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Abstract

Thrombotic thrombocytopenic purpura (TTP) frequently develops in patients with connective tissue diseases (CTDs). ADAMTS13 and von Willebrand factor (VWF) are closely related to the onset of TTP. We investigated the roles of ADAMTS13 and VWF in thrombotic events of patients with CTD. ADAMTS13 activity and VWF and VWF propeptide (VWFpp) levels in CTD, primary antiphospholipid antibody syndrome (pAPS), and controls were measured to examine their relationship with thrombosis. ADAMTS13 activity levels were significantly low in the patients with CTD but not in the patients with pAPS. No significant difference in the ADAMTS13 activity levels among the various CTD subgroups was found. The levels of VWF and VWFpp were significantly elevated in the patients with pAPS and CTD compared with that of control groups. Eleven patients with CTD developed TTP, and their ADAMTS13 activity levels were significantly lower than patients having CTD without TTP. However, the ADAMTS13 activity levels showed no difference between the patients having CTD with and without thrombotic events. The VWF antigen levels were significantly high in the patients having CTD with TTP. There were no significant differences in the VWF levels of the patients having CTD with TTP and thrombosis. The VWFpp levels were significantly high in the patients having CTD with TTP and thrombosis. The VWF and VWFpp levels were significantly high in the patients with pAPS. Decreased ADAMTS13 activity and elevated VWF and VWFpp levels were observed in patients with CTD. These abnormalities in patients with CTD may represent the increased risk of thrombosis in CTD.

Keywords

ADAMTS13 von Willebrand factor (VWF)VWF propeptide connective tissue disease antiphospholipid syndrome

Introduction

Population-based epidemiological studies have revealed an association between systemic autoimmune diseases and deep venous thrombosis (DVT)/venous thromboembolism (VTE). The etiopathogenesis of the increased risk of VTE in systemic autoimmune diseases is not entirely clear but multiple contributors have been explored.¹ Antiphospholipid antibody syndrome (APS)^2,3 is a well-known systemic thrombotic diathesis that is associated with the presence of antiphospholipid antibodies (aPLs). The mechanisms underlying the development of thrombosis, including cerebral thrombosis⁴ and VTE,⁵ and obstetric morbidity⁶ due to aPLs are poorly understood. Antiphospholipid antibody syndrome consists of the primary APS and secondary APS.^7,8 The underlying diseases of the secondary APS include various connective tissue diseases (CTDs), systemic lupus erythematosus (SLE)⁹ and the related autoimmune diseases, and idiopathic thrombocytopenic purpura.¹⁰

Thrombotic thrombocytopenic purpura (TTP)¹¹ presents specific symptoms, including microangiopathic hemolytic anemia, thrombocytopenia due to platelet consumption and organ dysfunction, and frequently associates with CTD.¹² A disintegrin-like and metalloproteinase with thrombospondin type I motifs 13 (ADAMTS13) is a metalloproteinase that specifically cleaves the multimeric von Willebrand factor (VWF).^13

–17 The severe deficiency in ADAMTS13 activity results from either a mutation of the ADAMTS13 gene^14,18 or by the presence of inhibitory antibodies against ADAMTS13.¹⁹ The large VWF multimers (UL-VWFMs) are produced and released by the injured vascular endothelial cells into the plasma of the patients with TTP.^20,21 Pre-pro VWF, synthesized in the endothelial cells and megakaryocytes, requires posttranslational modifications including signal peptide cleavage, C-terminal dimerization, glycosylation, sulfation, and N-terminal multimerization²² for activation. In the trans-Golgi areas, the VWF propeptides (VWFpp) are processed and stored together with mature VWF in α-granules (megakaryocytes) and Weibel-Palade bodies (endothelial cells). Responding to various physiological and/or pathological stimuli, the endothelial cells discharge VWFpp and VWF into the plasma, and VWFpp dissociates from VWF in plasma.²³

Elevated plasma levels of VWFpp have been reported in patients with thrombotic microangiopathy (TMA) and disseminated intravascular coagulation (DIC).^24,25

In the present study, we measured ADAMTS13 activity and VWFpp and VWF antigen levels in plasma samples from 103 patients with CTD or APS and 68 healthy volunteers (HV).

