Paroxysmal Nocturnal Haemoglobinuria‐Associated Acute Cutaneous Thrombosis and Haemolysis in the Setting of Parvovirus B19 and Varicella Zoster Virus Infection

ABSTRACT

A 28‐year‐old male with paroxysmal nocturnal haemoglobinuria (PNH) presented with headache, nasal bridge discomfort and haemoglobinuria. He developed a macular‐papular rash which rapidly progressed into purpura, necrosis and peri‐orbital oedema. Investigations demonstrated severe haemolytic anaemia and acute parvovirus B19 infection. A skin biopsy confirmed extensive necrotising vasculitis with intravascular thrombi, affecting the dermal and subcutaneous vessels. Eculizumab, corticosteroid and intravenous immunoglobulin were given, and within 24 h, symptoms markedly improved. The patient later developed breakthrough haemolysis in the setting of varicella zoster virus infection, which responded well to additional anti‐complement therapy. This case demonstrates that viral infections can precipitate acute thrombosis and severe haemolysis in PNH patients and that a combined treatment approach confers good recovery.

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1. Background

Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra‐rare, acquired disorder characterised by a mutation in the X‐linked phosphatidylinositol glycan Class A gene, leading to loss of the glycosylphosphatidylinositol‐anchored proteins, particularly CD55 and CD59. Consequently, erythrocytes are more susceptible to complement‐mediated intravascular haemolysis and increased platelet activation and aggregation, significantly increasing thrombosis risk, both arterial and venous, particularly during complement activation. PNH can manifest as intravascular haemolysis with symptomatic haemoglobinuria, pancytopenia and thrombosis. Untreated PNH causes morbidity and mortality, and a prior thrombotic event is associated with significantly reduced overall survival [1]. We present a case of cutaneous necrotising vasculitis in a patient with PNH, with acute parvovirus B19 (PVB19) infection that responded excellently to anti‐complement treatment and who later developed breakthrough haemolysis (BTH) in the setting of varicella zoster virus (VZV).

2. Case Description

A 28‐year‐old male was diagnosed with PNH and maintained on symptomatic packed red cell (pRBC) transfusions in a low‐resource healthcare system. During this time, he developed features of chronic haemolysis, requiring pRBC transfusions at monthly intervals. Six years later, after relocating to the United Kingdom, he presented with headache, nasal bridge discomfort and haemoglobinuria with dark red urine. He had no other comorbidities, known allergies or previous transfusion reactions.

Initial blood tests demonstrated bicytopenia with a haemoglobin of 67 g/L, platelets of 89 10⁹/L and a normal neutrophil count. However, subsequent blood tests, taken within hours of admission, demonstrated worsening anaemia with a haemoglobin of 36 g/L, mean corpuscular volume of 89 fL, white cell count (WCC) of 2.9 × 10⁹/L, neutrophils of 1.4 × 10⁹/L and platelets of 84 × 10⁹/L. Interestingly, a reticulocyte count was low at 3.5 × 10⁹/L, bilirubin was 9 µmol/L and haptoglobin was undetectable. Lactate dehydrogenase (LDH) was 649 IU/L (normal range < 240 IU/L), which was 2.7× the upper limit of normal (ULN). The blood film demonstrated features of brisk haemolysis with polychromasia, spherocytosis and nucleated RBCs. A direct antiglobulin test (DAT) was negative. Haematinics revealed a normal folate level, a raised vitamin B12, raised ferritin, but low serum iron at 6 µmol/L and low transferrin saturation at 10%. Renal function and a coagulation screen were normal. C‐reactive protein (CRP) was 8.5 mg/L. Virology screening, including hepatitis B surface antigen, hepatitis B core antibody, hepatitis C virus antibodies and human immunodeficiency virus, was negative. PVB19 serology was positive for both IgM and IgG and polymerase chain reaction (PCR) measured viral load at 324,000 IU/ml copies. Peripheral blood immunophenotyping identified a PNH clone in 99% of granulocytes, 97% of monocytes and 27% of RBC, of which 12.3% were Type II and 14.75% were Type III.

Initial treatment comprised transfusion of four units of pRBC, achieving a post‐transfusion haemoglobin of 75 g/L, intravenous piperacillin with tazobactam to cover potential nasal bridge infection and daily subcutaneous dalteparin 5000 units as venous thromboembolism prophylaxis. Around 24 h later, a florid macular‐papular rash emerged over the scalp, upper trunk and arms, sparing the lower limbs. Considering a potential drug reaction, antibiotics were stopped, and prednisolone 20 mg and chlorphenamine were commenced. Over the next 12 h the rash rapidly developed into retiform purpura, with areas of necrosis, and severe peri‐orbital oedema emerged (Figure 1). He remained afebrile and haemodynamically stable, and the decision to transfer to the national PNH centre was made.

