Antiphospholipid antibody syndrome-associated renal thrombotic microangiopathy improved not with rivaroxaban but with warfarin in a systemic lupus erythematosus patient without lupus nephritis

Abstract

A 34-year-old Japanese woman with systemic lupus erythematosus (SLE) was admitted to our hospital for exacerbation of renal dysfunction, hemolytic anemia and thrombocytopenia. Twenty-two years before admission, she was diagnosed with SLE. Eight years before, lupus anticoagulant (LAC) positivity was detected without any thrombotic findings. Fourteen months before, renal function started to worsen. Three months before, unprovoked left leg swelling appeared. She was diagnosed with deep vein thrombosis (DVT) by ultrasonography. Blood examination revealed mild anemia, thrombocytopenia, and renal dysfunction. Rivaroxaban was started after which the left leg swelling subsided. When she was referred to our hospital, LAC was positive, but hypocomplementemia nor elevation of serum anti-double-stranded DNA antibodies was detected. Renal biopsy showed acute and chronic thrombotic microangiopathy (TMA) without concurrent lupus nephritis. Brain magnetic resonance imaging showed new small multiple cerebral infarcts. Antiphospholipid antibody syndrome (APS), causing renal TMA, new cerebral infarction, and DVT was diagnosed. Rivaroxaban was changed to warfarin. Two months after admission, renal impairment improved, and the complete disappearance of DVT and brain infarcts was confirmed. This case suggests that warfarin may be more effective than direct oral anticoagulants in the treatment of APS-associated renal TMA.

Introduction

Antiphospholipid antibody syndrome (APS) is an intractable autoimmune disease characterized by the appearance of antiphospholipid antibodies (aPLs) and systemic manifestations such as arteriovenous thrombosis and pregnancy complications. Clinical features of APS include cerebral infarction, deep vein thrombosis (DVT), pulmonary embolism, thrombotic microangiopathy (TMA), renal failure, thrombocytopenia, and hemolytic anemia. APS is often associated with systemic autoimmune diseases such as systemic lupus erythematosus (SLE) [1].

The kidney is one of the main target organs of APS. The most characteristic acute lesion of APS nephropathy is TMA, whereas histologic features include acute thrombosis and chronic vascular lesions, such as interlobular fibrous intimal hyperplasia, arterial and arteriolar recanalizing thrombi, fibrous arterial occlusion, and focal cortical atrophy [2]. Although the frequency of APS nephropathy in SLE patients is 10–34% [3], pure TMA due to APS nephropathy without concurrent lupus nephritis is rare [4]. Heparin and warfarin are the main agents used for APS nephropathy, whereas there is insufficient evidence regarding the efficacy of direct oral anticoagulants (DOACs) [2].

No case with APS nephropathy in an SLE patient without lupus nephritis who was improved not with DOAC but with warfarin has been reported. We report here an APS patient with lupus anticoagulant (LAC) positivity complicated by SLE and DVT, who developed renal injury due to renal TMA without lupus nephritis and cerebral infarction during rivaroxaban therapy but was successfully treated with warfarin. This case suggests that warfarin may be more effective than DOACs in the treatment of APS-associated renal TMA.

Case report

A 34-year-old Japanese woman with SLE was admitted to our hospital for exacerbation of renal dysfunction, mild hemolytic anemia and thrombocytopenia. Twenty-two years before admission, she was diagnosed with SLE by malar rush, photosensitivity, polyarthritis, leukopenia, and positive results of anti-nuclear antibodies, anti-double-stranded DNA antibodies, and anti-Smith antibodies, and improved with prednisolone (PSL). Ten years before, hypertension was diagnosed, and an angiotensin receptor blocker was started. Eight years before, during her first pregnancy, her aPL profile was investigated for the first time with a positive result of LAC and negative ones of anti-beta2-glycoprotein I antibody (aβ2-GPI) and anti-cardiolipin antibody (aCL). As it was an unwanted pregnancy, artificial abortion was performed. As thrombotic findings were not observed, no antiplatelet agents such as aspirin were administered. PSL (5 mg/day) kept her no relapse of SLE. Seventeen months before, renal function was almost the same as at previous points [serum creatinine (Cr) 0.75 mg/dL and estimated glomerular filtration rate (eGFR) 72 mL/min/1.73m²]. Fourteen months before, however, it started to worsen (Cr 0.95 mg/dL and eGFR 55 mL/min/1.73m²) without any abnormalities on urinary dipstick or sediment tests. Three months before, unprovoked left leg swelling appeared. She visited another hospital and was diagnosed with DVT by ultrasonography. Blood examination revealed renal dysfunction (Cr 1.05 mg/dL and eGFR 49 mL/min/1.73m²), mild anemia (hemoglobin 10.9 g/dL), and thrombocytopenia (platelet 10.9 × 10⁴/μL). Rivaroxaban (15 mg/day) was started with improvement of the left leg swelling. Neither unfractionated heparin (UFH) nor low molecular weight heparin (LMWH) was used.

