Protein S and protein C deficiency with multiple infarcts in a human immunodeficiency virus-infected female child.

Thrombotic episodes have occurred in patients with human immunodeficiency virus (HIV) infection, and various abnormalities leading to hypercoagulable state have been reported. However, multiple cerebral infarctions in an HIV-infected child along with protein S and protein C deficiency are rare. We report such a case in an antiretroviral therapy-naive HIV-infected female child.

INTRODUCTION

Thrombosis is considered an uncommon complication in patients with acquired immunodeficiency syndrome (AIDS).[1] Recent literature describes an incidence ranging from 0.26% to 7.6%; higher incidence is seen in patients with active opportunistic infections (OIs) or malignancy and patients with AIDS.[2] Mechanisms such as presence of antiphospholipid antibody (APLA)-anticardiolipin antibody (ACLA),[3] decreased activities of natural anticoagulants (especially protein S),[4] increased platelet activation,[2] and use of protease inhibitor [1] have been postulated. We report a 9-year-old female child with AIDS who presented with multiple cerebral infarcts along with protein S and C deficiency.

CASE REPORT

A 9-year-old girl was referred to our pediatric human immunodeficiency virus (HIV) clinic with left-sided hemiparesis for 8 months and loss of vision and bladder and bowel control for the past 3 months. She had sudden onset weakness of left side of the body before 8 months which improved partially and then had a recurrence of weakness 3 months back along with generalized tonic-clonic seizures, blindness, loss of bladder, and bowel control. She was admitted to a hospital at that time, and computed tomography (CT) of the brain was done which was suggestive of right middle cerebral artery infarct and cerebrospinal fluid examination was normal. Her HIV ELISA was positive at that time. She was started on antituberculous therapy (ATT) by the attending physician. However, she had no clinical improvement. There was no fever, contact with tuberculosis (TB), or other illnesses in the past. Mother had died 2 years ago and father was also detected to be HIV-positive. She had a younger brother and sister and both were also found to be HIV infected. Her milestones were normal till age and she had received only bacillus Calmette–Guérin vaccine. On examination, she was wasted (weight = 12 kg, <5th centile; height = 102 cm, <5th centile) and had generalized lymphadenopathy, bilateral visual impairment with preserved pupillary reflex, left-sided hemiparesis with bilateral hypertonia and brisk reflexes, and dystonia. Other cranial nerves were normal, and other systemic examination was normal. Investigations reconfirmed positive HIV ELISA, hemoglobin was 7.1 g%, white cell count was 6300/cumm (48% polymorphs, 52% lymphocytes), platelet count was 370,000/cumm. Chest X-ray was normal. Magnetic resonance imaging of the brain showed severe cerebral atrophy with bilateral subdural fluid accumulation with bilateral internal cerebral artery occlusion with diffuse narrowing of the vertebrobasilar arteries and non-filling of the middle and anterior cerebral artery mainstem with extensive infarction within the cerebral cortex bilaterally with acute lesion in the occipital lobe suggestive of multiple infarcts in various stages of development [Figure 1]. Thrombotic workup in the form of ACLAs, APLAs, urine for homocystinuria, sickling test, antinuclear antibody, double-stranded DNA was negative. Cholesterol, prothrombin time (12.1 s), partial thromboplastin time (20.3 s), antithrombin III (165), factor V leiden antibody, and echocardiography were normal. Protein C (52% [normal = 70–140%]) and protein S (66% [normal = 70–140%]) were low. Her CD4 count was 59 cells/cumm (2.92%). She was started on three-drug antiretroviral therapy (ART) in the form of zidovudine, lamivudine, and efavirenz along with aspirin and warfarin. She had an improvement in her vision over a period of 3 weeks and her international normalized ratio was maintained at 1.5 times the normal level. Two months later, she again presented with seizures and fever. CT of the brain showed right subdural hematoma [Figure 2] which was evacuated by surgical intervention, and aspirin and warfarin were withheld. She has been continued on her ART, but there is no marked clinical improvement.

Figure 1

Magnetic resonance imaging showing multiple infarcts

Figure 2

Computed tomography of the brain showing right subdural hematoma

DISCUSSION

Acquired functional protein S deficiency has been seen in over 55% of HIV-infected children.[4] However, thrombotic complications due to the same in children are rarely reported. It has been found that AIDS, CD4 count <200/mm3, presence of OIs, AIDS-related neoplasms, or autoimmune disorders such as autoimmune hemolytic anemia may predispose to a thrombotic disease.[5] In our patient too, her CD4 count was less than even 100 cells/cumm and she already had AIDS. With acute OIs, it has been found that protein C and protein S levels may fall significantly which then increase once the OI is controlled.[6] In our patient, there was no OI. The child had been started on ATT by a doctor, but there was no evidence of TB clinically or on investigation in this child. Thus, the protein C and S levels seem to be low due to advanced HIV disease. Protein S deficiency has been found in over 50% patients with HIV and 8% patients without an OI.[6] However, combined protein C and protein S deficiency have rarely been encountered. In our patient, both protein C and protein S activity were found to be low. Although the presence of APLA-ACLAs had also been implicated for hypercoagulability in HIV-infected patients as earlier reported by us,[3] these antibodies were negative in our patient ruling out antiphospholipid syndrome. Other abnormalities reported include antithrombin deficiency [6] which was not found in our patient. Patients with documented thrombosis are treated with anticoagulants and/or aspirin to prevent recurrent thrombosis. However, in our patient following anticoagulants and aspirin, she developed a subdural hematoma which was removed. Thus, one would have to be very judicious in the use of anticoagulants and antiplatelet agents in these patients.

CONCLUSION

There is a tendency to thrombotic disease in advanced HIV disease and severe immunosuppression. Decrease in natural anticoagulants such as protein C and/or S may be a predisposing factor.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.