Materials and Methods

Laboratory data were serially investigated in 94 patients with CTD, 9 patients with primary APS, and 68 HV. The patients consulted the Department of Hematology or Department of Dermatology from January 1, 1994, to December 31, 2013. The diseases of the patients with CTD included SLE (n = 32), systemic sclerosis (SSc; n = 27), dermatomyositis (DM; n = 8), primary Sjogren syndrome (n = 5), overlap syndrome (n = 7), rheumatoid arthritis (RA; n = 8), and mixed CTD (MCTD, n = 7; Table 1). Normal plasma specimens were collected from 69 HV from April 1, 2010, to August 31, 2010, and then were stored before performing the assays.

Table 1.

Participants.

		F:M	Age	Total					TTP	THE	APS
CTD	SLE	86:8	57.0 (23.2-82.4)	94	32	SLE		28	4	11	9
	SLE				32	SLE + Sjs		4	0	0	0
	SSc				27	Limited	SSc	13	0	3	0
						Limited	SSc + Sjs	4	0	1	0
						Diffuse	SSc	9	1	0	0
						Diffuse	SSc + Sjs	1	0	1	0
	DM				8				1	0	0
	Primary Sjs				5				0	1	0
	OVS				7	SLE + limited SSc + Sjs		1	0	0	0
						SLE + limited SSc		1	0	0	0
						RA + SLE		1	0	0	0
						Limited SSc + RA		1	0	0	0
						Diffuse SSc + DM		2	1	0	0
						Diffuse SSc + RA		1	0	1	0
	MCTD				7				1	0	0
	RA				8	RA		5	2	1	0
	RA				8	RA + Sjs		3	1	1	1
						RA + Sjs		3	1	1	1
Primary APS		8:1	52.0 (43.0-61.0)	9	9				0	9	9
				103					11	29	19

Abbreviations: CTD, connective tissue disease; RA, rheumatoid arthritis; APS, antiphospholipid antibody syndrome; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; DM, dermatomyositis; Sjs, Sjogren syndrome; OVS, overlap syndrome; M, male; F, female; TTP, thrombotic thrombocytopenic purpura; MCTD, mixed CTD.

SLE,²⁶ SSc,²⁷ and Sjogren’s syndrome²⁸ were diagnosed according to the diagnostic criteria of the American College of Rheumatology. Thrombotic events were diagnosed using echography, venography, computed tomography, magnetic resonance imaging, magnetic resonance venography, or cerebral angiography (CAG). Thrombotic microangiopathy, which results in thrombocytopenia and hemolytic anemia due to the microangiopathy, was identified based on the laboratory data and clinical symptoms such as neurological dysfunction, renal failure, and fever.¹³ Thrombotic thrombocytopenic purpura was diagnosed when a patient had TMA and neurological symptom(s) due to TMA.

The human plasma obtained from the whole blood treated with a 1/10 volume of 3.8% sodium citrate by centrifugation at 3000 × g at 4°C for 15 minutes. The plasma sample was stored at −80°C until analysis. All assays were performed within 2 years after sampling. Old data were obtained from only patients with TMA, and these assays were performed at the onset of TMA. The ADAMTS13 activity was measured using a FRETS-VWF73 peptide, which was chemically synthesized by the Peptide Institute, Inc (Osaka, Japan) according to the methods of Kokame et al.¹⁸ The plasma levels of VWF and VWFpp were measured with a VWF & Propeptide assay kit (GTi DIAGNOSTiCs, Waukesha, Wisconsin).²⁴ Hemoglobin levels and platelet counts were measured using a fully automated hematology analyzer XE-2100 (Sysmex, Kobe, Japan). The prothrombin time (PT), activated partial prothrombin time (APTT), and lupus anticoagulant (LA) were measured as described previously (25).

The study protocol was approved by the Human Ethics Review Committee of Mie University School of Medicine (approve number 2629), and informed consent was obtained from the patients.

Statistic Analysis

The data are expressed as the medians (25th-75th percentile). Mann-Whitney U test was used to examine the statistical significance of difference between the groups. The P values of <.05 were considered to indicate a statistically significant difference.

Results

The thrombotic events developed in 11 (34.4%) patients with SLE, 5 (18.5%) patients with SSc, 1 (12.5%) patient with DM, 1 (14.3%) patient with OVS, and 2 (25.0%) patient with RA. The ADAMTS13 activity levels in the patients with CTD (78.7%: 56.0%-97.2%) were significantly lower than that in HV (107%: 93.7%-124%; P < .001). However, the ADAMTS13 activity levels of the primary patients with APS showed no difference to that of the CTD or HV (Figure 1A). The VWF antigen levels in the patients with primary APS (257 U/dL: 165-347 U/dL) were significantly higher than both of the levels in the CTD (152 U/dL: 110-215 U/dL; P < .001) and HV (69.5 U/dL: 55.0-102 U/dL, P < .001; Figure 1B).