Because of renal dysfunction, she was admitted to our hospital. Although her blood pressure had been well controlled before admission, it was high on admission (156/94 mmHg). Physical examination revealed no abnormalities in the limbs, heart, lungs, abdomen, or skin, and no musculoskeletal or neurological findings. She had no diarrhea. Abnormal laboratory findings included hemolytic anemia, thrombocytopenia, renal dysfunction, but no decrease of disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) activity (Table 1). The aPL profile was the same as that noted 8 years before. As neither hypocomplementemia nor elevation of serum anti-double-stranded DNA antibodies was detected, the SLE was considered to be in remission.

Table 1.

Laboratory characteristics at the administration

	Value	Normal range
Urinalysis
Protein	(3 +)	(−)
Occult blood	(−)	(−)
Granular cast	(−)	(−)
β-2 microglobulin (μg/L)	9923	16–518
N-acetyl-β-D-glucosaminidase (IU/L)	30.7	1–4.2
Blood count
White blood cell (/μL)	4500	3300–8800
Red blood cell (/μL)	312 × 104	430–550 × 104
Hemoglobin (g/dL)	7.7	13.5–17.0
Hematocrit (%)	23.8	39.7–51.0
Platelet (/μL)	12.9 × 104	13.0–35.0 × 104
Erythrocyte fragmentation	(−)	(−)
Serum chemistry
BUN (mg/dL)	26.1	8.0–20.0
Cr (mg/dL)	2.31	0.60–1.00
eGFR (mL/min/1.73m2)	21	> 60
UA (mg/dL)	5.4	3.6–7.0
Na (mEq/L)	139	135–149
K (mEq/L)	3.1	3.5–4.9
Cl (mEq/L)	101	96–108
Total bilirubin (mg/dL)	0.7	0.4–1.5
ALP (IU/L)	199	115–359
AST (IU/L)	19	13–33
ALT (IU/L)	13	8–42
LDH (IU/L)	276	119–229
Total protein (g/dL)	6.9	6.7–8.3
Albumin (g/dL)	3.9	4.0–5.0
Haptoglobin (mg/dL)	< 10	19–170
Coagulation system
PT (%)	73	70–130
APTT (second)	91.7	22.0–43.0
Fibrinogen (mg/dL)	415	160–450
d-dimer (mg/dL)	0.8	0.0–1.0
Immunological findings
CRP (mg/dL)	0.18	0.0–0.3
CH50 (U/mL)	30.4	25.0–48.0
C3 (mg/dL)	93	65–135
C4 (mg/dL)	19	13–35
Anti-ds-DNA antibody (IU/mL)	< 10	< 10
Anti-β2-GPI antibody (IU/mL)	< 1.2	< 1.2
Anti- cardiolipin antibody (IU/mL)	< 8	< 8
Lupus anticoagulant (IU/mL)	2.61	< 1.29
ADAMTS13 activity (%)	100	> 10

BUN blood urea nitrogen, Cr creatinine, eGFR estimated glemerular filtration rate, UA uric acid, ALP alkaline phosphatase, ALT alanine aminotransferase, AST aspartate aminotransferase, LDH lactate dehydrogenase, PT prothrombin time, APTT activated partial thromboplastin time, CRP C-reactive protein, CH50 total hemolytic complement, GPI glycoprotein I, ADAMTS13 disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13

Renal biopsy showed acute and chronic TMA (Fig. 1). Sixteen of 64 glomeruli (25%) were sclerotic in an obsolescence-type manner. Remaining glomeruli were diffusely collapsed, and tubulointerstitium was largely injured with tubular atrophy, interstitial fibrosis and inflammatory cell infiltration. Double contour of the glomerular basement membrane was noted globally and was associated with mesangiolysis and endothelial cell swelling. Segmental glomerulosclerosis was focally observed together with intraglomerular foam cell infiltration. Arterioles were occluded by thrombus and the lumens were severely narrowed by fibro-intimal multi-layering. Immunofluorescence showed no deposition of immunoglobulins or complements. Electron microscopy confirmed subendothelial space widening, suggesting subendothelial edema induced by endothelial cell injury. Brain magnetic resonance imaging (MRI) showed new small multiple cerebral infarcts. APS, causing renal TMA and new cerebral infarction, was diagnosed. Rivaroxaban was changed to warfarin with a target PT-INR of 2–3. Hypertension improved promptly with a calcium channel blocker. The prednisolone dose was not increased because no flare of SLE was detected. Two months after admission, renal function improved (Fig. 2). Complete disappearance of DVT and brain infarcts was confirmed by leg ultrasonography and brain MRI, respectively.

Fig. 1.

