than the group fed placebo. Total time of thrombus duration was similar in all three treated groups. Thus while the kinetics of thrombus formation was not significantly affected by the dose of hydroxychloroquine, thrombus size may be altered in a dose-dependent fashion.

View this table: [in this window] [in a new window]   Table 2. Dynamics of Thrombus Formation in Mice Treated With Different Doses of Hydroxychloroquine and IgG-APS

	Discussion

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In the mouse model reported in this study, monoclonal and polyclonal antiphospholipid antibodies have previously been demonstrated to have thrombogenic properties.^{12 13 14} In this report, hydroxychloroquine was found to significantly diminish both thrombus size and thrombus duration in mice that were previously injected with IgG-APS. This effect appears to be rapid in onset, as it was observed only 2 hours after the administration of hydroxychloroquine. On the basis of the second series of experiments, it may also be dose related. The rapidity of the drug effect may be related to the pharmacokinetics of hydroxychloroquine, as the drug is both rapidly absorbed from the gastrointestinal tract and quickly diffuses across cell membranes.¹⁹ Once in the intracellular environment, the drug becomes protonated and thereby trapped, to the extent that it is concentrated at least 20-fold in the cellular fraction of whole blood.²⁰ This is consistent with the observation in this study that significant drug levels were achieved in whole blood samples within 2 hours of oral administration.

Clinically, there is evidence that hydroxychloroquine may have a role to play in the prevention of thromboembolic disease, though this has remained controversial. The incidence of deep venous thrombosis was found to be 5% in 107 general surgical patients who received hydroxychloroquine in the perioperative period compared with an incidence of 16% in a similar control group.⁵ In the 1970s, Sir John Charnley and colleagues became enthusiastic supporters of the use of hydroxychloroquine as prophylaxis against thromboembolism in patients undergoing hip replacement. In their series, a significant reduction in the incidence of postoperative pulmonary embolism was observed in patients receiving anywhere from 600 to 1600 mg of hydroxychloroquine daily, beginning the day before surgery and continuing until the time of hospital discharge.^{6 21} Unfortunately, these large case series were not rigorously tested in a double-blind, prospective trial. One such double-blind, randomized trial involving hydroxychloroquine versus placebo being given to patients after elective hip surgery failed to reveal any significant difference in the incidence of thromboembolism between the two groups.²²

There are several reports that indicate that antimalarial drugs such as chloroquine and hydroxychloroquine have a possible antithrombotic effect. Platelet aggregation induced by ADP, collagen, and ristocetin can be inhibited by chloroquine, and the inhibition is dose dependent.^{23 24} More recently, chloroquine was found to inhibit the release of arachidonic acid from the membrane phospholipids of thrombin-stimulated platelets.²⁵ This appears to be mediated through inhibition of activated phospholipase A2 by chloroquine. Quinacrine, a related antimalarial compound, has also been identified as an inhibitor of phospholipase A2 and similarly blocks thrombin-induced secretion and release of arachidonic acid from platelet phospholipids.^{26 27} This inhibition can be overcome by the addition of lysophosphatidic acid, which is normally formed as a result of the action of phospholipase A2 on phosphatidic acid.²⁷

In addition to their effect on platelets, antimalarial drugs also appear to inhibit intravascular aggregation of erythrocytes. This "desludging" effect has been well described in the treatment of malaria.⁷ However, it has also been noted to occur in the vessels of the bulbar conjunctiva in patients with other vascular disease processes as well as in the retinal veins of rheumatoid arthritis patients.^{8 28} In spite of this, it remains controversial as to whether hydroxychloroquine and chloroquine truly alter the rheological properties of red blood cells. Indeed, whole blood and plasma viscosities, as well as erythrocyte sedimentation rates, were found to be the same in patients with rheumatoid arthritis irrespective of treatment with hydroxychloroquine, sodium aurothiomalate, or D-penicillamine.²⁹ On the other hand, a more recent clinical study found a significant reduction in plasma viscosity as well as whole blood viscosity in postoperative patients treated with hydroxychloroquine.³⁰

Whether the administration of hydroxychloroquine for a longer period of time could have resulted in a stronger antithrombotic effect remains unknown. Hydroxychloroquine has a calculated half-life of >45 days¹⁶ ; thus the drug would need to be administered for several months before any steady state could be expected. Metabolites of hydroxychloroquine, including desethylhydroxychloroquine, may also play a role in inhibiting thrombus formation, though any therapeutic benefit of such metabolites is also not clear.³¹

To our knowledge, this study is the first of its kind to demonstrate a direct effect of hydroxychloroquine on induced thrombi in blood containing high titers of anticardiolipin antibodies. The exact mechanism by which hydroxychloroquine reverses thrombogenic properties of anticardiolipin antibodies is unclear. However, one possible mechanism is that hydroxychloroquine may affect the enhanced platelet aggregation and activation of platelets produced by antiphospholipid antibodies, as shown previously.^{32 33} Other antiplatelet drugs such as aspirin, ticlopidine, and persantine may have a similar effect, though these have not been studied in this model.

The potential role of hydroxychloroquine in the management of patients with APS remains unclear. It is conceivable that it may be of benefit in patients who are unable to tolerate high levels of anticoagulation with warfarin due to hemorrhagic side effects, or in those who continue to experience thrombotic events despite warfarin therapy. Hydroxychloroquine may also be useful in patients found to have significant titers of anticardiolipin antibodies or a positive lupus anticoagulant test, who have not had any previous thromboembolic events.

	Acknowledgments

 
This study was partially supported by a grant from the Heart and Lung Institute of Jewish Hospital, Louisville, Ky. We thank Dr Nicol at Sanofi Winthrop for the generous gift of hydroxychloroquine and for covering the costs of determining hydroxychloroquine levels in mouse blood samples. We thank Gloria Nygard for her expert technical assistance with this drug analysis.

Received April 21, 1997; revision received August 11, 1997; accepted September 1, 1997.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Edwards, M. H. Articles by Harris, E. N. Search for Related Content PubMed PubMed Citation Articles by Edwards, M. H. Articles by Harris, E. N. Pubmed/NCBI databases Compound via MeSH Substance via MeSH