FIGURE 1.

(a, b) photographs demonstrating retiform purpura, with areas of necrosis and periorbital oedema taken on 17 April 2023 prior to eculizumab treatment. (c, d) photographs taken on 10 May 2023 after eculizumab treatment.

He arrived at the PNH centre 72 h after initial presentation. Repeat virology screening confirmed positive PVB19 IgM and IgG with PVB19 DNA copies of 843436 IU/mL. Extended virology screening was negative for hepatitis E virus serology, human T‐lymphotropic virus 1&2 antibodies and cytomegalovirus, adenovirus, herpes simplex virus and VZV PCR. Blood and urine cultures were negative. D‐dimer was > 20,000 ng/mL, and a subsequent ultrasound Doppler did not demonstrate venous thrombosis. A CT thorax with venogram showed diffuse soft tissue oedema in the upper anterior chest wall, involving the superior mediastinum, likely inflammatory/infectious in nature. Liver and renal ultrasounds and a superior mesenteric arterial scan were also unremarkable, with no thromboses. Histology of a diagnostic biopsy from right forearm skin (Figure 2) demonstrated plugging of the superficial and mid‐dermal vessels by a combination of red cells and fibrin thrombi with associated red cell extravasation. Within the vessel walls, areas of fibrinoid necrosis and neutrophil infiltrations were seen. These changes were most pronounced in the medium‐sized muscular‐walled vessels of the subcutis, which showed extensive necrotising vasculitis. Notably, screening tests for autoimmune antibodies, vasculitis, thrombophilia and protein electrophoresis were negative. Complement levels were low, with C3 at 0.81 g/L and C4 at 0.03 g/L. Urine protein creatinine ratio was raised at 42.3 mg/mmol.

FIGURE 2.

Right forearm skin biopsy haematoxylin and eosin stain at ×200 (A) and ×400 (B) magnification. Plugging of superficial and mid‐dermal vessels by red cells and fibrin thrombi with associated red cell extravasation. Areas of fibrinoid necrosis and neutrophil infiltrations within the vessel walls.

A diagnosis of PNH‐associated necrotising vasculitis and acute cutaneous thrombosis, likely exacerbated by PVB19 infection, was made. He was initiated on loading dose eculizumab with meningococcal vaccination, daily intravenous methylprednisolone 500 mg and intravenous immunoglobulin (IVIG). Intravenous meropenem and vancomycin were commenced to provide broad‐spectrum antibiotic cover. Folic acid supplementation and transfusion support were continued. After 3 days of methylprednisolone, a weaning course of oral prednisolone was commenced. Within 24 h of this treatment combination, the facial oedema and rash improved. By the end of this 10‐day admission, the patient's skin improved drastically, blood counts recovered, and transfusion requirements reduced. He was discharged with a weaning prednisolone course, topical corticosteroids, emollients, folic acid, prophylactic antibiotics and weekly eculizumab was continued in the outpatient setting. Following discharge, the patient's rash continued to improve (Figure 1), he became transfusion‐independent and was switched to long‐acting anti‐complement therapy (ravulizumab), with good control of haemolysis and no further thrombosis.

Around 24 months post‐discharge, he presented locally with a 2‐day history of fevers, myalgia, abdominal pain, jaundice and dark urine. He was febrile on arrival, with a temperature of 39.2°C, despite regular paracetamol. At this time, his PNH treatment was 8‐weekly ravulizumab, with his last dose 14 days prior. Initial blood tests demonstrated anaemia, with a haemoglobin of 84 g/L, normal platelet and WCC and raised total bilirubin of 173 µmol/L, with conjugated bilirubin of 43 µmol/L. A blood film showed polychromasia with spherocytes and schistocytes, consistent with haemolysis. Subsequent blood tests within 24 h demonstrated a rapid progression of anaemia with a haemoglobin to 65 g/L, raised reticulocytes of 210 × 10⁹/L, a raised LDH of 1664 unit/L (6.9× ULN) and an unconjugated bilirubinaemia. DAT was positive for C3d 3+. Vitamin B12 and folate were normal, but serum iron was low at 7 µmol/L. Renal and liver function were normal. He had a raised CRP of 108 mg/L.