Figure 1.

Plasma ADAMTS13 activity (A), VWF (B), and VWF propeptide (C) levels in patients with CTD, pAPS, and HV. CTD indicates connective tissue disease; pAPS, primary antiphospholipid antibody syndrome; HV, healthy volunteers; VWF, von Willebrand factor. ADAMTS13, a disintegrin-like and metalloproteinase with thrombospondin type I motifs 13. ※※※, P < .001; ※※, P < .01; ※, P < .05.

The VWFpp antigen levels in the patients with CTD (143 U/dL: 99.3-205 U/dL) and primary APS (225 U/dL: 131-244 U/dL) were significantly higher than that in HV (85.0 U/dL: 62.0-102 U/dL; P < .001 or P < .01, respectively; Figure 1C), however, no difference was found between that of the CTD and pAPS.

The ADAMTS13 activity levels in each subgroup of patients with CTD were lower than that of HV, but no significant difference in ADAMTS 13 activity levels was found among the CTD subgroups (Figure 2A). Interestingly, the ADAMTS13 activity levels in MCTD and RA groups showed difference between that of pAPS. The VWF antigen levels in all the CTD subgroups increased compared with HV (Figure 2B). The VWF antigen levels in SSc were lower than that of pAPS. Except MCTD, VWFpp levels were significantly higher in the CTD subgroup than that of HVs (Figure 2C).

Figure 2.

Plasma ADAMTS13 activity (A), VWF (B), and VWF propeptide (C) levels in patients with various CTD and pAPS. CTD, connective tissue disease; pAPS, primary antiphospholipid antibody syndrome; HV, healthy volunteer; VWF, von Willebrand factor; ADAMTS13, a disintegrin-like and metalloproteinase with thrombospondin type I motifs 13. ※※※, P < .001; ※※, P < .01; ※, P < .05 in comparison with HV; ＃, P < .05 between each CTD.

Eleven patients with CTD: SLE (n = 4), RA (n = 3), SSc (n = 1), DM (n = 1), OVS (n = 1), and MCTD (n = 1) developed TTP. The ADAMTS13 activity levels in patients having CTD with TTP without thrombotic event (THE) (21.9%: 2.38%-39.4%) were significantly lower than any of whole CTD patient population (P < .001), CTD THE−/TTP−, CTD THE+/TTP+, CTD THE−/TTP+, and CDT THE+/TTP−. An ADAMTS13 activity level of less than 10% was observed in 4 patients with TTP. There was no significant difference in the ADAMTS13 activity levels of patients having CTD with and without thrombosis (Figure 3A).

Figure 3.

Plasma ADAMTS13 (A), VWF (B), and VWF propeptide (C) levels in patients with CTD and TTP. lane 1, all patients with CTD; lane 2, patients having CTD without THE or TTP; lane 3, patients having CTD with THE or TTP; lane 4, patients having CTD without THE but with TTP; lane 5, patients having CTD without TTP but with THE. ※※※, P < .001; ※※, P < .01; ※, P < .05 in comparison with HV. ADAMTS13 indicates a disintegrin-like and metalloproteinase with thrombospondin type I motifs 13; VWF, von Willebrand factor; CTD, connective tissue disease; TTP, thrombotic thrombocytopenic purpura.

The VWF levels were significantly higher in patients having CTD with TTP (217 U/dL: 161-268 U/dL) than in the whole CTD patient population (152 U/dL: 110-215 U/dL) and in patients having CTD without thrombosis (142 U/dL: 109-187 U/dL). There was no significant difference in the VWF levels of the patients having CTD with TTP and the patients having CTD with thrombosis (Figure 3B). The VWFpp levels were significantly higher in patients having CTD with TTP (210 U/dL: 190-311 U/dL) than in the whole CTD patient population (147 U/dL: 99.0-206 U/dL; P < .01) and patients having CTD without thrombosis (118 U/dL: 93.0-169 U/dL; P < .001). This level was significantly higher in patients having CTD with thrombosis (177 U/dL: 118-241 U/dL) than in patients having CTD without thrombosis (118 U/dL: 93.0-169 U/dL, P < .05; Figure 3C).

