Systemic Sclerosis with Thrombotic Thrombocytopenia Purpura and Malignant Hypertension

Abstract

Thrombotic thrombocytopenia purpura (TTP) is a rare clinical syndrome characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, neurologic symptoms, acute renal impairment, and fever. It has been seldom reported in systemic sclerosis (SSc). Systemic renal crisis is an infrequent complication of SSc, and is characterized by new onset malignant hypertension, rapidly progressive oliguric renal failure, and MAHA. In this study, we present a case of SSc of 1 month duration, with TTP accompanied by new onset malignant hypertension. The patient responded to plasmapheresis but still died of septic shock.

• thrombotic thrombocytopenia purpura
• systemic sclerosis
• systemic renal crisis
• acute renal impairment
• continuous venovenous hemofiltration

INTRODUCTION

Thrombotic thrombocytopenia purpura (TTP), first described by Moschowitz E in 1925,¹ is a rare clinical syndrome characterized by a pentad of symptoms: microangiopathic hemolytic anemia (MAHA), thrombocytopenia, neurologic symptoms, acute renal impairment, and fever. Untreated TTP is often fatal, whereas plasmapheresis could be lifesaving. TTP could be idiopathic or induced by conditions including infections, drugs, pregnancy, tissue transplantation, and some autoimmune diseases such as systemic lupus erythematosus.^2,3 There were seldom reports of TTP as a rare complication of systemic sclerosis (SSc). TTP combined with SSc must always be distinguished from scleroderma renal crisis (SRC) for totally different pathogenesis and strategies of treatment. In this report, we present a case of SSc with TTP, accompanied by malignant hypertension and severe oliguric renal impairment.

CASE REPORT

A 70-year-old woman was admitted to our hospital because of progressive skin thickening and tightening for nearly 1 month. She had no arthralgia, morning stiffness, dysphagia, dyspnea, or palpitation. She had no history of pulmonary, cardiovascular, or renal diseases. She was afebrile during the admission, with normal heart rate and blood pressure. Physical examination revealed systemic skin tightening with wax-like appearance, moderate tissue swelling, and decreased skin temperature in extremities. She had digital ulcers and cyanosis in extremities. Raynaud’s phenomenon was observed. Initial laboratory tests showed: HB, 100 g/L; PLT, 209 × 10⁹/L; WBC, 6.74 × 10⁹/L; N, 73.9%; TB, 13.2 mmol/L; IB, 8.2 mmol/L; ALT, 86 IU/L; AST, 133 IU/L; ALB, 28.0 g/L; Cr, 50.0 μmol/L; LDH, 662 IU/L; PT, 11.7 s; APTT, 40.1 s; and FIB, 3.53 g/L. Serum immunological test revealed mild decrease of C3 and C4. Serology was positive for antinuclear antibodies (++) with a homogeneous pattern, strongly positive for anti Scl-70 antibody (+++), and negative for anti-SS-A, anti-SS-B, and anti-dsDNA antibodies. High-resolution computed tomography (CT) showed diffuse patch shadow in bilateral lungs.

The patient was diagnosed with diffuse SSc.⁴ Corticosteroid was given. However, she started to be febrile (ranging from 37.4°C to 37.8°C) since the third day. In addition to that, HB and PLT were noticed declining fast, accompanied by notable urine output reduction (Figure 1). On the sixth hospitalized day, when she had a urine output of only 200 mL, the patient suffered from sudden palpitation and orthopnea, with heart rate (HR) at 110 bpm and blood pressure (BP) at 201/116 mmHg. After nitroglycerin, furosemide, and Cedilanid administered, the patient gradually relived. However, orthopnea relapsed only a few hours later, with HR at 102 bpm and BP at 183/122 mmHg. Emergency laboratory test revealed: HB, 74 g/L; PLT, 25 × 10⁹/L; WBC, 11.85 × 10⁹/L; TB, 44.7 mmol/L; IB, 32.8 mmol/L; LDH, 2692 IU/L; Cr, 200.1 μmol/L; BNP, >35,000 pg/mL; and Tn-T, 1259.0 ng/L. Coombs’ test result was negative. Schistocytes were found on peripheral blood smear. Unexpectedly, there was only a slight elevation of supine rennin (0.97 ng/mL) and angiotensin II (58.21 ng/L). Pulmonary infection was identified by chest CT scan. She developed acute respiratory depression syndrome (ARDS) soon and relied upon mechanical ventilation then.