A maculopapular rash developed over his back and torso, which over 24 h became widespread and vesicular (see Figure S1), and he remained febrile. A diagnosis of VZV infection, precipitating acute haemolysis, was suspected. He was treated with 2 units of pRBC, intravenous aciclovir, ciprofloxacin and gentamicin. A subsequent skin swab was positive for VZV. Plasma PCR detected VZV DNA and VZV IgG was < 10, demonstrating an acute VZV infection with no prior immunity. PVB19 serology remained positive for IgG but negative for IgM, with no detectable viral load by PCR. All other microbiology testing was negative. He required daily pRBC transfusion due to ongoing haemolysis. After 5 days, he was transferred to the PNH centre where he received a dose of eculizumab on Day 6. Following this, the rash significantly improved, haemoglobin stabilised and urine became clear. After 7 days of intravenous ciprofloxacin and 5 days of intravenous aciclovir, he was discharged to complete 7 days of oral aciclovir.

3. Discussion

This is a case of PVB19‐associated cutaneous thrombosis and necrotising vasculitis in a PNH patient who responded rapidly to eculizumab. The severe anaemia seen likely resulted from a combination of PVB19‐induced red cell aplasia, demonstrated by reticulocytopenia, and haemolysis exacerbated by the acute infection. As a result, combined treatment with complement‐inhibition and IVIG, to target the underlying PVB19, alongside supportive measures, was crucial. This treatment strategy resulted in rapid improvement of the patient's clinical and biochemical condition. Despite being well controlled on long‐term anti‐complement therapy, the patient later experienced breakthrough haemolysis in the setting of VZV infection, requiring additional eculizumab treatment. Together, this demonstrates the ability of viral infections to precipitate acute PNH‐related haemolysis and thrombosis even in the cutaneous vasculature.

PNH‐associated thrombosis remains a leading cause of mortality [2], yet the underlying mechanisms and the predilection to unusual sites are not completely understood. Management of PNH‐associated thrombosis depends on the location and nature of the thrombus. Cutaneous thrombosis during acute PVB19 infection in PNH has been reported only twice previously [3, 4], therefore, the management of cutaneous necrotising vasculitis is ill‐defined.

Anti‐complement therapies are the mainstay of treatment for PNH and eculizumab is a humanised monoclonal antibody that inhibits the terminal complement system by binding complement protein C5. Eculizumab has demonstrated rapid reduction of intravascular haemolysis and significant clinical benefits in PNH across a series of multinational clinical trials [5, 6, 7]. As well as reducing haemolysis, long‐term eculizumab treatment reduces the risk of clinical thromboembolism in PNH patients [8]. In our case, eculizumab, alongside supportive measures, resulted in a rapid resolution of cutaneous necrotising vasculitis and thrombosis.

Despite long‐term anticomplement therapy, PNH patients experience haemolytic exacerbations, particularly during periods of physiological stress, known as BTH, which remains a therapeutic challenge. BTH can be defined as the appearance of at least one new PNH symptom, or worsening of pre‐existing symptoms, with a LDH > 1.5×ULN, having previously been normal, and a drop in Hb > 2 g/L from previous levels [9]. In this case, BTH was precipitated by VZV infection, which highlights the importance of vaccination and a potential role for antiviral therapies in managing BTH in PNH patients. Given that the patient presented at a local hospital, remained clinically stable and was within 14 days of receiving long‐acting anti‐complement therapy, he did not receive additional eculizumab treatment until his arrival at the PNH centre, 6 days after presentation. Although additional anti‐complement therapy plays a role in managing BTH, comprehensive guidelines in managing these events do not exist and the limited availability of these treatments can pose logistical barriers and delays in management.

In summary, this case demonstrates that viral infections can precipitate cutaneous thrombosis and breakthrough haemolysis in PNH patients which responds rapidly to eculizumab treatment. There is a clear need for clinical guidelines outlining the management of breakthrough haemolysis in patients with acute viral infection.

Author Contributions

L.J.P. drafted the case report with contributions from all co‐authors. A.R. and J.L. provided details regarding the initial patient presentation. H.D. and T.S. contributed information about the patient's subsequent presentation at the local hospital. T.N.B. contributed to the description and interpretation of the dermatological manifestations. J.B. provided input on the histopathological findings and provided the histopathology images. A.K., R.T., and S.G. critically reviewed the manuscript and contributed to its revision.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supporting Information

Data Availability Statement

The authors have nothing to report.