There were no significant differences in the ADAMTS13 activity levels among patients having CTD with and without thrombosis, primary APS, and secondary APS (Figure 4A). The VWF levels were significantly higher in the patients with primary APS (257 U/dL: 165-347 U/dL) than in patients having CTD without thrombosis (142 U/dL: 109-187 U/dL; P < .05; Figure 4B). The VWFpp levels were significantly higher in patients having CTD with thrombosis (206 U/dL:113-298 U/dL) and patients with APS (177 U/dL: 124-236 U/dL; P < .05) than in patients having CTD without thrombosis (118 U/dL:93.0-169 U/dL; Figure 4C). Systemic sclerosis developed several THE cases. Then we divided SSc into 2 groups: the diffuse type SSc and the limited type SSc. However, no significant differences in the ADAMTS13 activity, VWF, and VWFpp levels were found between the limited- and diffuse-type SSc (Table 2).

Figure 4.

Plasma ADAMTS13 activity (A), VWF (B), and VWF propeptide levels (C) in patients with CTD and APS. lane 1, patients having CTD without THE; lane 2, patients having CTD without APS but with THE; lane 3, patients with secondary APS; lane 4, patients with primary APS; lane 5, patients with secondary APS and patients with primary APS. ADAMTS13 indicates a disintegrin-like and metalloproteinase with thrombospondin type I motifs 13; VWF, von Willebrand factor; CTD, connective tissue disease; APS, antiphospholipid antibody syndrome. ※※※, P < .001; ※※, P < .01; ※, P < .05 ※※※, P < .001; ※※, P < .01; ※, P < .05.

Table 2.

ADAMTS13, VWF, and VWFpp Levels in Patients With Limited-Type and Diffuse-Type SSc.

		Median (2.5%-97.5%)	P Value
ADAMTS13, %	Limited	87.3 (31.2-140)	.45
ADAMTS13, %	Diffuse	73.5 (27.5-127)	.45
VWF, U/dL	Limited	145 (64.0-367)	.84
VWF, U/dL	Diffuse	145 (98.0-344)	.84
VWFpp, U/dL	Limited	136 (38.0-301)	.21
VWFpp, U/dL	Diffuse	145 (89.0-333)	.21

Abbreviations: ADAMTS13 indicates a disintegrin-like and metalloproteinase with thrombospondin type I motifs 13; VWF, von Willebrand factor; VWFpp, VWF propeptide; SSc, systemic sclerosis.

The frequency of elevated VWF or VWFpp (more than 200 U/dL) and reduced ADAMTS13 activity (less than 50%) was high in patients with RA or those with MCTD and low in those with primary Sjogren syndrome (Figure 5). The levels of lactate dehydrogenase (P < .001) and LA (P < .05) were significantly higher, and PT (P < .05) and APTT were significant longer in patients with reduced ADAMTS13 activity and elevated VWF or VWFpp than in those without (Table 3).

Figure 5.

Clinical profiles of patients having CTD with and without increased VWF/VWFpp or decreased ADAMTS13 activity. Closed bars, with reduced ADAMTS13 activity (less than 50%) and elevated VWF or VWFpp (more than 200 U/dL); open bars, without reduced ADAMTS13 activity (less than 50%) and elevated VWF or VWFpp (more than 200 U/dL). ADAMTS13 indicates a disintegrin-like and metalloproteinase with thrombospondin type I motifs 13; VWF, von Willebrand factor; CTD, connective tissue disease; VWFpp, VWF propeptide.

Table 3.

LDH, PT, APTT, and LA Levels in Patients With and Without Elevated VWF/VWFpp and Reduced ADAMTS13 Activity.

		Median (2.5%-97.5%)	P Value
LDH, IU/L	With elevated VWF/VWFpp and reduced ADAMTS13	1338 (207.0-2016)	<.001
LDH, IU/L	Without elevated VWF/VWFpp and reduced ADAMTS13	206.0 (127.7-1833)	<.001
PT, second	With elevated VWF/VWFpp and reduced ADAMTS13	11.0 (10.6-13.9)	<.05
PT, second	Without elevated VWF/VWFpp and reduced ADAMTS13	10.7 (9.69-13.0)	<.05
APTT, second	With elevated VWF/VWFpp and reduced ADAMTS13	32.2 (28.6-43.6)	<.001
APTT, second	Without elevated VWF/VWFpp and reduced ADAMTS13	27.90 (23.35-40.83)	<.001
LA	With elevated VWF/VWFpp and reduced ADAMTS13	0.98 (0.80-1.1)	<.05
LA	Without elevated VWF/VWFpp and reduced ADAMTS13	0.80 (0.70-0.96)	<.05

Abbreviations: LDH, lactate dehydrogenase; PT, prothrombin time; APTT, activated partial thromboplastin time; LA, lupus anticoagulant (Russell viper venom time: dRVVT); ADAMTS13 indicates a disintegrin-like and metalloproteinase with thrombospondin type I motifs 13; VWF, von Willebrand factor; VWFpp, VWF propeptide.

