Melbourne evidence confirms VITT platelet activation and IVIg treatment benefit

Melbourne specialists have reported a case that confirms the beneficial role that IVIg treatment plays in reducing platelet activation in VITT.

The case is the first to show direct evidence supporting suggestions that components of serum/plasma from patients with VITT can activate platelets from healthy donors and details the treatment and response of a 55 year old woman presenting to hospital with chest pain 14 days after the first dose of the Astra Zeneca vaccine.

Writing in the British Journal of Haematology Professor Peter Karlheinz, Head of Atherothrombosis and Vascular Biology at Baker Heart and Diabetes Institute, and colleagues from the Alfred Hospital and Monash University said the patient had a a background history of hypertrophic cardiomyopathy, ischaemic heart disease, obstructive sleep apnoea, epilepsy, and schizophrenia.

Consistent with a diagnosis of VITT, her platelet count was 45 x 109/l with a D-dimer of 65.94 μg/ml and ‘strongly positive’ HIT enzyme-linked immunosorbent assay (ELISA, 143.9%; normal cut-off 105%).

A subsequent CT pulmonary angiogram revealed bilateral pulmonary emboli while venous doppler ultrasonography showed a proximal deep vein thrombosis involving the popliteal vein.

The team commenced therapeutic anticoagulation with fondaparinux 75 mg subcutaneously daily and IVIg was administered at a dose of 90 g (1 g/kg).

Blood samples were also taken before and after the administration of IVIg for flow cytometry analysis of platelet activation.

The researchers report that over the following five days the patient’s platelet count steadily increased, which was associated with a concordant fall in the D-dimer.

But six days after the initial dose of IVIg the patient developed chest pain and dyspnoea. The clinical finding was associated with a reduction in platelet count to 108 x 109/l.

While further imaging with a CT pulmonary angiogram revealed a reduction in thrombus burden of the left lung it also picked up extension of thrombosis within the segmental and subsegmental vessels of the right lower lobe.

Switching from fondaparinux to anticoagulanion with bivalirudin and a further dose of IVIg (1 g/kg) the specialists said platelet count increased to 157 x 109/l remaining normal over the following days, the team reported.

Platelet activation

Commenting on the treatment protocol, Professor Karlheinz and colleagues said a significant percentage of platelets were positive for markers of platelet activation prior to IVIg administration.

Some 13% of platelets expressed activated glycoprotein IIb/IIIa (GPIIb/IIIa, CD41/CD61, aIIbb3) with 191% demonstrating P-selectin [CD62P, granule membrane protein-140 (GMP- 140)] surface expression, he notes.

There was also significant increase in platelet–monocyte aggregates, with 26.5% of monocytes displaying evidence of bound platelets. It’s an important finding they said as the aggregates are not only a sensitive marker of platelet activation but are also likely reflective of enhanced monocyte activation as a feature of VITT.

But on repeat testing after IVIg treatment showed levels of PAC-1 binding, P-selectin expression, and platelet– monocyte aggregates had returned to a level comparable to a healthy donor – a turnaround that investigators described as ‘striking’.

“Platelet–monocyte aggregates have previously been associated with venous thromboembolic disease, HIT, and severe COVID-19 infection, the number of platelet–monocyte aggregates detected, and the finding that this number is reduced after IVIg administration is a novel and important finding.”

The finding also also ‘strongly’ suggests that the changes are the result of pathological VITT antibodies, the group added.

Similar trends were also seen with platelet–neutrophil aggregates, which is of particular relevance as neutrophil extracellular trap formation has been proposed to be involved in VITT.

Regarding the thrombus extension experienced six days after IVIg administration, Professor Karlheinz and colleagues said the event suggests that high levels of Ig are required to competitively inhibit platelet FccRIIa receptor binding.

“This raises the interesting possibility of whether changes in platelet activation markers can be utilised to assess the response to IVIg treatment and/or potentially help predict treatment relapse.”

The group adds that the patient is now stably anticoagulated with  bivalirudin and is being transitioned to oral anticoagulation with a vitamin K antagonist, because of the known interactions of carbamazepine with direct oral anticoagulants.

The case report is published in the British Journal of Haematology .

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