Detection of anti-heparin-PF4 complex antibodies in COVID-19 patients on heparin therapy

Dear Sir,

Patients with COVID-19, the disease caused by infection with the new coronavirus SARS-CoV-2, have, as known, amplified reaction of the mechanisms of inf lammation and coagulation with severe respiratory failure, multi-organ toxicity and multi-district thrombosis¹. Heparin is one of the most widely used drugs in the management of COVID-19, although there is not complete agreement on when to start therapy, the type of heparin to use and the most effective dosages². Many patients with this infection have thrombocytopenia³, which is more pronounced in the severe forms. We wondered if this could be linked not only to the general clinical picture and the therapies used, but also to the formation of anti-heparin antibodies.

We studied six patients in the Intensive Care Unit who were treated with unfractionated heparin and ten patients in the Infectious Diseases or Pneumology Department who were treated with low molecular weight heparin (LMWH). We searched for antibodies using a latex immunological test for the determination of total immunoglobulins (IgA; IgM; IgG) against the PF4-heparin complex, using an automated instrumental system (HemosIL HIT-Ab_(PF4-H), Instrumentation Laboratory Bedford, MA, USA).

Table I shows the trend inn platelet count in the last 10 days before the search for antibodies in patients treated with unfractionated heparin.

Table I.

Presence of heparin antibodies in patients with COVID-19 treated with unfractionated heparin

Intensive care patients	Sex	Age	Day 10	Day 4	Test day	Test result
1) DA	Female	77	216	108	49	Positive
2) LC	Male	78	211	193	58	Negative
3) RL	Female	77	222	162	68	Negative
4) BAR	Male	70	158	142	64	Positive
5) PGA	Male	71	232	120	74	Negative
6) DLF	Male	73	208	101	58	Positive

Heparin antibodies were present in three of the six patients being treated with unfractionated heparin, while they were absent in all patients treated with LMWH. In the three positive patients the heparin was replaced with fondaparinux at a dose of 7.5 mg, which was followed by a progressive increase in platelet counts. Despite the small number of patients, the incidence of anti-PF4-heparin complex antibodies seems to be higher than we are used to seeing in our clinical practice. We, therefore, thought it appropriate to report this observation, so that the possibility of heparin antibodies can be considered in patients with SARS-CoV-2 infection, taking into account that: (i) the particular condition of COVID-19 makes the formation of anti-heparin antibodies more likely; (ii) such antibodies may have a significant impact on the clinical course; and (iii) this risk must be considered in the choice of the most suitable therapy.