Discussion

ADAMTS13 is an enzyme that cleaves UL-VWFMs to control activation or aggregation of the platelets. Decrease of ADAMTS13 levels in patients with CTD implicates increase in the risk of the hypercoagulable conditions in patients with CTD by activation of the platelets. The antiplatelet agents have been indicated for the threat condition for the ischemic disorders in patients with CTD.²⁹ Decreased ADAMTS13 levels have been reported in the patients with TMA,¹¹ DIC,²⁶ and liver disease.³⁰ Interestingly, the ADAMTS13 activity levels of the patients with CTD in the present study were significantly decreased. The main causes of the reduction of the ADAMTS13 activity are consumption or presence of the inhibitors of ADAMTS13 including TTP and liver injuries. The patients with CTD frequently develop TTP, especially patients with SLE.³¹ Therefore, various conditions that inhibit ADAMTS13 activity may frequently develop in patients with CTD. In contrast, the ADAMTS13 activity was not decreased in the patients with primary APS, indicating no significant association with TTP. The patients having APS with reduced ADAMTS13 levels are rarely reported except the SLE cases with APS.³² In the present study, no significant differences were detected in the ADAMTS13 activity levels among the CTD subgroups; however, the study population was too small to prove this result. Significant low level, less than 10%, of ADAMTS13 activity commonly present in patients with TTP, however, this was only observed in 4 of the patients having CTD with TTP in the present study. Reduced ADAMTS13 activity has been reported in patients with SLE.³² This might be resulted from lower incidence of typical TTP and severe SLE in the present study compared with previous reports.^12,31

The serum VWF and VWFpp antigen levels, which are the markers of the vascular endothelial cell injury, were significantly elevated in the patients with CTD as well as the patients with primary APS. This suggests the presence of a common mechanism in CTD and APS: the vascular endothelial cell injury.

Because of the size of the population and the severity of CTD, the differences in the VWF and VWFpp levels in CTDs might be influenced. The VWFpp levels were significantly high in patients having CTD with TTP or thrombosis, which suggests that TTP and thrombosis induce vascular endothelial cell injuries in patients with CTD. Consistent with previous reports, the VWFpp level was more sensitive to thrombosis than the VWF level.^24,25 In addition, there was no significant difference in the ADAMTS13 activity levels of patients having CTD with and without thrombosis. The present study implicated that there was no direct relation between ADAMTS13 activity and thrombosis.

Except SLE, SSC is an only disease subgroup that developed several THE cases. Diffuse type SSc has generalized involvement with inflammatory reactions but not limited type SSc. Then, we investigated the ADAMTS13 activity, VWF, and VWFpp levels in the limited- and diffuse-type SSC. However, there were no significant differences in the ADAMTS13 activity, VWF, and VWFpp levels of patients with limited-type and diffuse-type SSc. A further study with a larger population focusing the specific antibodies and thrombosis is required.

Patients having CTD with elevated VWF or VWFpp or a reduced ADAMTS13 activity might thus have a high risk for TTP or APS. Primary APS had a low frequency of TTP, however patients having CTD with APS might have a high risk for TTP. Reduced ADAMTS13 activity and elevated VWF or VWFpp were frequently observed in patients with RA and MCTD, suggesting that RA or MCTD might lead to a high risk for TTP.

In conclusion, decreased ADAMTS13 levels and elevated VWF and VWFpp levels were observed in patients with CTD. These abnormalities may have close relation to thrombosis and vascular injury in CTD.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Our work is supported in part by research grants from the Japanese Ministry of Health, Labour and Welfare and the Japanese Ministry of Education, Science, Sports and Culture.

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Plasma ADAMTS13,von Willebrand Factor (VWF),and VWF Propeptide Profiles in Patients With Connective Tissue Diseases and Antiphospholipid Syndrome

Abstract

Keywords

Introduction

Materials and Methods

Statistic Analysis

Results

Discussion

Footnotes

Declaration of Conflicting Interests

Funding

References