Renal pathological findings. a Glomeruli were diffusely collapsed, and tubulointerstitium was largely injured with tubular atrophy, interstitial fibrosis and inflammatory cell infiltration [Periodic acid methenamine silver (PAM) staining, × 100]. b Segmental glomerulosclerosis was observed together with foam cell infiltration into the glomerular capillary. Arteriole was occluded by thrombus at the glomerular vascular pole, leading to glomerular ischemia (PAM staining, × 200). c Double contour of the glomerular basement membrane was noted globally and was associated with mesangiolysis and endothelial cell swelling (PAM staining, × 400). d The arteriolar lumen was severely narrowed due to thrombus [Hematoxylin Eosin (HE) staining, × 400]. e Vascular lumen was narrowed by fibro-intimal multi-layering, suggesting arteriolar reperfusion (PAM staining, × 400). f Electron microscopy confirmed subendothelial space widening (arrows), suggesting subendothelial edema induced by endothelial cell injury. Vacuolation and podocyte detachment were also noted (electron microscopy, scale 6 μm)

Fig. 2.

Clinical course. After switching from rivaroxaban to warfarin, the renal impairment and thrombocytopenia showed improvement. DVT deep vein thrombosis, eGFR estimate

Discussion

This case showed a rare type of APS nephropathy, pure TMA without concurrent lupus nephritis, and suggested that warfarin might be more effective than DOACs for APS nephropathy.

This case was diagnosed with TMA due to APS without concurrent lupus nephritis. Although APS nephropathy including TMA has developed in some SLE patients [5], pure TMA without concurrent lupus nephritis was reported only in a few cases in SLE patients [4]. In the present case, as immunofluorescence showed no deposition of immunoglobulin or complement, and the SLE was in remission as judged by no hypocomplementemia or elevation of serum anti-double-stranded DNA antibodies, concurrent lupus nephropathy was excluded. Renal pathology revealed that some findings including arterioles obstructed by old thrombi and organized components, diffuse collapsed glomeruli, and no tubulitis suggested that the extensive tubulointerstitial damage was caused by chronic ischemic changes due to vascular occlusion upstream to the glomeruli. Furthermore, other findings including mesangiolysis with endothelial cell swelling and arterioles obstructed by non-organized fibrin thrombi indicated that acute TMA was superimposed on chronic TMA. Catastrophic APS was considered unlikely because of the chronic course of the renal dysfunction and its improvement without the addition of immunosuppressive therapy [5]. The absence of erythrocyte casts in the tubular lumen suggested anticoagulant-related nephropathy to be less likely. As she had maintained normal kidney function during a 10-year course of well-controlled hypertension, a causal relationship between young-onset hypertension and APS nephropathy was considered less likely. Although she had not had refractory hypertension, the exacerbation of hypertension during this episode might have exerted some impact on the endothelial damage and TMA because we added an antihypertensive drug in addition to warfarin which might suppress the progression of renal damage.

The present case showed deterioration of renal function during rivaroxaban therapy, but improvement after warfarin was substituted, suggesting that warfarin may be more effective than DOACs in APS nephropathy. The reason why DOACs are not more effective for APS than warfarin has yet to be elucidated. Warfarin which inhibits multiple coagulation factors may more strongly inhibit the coagulation cascade and suppress thrombus formation than DOACs which inhibit a single coagulation factor [6]. Warfarin also has a longer half-life in blood than DOACs [6]. In a mouse model, it was reported that dabigatran, a direct thrombin inhibitor, promoted arterial thrombus formation via platelet aggregation more than warfarin [7]. In addition, the recent randomized trial showed that rivaroxaban had higher thrombotic risks than warfarin in patients with thrombotic APS [8]. Thus, warfarin may be more useful than DOACs for the prevention and therapy of thrombotic formation in APS.

The present case with LAC positivity and SLE should have received low-dose aspirin (LDA) before the onset of DVT, and UFH or LMWH at its onset. Although there is still no consensus on the use of LDA to prevent primary thrombosis for APS [1], primary thromboprophylaxis with LDA is recommended in asymptomatic cases with LAC positivity and SLE [9]. A meta-analysis showed that primary thromboprophylaxis with aspirin was effective in high-risk aPL positive patients with SLE [9]. It is necessary to regularly check the aPL profiles in SLE patients because SLE with aPL positivity has an increased risk of thrombosis. In addition, when venous thrombosis develops for the first time in APS, initial treatment with UFH or LMWH has been recommended recently [9].

We presented an APS patient with LAC positivity and DVT complicated by SLE who developed worsening renal injury due to renal TMA without concurrent lupus nephritis and new cerebral infarction in spite of rivaroxaban but improved after warfarin therapy. Warfarin may be more effective than DOACs for APS nephropathy.

Compliance with ethical standards

Conflict of interest

None of the authors have any conflicting interests to declare.

Human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was obtained from the patient in the study.