Figure 1. Hemoglobin (HB), platelet count (PLT), lactate dehydrogenase (LDH), serum creatinine (sCr), blood pressure (BP), and urine output (UO) in relation to therapy.

Upon a provisional diagnosis of TTP, plasmapheresis (PE) was initiated, with plasma exchange volume of 2000 mL/day. On account of persistent anuria, continuous veno-venous hemofiltration (CVVH) was conducted simultaneously. After nine sessions of PE therapy and four times of fresh frozen plasma infusion (300–400 mL each time), PLT was slowly rebounding and reached over 100 × 10⁹/L at the third week, accompanied by skin tightening wearing off gradually. Hypertension did not last beyond 1 week though no angiotensin-converting-enzyme inhibitors (ACEIs), but nitroglycerin was given. Nonetheless, her renal function never improved, and her condition started to deteriorate since the fourth week because of persistent pulmonary infection, which finally turned into severe sepsis. She died of septic shock on the 42nd day of admission.

DISCUSSION

Both TTP and SRC are rare complication of SSc. TTP combined with SSc usually mimic SRC, as both of them can present with thrombopenia, MAHA, and acute renal impairment, and both can be life threatening. However, the pathogenesis is quite different.

SRC, first reported in 1952,⁵ occurred in ∼4% of SSc patients as an infrequent catastrophic complication.⁶ It is characterized by new onset malignant hypertension and rapidly progressive oliguric renal failure, frequently accompanied by MAHA. Although the pathogenesis of SRC remains poorly understood, endothelial injury is considered to be the trigger of the disorder, and moreover, it is well acknowledged that the renin–angiotensin system plays an important role. There is a remarkable increase in plasma rennin level, usually 10 times more than normal before treatment.⁷ In accordance with this, renal biopsy reveals arterial onion skin lesion and juxtaglomerular apparatus hyperplasia as typical pathologic changes in SRC.⁸ The application of ACEI has dramatically improved the outcome of SRC patients. Before the availability of ACEI, the survival rate was <10% in the first year, while the 5-year cumulative survival rate was reported recently around 90%.⁹ In this way, rapid control of blood pressure by using ACEI is the mainstay of treatment of SRC.

On the other hand, in recent years, researchers have identified that idiopathic TTP is mainly due to the deficiency of a circulating metalloprotease named ADAMTS13.¹⁰ The microvascular thrombi found in vital organs such as brain, kidney, and intestine in TTP are primarily composed of platelets and von Willebrand factor (VWF). VWF is involved in mediating the aggregation of platelets, while ADAMTS13 is a VWF-cleavages metalloprotease. Also, it is supposed that PE could remove some ADAMTS13 inhibitors (e.g., autoantibody) and replenish the deficient ADAMTS13, thus effective in the treatment of TTP. Besides, the deficiency of ADAMTS13 would be helpful in the diagnosis of TTP.¹¹ Unfortunately, the test of plasma ADAMTS13 was unavailable in our hospital.

In this case, the patient mainly presented with MAHA, sudden new onset malignant hypertension, and severe oliguric renal impairment, which quite meet the manifestation of SRC. In addition to that, those manifestations happened to occur after the use of corticoids, which has been recognized to be a common trigger of SRC.¹² However, plasma test failed to reveal markedly increased rennin level (failed to test in different time points). Consequently, her hypertension was probably due to the fluid overload, which was induced by impaired renal function, as the BNP level suggested. Besides, the PE therapy had indeed ameliorated her MAHA. Therefore, it was more reasonable to consider it as TTP instead of SRC. Nevertheless, it was unfortunate that the patient was all along too weak to receive renal biopsies, which, though not routinely warranted in SRC nor TTP, might be conducible to the differential diagnosis. It was noteworthy that her renal impairment was much more severe than the usual TTP, and it seemed more alike with the performance of SRC. We thought it was partly attributed to the sepsis she suffered. The strikingly rapid development of her new onset SSc might contribute to that too. However, TTP might coexist with SRC occasionally.^13,14 But the pathophysiology still remains unclear. Endothelial injury might be a common trigger.^10,12

CONCLUSION

We presented a case of SSc combined with TTP, accompanied by new onset malignant hypertension and progressive severe renal impairment, which was somehow difficult to distinguish from SRC. Renin level test, as well as response to PE therapy and antihypertensive agents helped to make a differential diagnosis. Yet, sepsis had complicated the condition and was a key contributor to the poor outcome.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.