Complement-Mediated Thrombotic Microangiopathy and Spontaneous Splenic Rupture Associated With Cytomegalovirus Infection

Abstract

This is a case report of a previously healthy female patient with complement-mediated thrombotic microangiopathy (TMA) caused by a systemic cytomegalovirus infection that was successfully treated with plasmapheresis, steroids, and parenteral valganciclovir. Complement-mediated TMA is the result of various genetic mutations leading to complement abnormalities with overactivation of alternate complement pathway in response to a triggering infection. She also had splenic rupture without splenomegaly and was managed successfully without splenectomy.

Introduction

Complement-mediated thrombotic microangiopathy (TMA) is characterized by a triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute renal failure (ARF).^1,2 It sometimes presents following an event causing activation of complement in a predisposed individual with genetic abnormalities involving complement factors or autoantibodies against complement regulators. Spontaneous splenic rupture is a rare complication of cytomegalovirus (CMV) infection and potentially life-threatening. The goal is to resuscitate the patient and conservatively manage to avoid splenectomy. Cytomegalovirus (CMV) is a DNA virus with high seroprevalence. Although it is well known for causing serious infections in immunocompromised and transplant patients, CMV has been reported with serious complications in previously healthy immunocompetent patients. Here, we are reporting a case of a previously healthy female patient with complement-mediated TMA and splenic rupture caused by a systemic CMV infection that was successfully treated with plasmapheresis, steroids, and parenteral valganciclovir.

Case Report

A 35-year-old Caucasian female patient presented with a 1-week history of nausea, vomiting, diarrhea, and malaise. The patient had a postpartum hemorrhage (PPH) due to retained products of conceptions (RPOCs) 7 months previously, but medical history was otherwise unremarkable. Initially, the patient was hemodynamically stable. Labs showed hemoglobin of 9.1 g/dL (normal, 11.7-15.5 g/dL), platelets of 24 × 10⁹/L (normal, 150-450 × 10⁹/L), creatinine of 1.6 mg/dL (normal, 0.40-1.00 mg/dL), lactate dehydrogenase (LDH) of 1095 U/L (normal, 100-235 U/L), haptoglobin of <30 mg/dL (normal, 32-228 mg/dL), direct Coombs test was negative, C3 was 53 mg/dL (normal, 86-184 mg/dL), C4 was normal, and schistocytes were seen on peripheral smear. While evaluation of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura (TTP) was ongoing, the patient’s clinical condition deteriorated with circulatory shock, acute abdominal pain, and drop in hemoglobin to 3.4 g/dL. Emergent computed tomography angiogram of the abdomen and pelvis showed splenic rupture with active bleeding (Figure 1). Massive transfusion protocol was activated with 8 units of packed red blood cells, 3 units of platelets, and 3 units of fresh frozen plasma given. She underwent an emergent splenic artery embolization for hemostasis by interventional radiology. Transfusion of such a high volume of blood products in the setting of poor kidney function led to massive pulmonary edema with acute respiratory failure requiring intubation. Continuous renal replacement therapy with ultrafiltration was started for volume overload. Continuous renal replacement therapy was discontinued before 24 hours, and the patient was extubated the next day. The patient received 3 sessions of plasmapheresis, while the ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeats, member 13) test was awaited. The ADAMTS-13 activity came back at 62% (reference range >67). It is slightly below the normal reference range—that value is not consistent with TTP but is in the range that can be observed with complement-mediated TMA. Also, ADAMTS-13 inhibitor was reported to be less than 0.4 (considered negative). Prednisone 60 mg was started empirically. Cytomegalovirus IgM and IgG both tested positive and was later confirmed by CMV DNA by polymerase chain reaction (PCR). Valganciclovir 900 mg twice a day was started and planned for 3 weeks for treatment of systemic CMV infection. The patient responded well to the treatment as evidenced by the improvement in cell counts and renal function. Repeat CMV DNA by PCR following treatment was undetectable.

Figure 1.

CT Scan abdomen and pelvis with splenic rupture.

As mentioned earlier, the patient had PPH due to RPOCs 7 months before these events. At that time, blood pressure was normal, CMV titers were negative, and there was no observed hemolysis, thrombocytopenia, and renal dysfunction. She underwent dilation and curettage for RPOCs and PPH resolved.

Discussion

Complement-mediated TMA is the result of dysregulation of the alternative complement pathway on the endothelial lining of vessels leading to endothelial damage. It is rare but frequently results in end-stage renal disease. These patients have poor outcomes after kidney transplant due to recurrence of complement-mediated TMA leading to high rate of transplant failure. ³ As such, early identification and treatment are important.

In our patient, complement-mediated TMA was suggested by combination of MAHA (direct Coombs test negative, schistocytes on peripheral smear, elevated LDH, low haptoglobin), thrombocytopenia (platelets of 24 000/µL), ARF (creatinine of 1.4, blood urea nitrogen of 47 mg/dL), low C3 with normal C4, and normal ADAMTS-13 level. The trigger was thought to be CMV systemic infection with CMV IgM >4.0, CMV IgG 3.0, and CMV DNA detected on PCR. Moreover, treatment with valganciclovir led to rapid recovery. The patient did not require eculizumab, a humanized anti-C5 monoclonal antibody that blocks the terminal complement pathway and is used to treat complement-mediated TMA.^4,5 Our case highlight the fact that secondary TMAs can resolve by treating the underlying infection. The patient also received prednisone 60 mg once a day. Steroids are known to inhibit complement activation by both classical and alternative pathways.^6-8

Cytomegalovirus is a DNA virus that belongs to the Herpesviridae family that is known to increase the expression of endothelial adhesion molecules and von Willebrand factor. ⁹ About 50% of the population in developed countries are seropositive. ¹⁰ The CMV infection is well studied in kidney transplant patients, frequently triggering complement-mediated TMA leading to transplant failure. Our patient was otherwise healthy, and treating CMV infection with valganciclovir led to early recovery. She has no other known risk factors for complement-mediated TMA, such as HIV, autoimmune disease, malignancy, organ transplant, irradiation, or drug exposure (eg, tacrolimus).^1,2,8,11,12

Complement-mediated TMA is described in association with various mutations in genes of complement factors or with autoantibodies against complement regulators. Around 60% of patients with complement-mediated TMA have an identified complement abnormality. ¹² Although 30% to 50% are diagnosed without an identified mutation, it is hard to rule out genetic mutation in those patients as there are several heterogeneous mutations involved; not all of them are known, and testing for them is not readily available.

Atraumatic splenic rupture is a rare complication of CMV infection. Typical signs include left upper quadrant abdominal pain, signs of peritonitis, and hemorrhagic shock. The absence of prodromal symptoms in acute CMV infection in immunocompetent adults exposes these patients to delayed diagnosis and management. Our patient was resuscitated with blood product transfusion and underwent prompt embolization. Splenectomy is reserved for patients who do not respond to conservative management and are hemodynamically unstable.