HIV-Associated Thromboembolic Phenomenon due to Protein C Deficiency

Introduction

Thromboembolic abnormalities are an important complication observed in HIV-infected patients, and their frequency increases with the progression to AIDS. Among HIV-infected individuals, thromboembolic phenomenon occurs in 0.19% to 7.63% patients per year. ¹ HIV infection is associated with a 2- to 10-fold increase in the risk of thromboembolism when compared to general population of the same age. ² Inherited protein C deficiency is a strong risk factor for venous thrombosis, but whether acquired deficiency due to infections like HIV is also a risk factor is unknown. ³ We thus report a case of HIV-associated thromboembolic phenomenon due to protein C deficiency.

Case

A 12-year-old HIV-infected girl diagnosed in 2008 presented again in January 2013 with facial palsy. She had been started on antiretroviral therapy (ART) consisting of zidovudine (ZDV), lamivudine (3TC), and nevirapine (NVP) in 2010, to which she was noncompliant (parents were giving the medicine intermittently and not giving NVP since the past 6 months). She was also treated for tuberculosis and herpes zoster infection, in 2010. On physical examination, her height was 124 cm (less than third percentile), and she weighed 19.95 kg (less than third percentile). Her general examination was normal. On systemic examination, she was found to have left facial palsy of upper motor neuron type. Other systemic examination was normal. Her CD4 count was 295 cells/mm³, in August 2011. She was shifted to second-line ART comprising abacavir (ABC), didanosine (ddI), and lopinavir/ritonavir (LPV/r). She was asymptomatic for a year but was not compliant with the above-mentioned therapy and presented with left facial palsy of upper motor neuron type in January 2013. Magnetic resonance imaging (MRI) of the brain indicated she had infarct in left basal ganglia due to the involvement of left middle cerebral artery. On evaluation, her CD4 count was 407 cells/mm³ and viral load was 3672/mL, while cerebrospinal fluid was normal. A thrombotic workout was done which showed a negative factor V leiden mutation, normal levels of antiphospholipid antibodies (APLAs) and anticardiolipin antibodies (ACLAs), normal antithrombin levels (80%), and deficient protein C levels (59%, normal 70%-110%). She was started on aspirin and advised proper adherence to ART. Her facial palsy improved in 3 days. She had no residual neurological deficit on follow-up till July 2013. She was also advised an HIV-resistance testing.

Discussion

Venous thromboembolism (VTE) occurs due to stasis, vascular endothelial damage, or a hypercoaguable state in an individual. ⁴ HIV infection is considered an important prothrombotic condition and is known to be associated with higher incidence of VTE phenomenon. In HIV-infected individuals, VTE may be due to multifactorial reasons. Low CD4 count (<200/mm³) and decreased concentrations of both protein S and protein C in HIV-infected patients due to their consumption as an anti-inflammatory mediator may be involved with the high risk of developing VTE. ⁵ In our patient, although the CD4 counts were normal, the child had active HIV disease as she still had a viral load of more than 3000 copies/mL in spite of being on second-line ART for the past 1 year because of improper compliance to ART, which could have predisposed her to thrombosis. On evaluation, we found out that protein C was deficient. She was also on protease inhibitors that could be a risk factor for thromboembolic phenomenon, ⁶ but she was not very compliant to the therapy, thus making ART as a less likely cause of thrombosis in this child. Other risk factors like APLAs, including ACLAs and lupus anticoagulant, ⁶ were negative in our patient.

The association between protein C deficiency and VTE in HIV infection is not as clear as that of protein S deficiency. Normally the inactive form of protein C is activated by the thrombin–thrombomodulin complex, which converts protein C to activated protein C that interacts with its cofactor protein S on phospholipid surfaces and inactivates factor V and factor VIII by proteolysis, thereby preventing thrombus formation. Hence, hereditary deficiencies are a risk factor for VTE. ⁷ In acquired case as in HIV infection, the pathology is multifactorial, causing altered synthesis and metabolism as well as low-grade disseminated intravascular coagulation with consumptive coagulopathy which is a result of upregulation of cytokines responsible for endothelial activation with downregulation of fibrinolytic proteins that predispose an individual to VTE phenomenon. These differences may be due to HIV infection itself, considering the fact that the same cytokines needed for activating the coagulation system may be involved in the setting of progressive HIV infection. ^5,8 However, not all patients with protein C or protein S deficiency experience thrombotic events. ⁹

In our case, the patient presents with facial palsy due to middle cerebral artery embolism as diagnosed on MRI. Anticoagulants and thrombolytic agents like aspirin and warfarin form the mainstay of management in children. Surgery is less indicated in children with arterial thrombosis but may be needed if an abscess develops from such an arterial lesion. ¹⁰ This patient was initiated on aspirin therapy and had clinical recovery.

Conclusion

HIV infection should be considered as a differential diagnosis in an episode of thromboembolic phenomenon in children.