Case of HIV associated TTP Dr Kashmyree Dabeedin StR Acute Medicine Medway NHS Foundation Trust, Gillingham, Kent

 A 46 year old Nigerian woman was admitted for management of worsening menorrhagia. Prior to laparoscopic myomectomy for multiple uterine fibroids, she was having further investigations for widespread lymphadenopathy found on recent follow up CT scan (mediastinal, supraclavicular, axillary and fundal).  MRI pelvis done earlier had shown a large uterine fibroid and a large left external iliac lymph node but no aggressive features.  As part of the work up for lymphadenopathy and anaemia, an HIV test carried out by the haematology team 2 weeks prior to admission was positive. Background

 24hrs following admission, she developed some R. sided weakness at night. She was suspected to have Stroke or TIA. Urgent non contrast CTH was normal.  Next morning she remained hemodynamically stable without signs of stroke/meningism except for a mild photophobia and some confusion (GCS 14/15).  Bloods: Hb 78, MCV 79.5, Plt 22, WCC 8.9, Neut 6.17, U&E’s/LFT’s/clotting were normal.  Blood film showed moderate anisocytosis and poikilocytosis, polychromasia, shistocytes and markedly reduced platelets.  Meanwhile, HIV result was notified to the HIV team ( HIV-1 RNA copies/ml ). She was reviewed by the HIV team. Severe immunosuppression was suspected as she gave history of LSI in Nigeria over 13 years ago.

 Just after review, she sustained a peri-arrest and developed slurred speech and seizures. Rectal diazepam was administered with partial recovery, GCS (13/15). She was treated for suspected HIV-related meningoencephalitis and received empirical antibiotics (cefotaxime) and anti-viral (aciclovir). Contrast CTH was expedited.  LP could not to be performed prior to drug administration due to marked low Platelet count of 14 and deranged clotting.  She was transferred to HDU for close monitoring. She continued to have seizures and GCS dropped to 6/15 requiring intubation and subsequent transfer to ITU.  She was ventilated and commenced on a keppra/phenytoin and propofol infusion for intractable seizures. She was also started on anti-retrovirals Truvada + Raltegravir.

 LP performed under platelet and FFP cover showed high HIV viral load ( HIV-1 RNA 163,705 copies/ml) but was otherwise normal. MRI head was suggestive of meningoencephalitis.  During her ITU stay, she remained unstable, requiring inotropes and developed a right Deep Vein Thrombosis(DVT) along with a Pulmonary embolism( PE).  CD4 count was 316. Her thrombocytopenia remained persistent and failed to increase with transfusion. Rpt Blood film: leucoerythroblastic film with howell-jolly bodies, polychromasia. Quite a few red cell fragments noted. High suspicion of TTP if not septic.

 A probable diagnosis of Thrombotic Thrombocytopenic Purpura, TTP was suggested by the Haematology Team. This was confirmed by positive ADAMTS 13 test carried out at University College Hospital, London (UCH). (ADAMTS13 VWF cleaving protease < 5% [Range %])  She was transferred to UCH and treated with plasmaphoresis followed by methylprednisolone.  She made a good recovery and was discharged from hospital after 1 month.  AFB test requested by the HIV team was positive on bronchoalveolar lavage and she was also commenced on TB treatment.

 TTP is an acute prothrombotic disorder due to a deficiency of the von Willebrand factor cleavage protease ADAMTS13. 1  HIV-associated TTP is an acquired form of ADAMTS13 deficiency due to autoantibodies directed against ADAMTS13. 6,7 This impairs the cleavage of ultra large VWF multimers (ULVWF) into smaller sizes, leading to the formation of platelet-VWF thrombi in the microcirculation.  TTP is characterised by microvascular platelet deposition and thrombus formation in selected organs, resulting in microangiopathic haemolytic anaemia (MAHA), thrombocytopenia, variable renal and neurologic dysfunction and fever. 3  Thrombocytopenia may be due to direct infection of megakaryocytes by the virus, immune-mediated destruction, impaired haematopoiesis, toxic effects from medications and microangiopathic anaemia syndromes. HIV- associated TTP - Pathophysiology

 Evidence of MAHA and thrombocytopenia in the absence of DIC and other causes of thrombotic microangiopathy.  A schistocyte count of 1 % or more in conjunction with thrombocytopenia suggests TTP if other causes of MAHA have been excluded. 8  Low plasma levels of ADAMTS13 is highly specific.  PT, APTT and fibrinogen levels are mostly normal (cf DIC where they are raised) Laboratory diagnosis of HIV-associated TTP

 As with congenital non-HIV-associated TTP, HIV-associated TTP was originally characterised by the pentad.  However, revised diagnostic criteria state that TTP must be considered in the presence of thrombocytopenia and MAHA alone (Galbusera et al, 2006). It is an important diagnosis to make because the untreated mortality is 90%.  Treatment regimens include highly active antiretroviral therapy (HAART) or combined antiretroviral therapy(cART), infusion of fresh frozen plasma, plasma exchange, steroids and immunomodulatory agents. Features and Treatment of HIV-associated TTP

 A study of 24 patients with HIV-associated TTP emphasises the importance of the prompt initiation/re-initiation of cART in parallel with plasma exchange and steroid treatment that lead to prompt remission. 4  Adjunct immunomodulatory agents such as rituximab have been used with some success in refractory cases. 4  HIV-associated TTP seem to be far more responsive to plasma infusion treatment regimens than their HIV-negative counterparts, suggesting a different pathophysiology. 5 Treatment: cont’d

 HIV-associated TTP seems to be more heterogenous disorder than idiopathic TTP or TTP secondary to drugs or other underlying conditions.  It is thought that infection with HIV might trigger the disease through the inflammatory process. Inflammatory cytokines stimulate the release of extreme amounts of VWF. The cytokines also downregulate the release of the VWF-cleaving protease ADAMTS13. 9  It is also characterized by the classically described pentad of MAHA, thrombocytopenia, fluctuating neurological disturbances, renal failure and fever.  Not all these features are present in every case, and this often leads to missed or delayed diagnosis.  With advanced HIV disease, the presence of both thrombocytopenia and schistocytosis are frequently observed. In such cases, the diagnosis of HIV associated TTP should be considered.  Neither HIV-infection per se, nor the use of HAART, has any effect on ADAMTS13 levels, making it a useful diagnostic tool to diagnose HIV- positive patients with TTP. Conclusion

Thank you !

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