Abstract

Introduction

Heparin-induced thrombocytopenia (HIT) is a transient, autoimmune-like, prothrombotic disorder caused by heparin-dependent, platelet-activating IgG reactive against platelet factor 4/heparin (PF4/H). There is an emerging literature (Am J Med 2008;121:632-6. J Thromb Haemost 2008;6:1598-1600; Thromb Haemost 2013;109:669-75) pointing to rare instances of “spontaneous” HIT in patients without preceding heparin. We report 2 new cases and propose a definition for this controversial disorder. CASE #1. A 62-y.o. man presented with left middle cerebral artery stroke and thrombocytopenia (platelet count, 65×109/L). There was no previous history of thrombocytopenia, surgery, hospitalization, or heparin exposure. Clot extraction performed with heparin was complicated by further platelet count decline to 27 (nadir) and progressive thrombosis of the carotid artery. Aspirin was started, and the platelets recovered to >150 by day 13. CASE #2. A 54-y.o. female developed right leg swelling, left-upper extremity weakness/paresthesias, and thrombocytopenia (61×109/L) 15 days post-shoulder hemiarthroplasty; no intra-/postoperative heparin had been given. Brain MRI demonstrated acute infarct in the left posterior inferior cerebellar artery territory; angiography showed non-visualization of the left vertebral artery. Ultrasound revealed right lower-limb deep-vein thrombosis. Heparin treatment resulted in further platelet count fall to 37 (nadir). Treatment with argatroban, followed by fondaparinux, was associated with platelet count recovery to >150 by day 39.

Methods

Testing for HIT antibodies was performed by commercial EIA-IgG/A/M (Immucor GTI Diagnostics), in-house EIA-IgG (McMaster), and serotonin-release assay (SRA).

Results

Both patients’ sera (obtained before any heparin administration) tested strongly positive for HIT antibodies (Table), including strong platelet activation at 0.1 and 0.3 IU/mL heparin, as well as at 0 U/mL heparin, with no platelet activation at 100 IU/mL heparin: these serological features are characteristic of “delayed-onset HIT” (Ann Intern Med 2001;135:502-6). Antibody reactivity declined markedly by 2 to 4 weeks (including loss of platelet-activating properties at 0 IU/mL heparin), in keeping with the usual transience of HIT antibodies (N Engl J Med 2001;344:1286-92), and paralleling both patients’ platelet count recovery.

Table

Two patients with spontaneous HIT.

Patient no. (Age, sex), Day of blood sampleSerotonin-release (%)EIAs (absorbance, optical density units)*
0 IU/mL UFH0.1 IU/mL UFH0.3 IU/mL UFH100 IU/mL UFHAnti-PF4/H EIA-IgG (normal, <0.45 U)Anti-PF4/polyvinyl sulfonate EIA-IgG/A/M (normal, <0.40 U)
1 (62, male) 
Day 0 100 100 100 1.821 1.011 
Day 14 12 61 0.651 0.481 
2 (54, female) 
Day 0 81 100 100 2.731§ 2.084 
Day 28 81 100 1.625§ 1.734 
Patient no. (Age, sex), Day of blood sampleSerotonin-release (%)EIAs (absorbance, optical density units)*
0 IU/mL UFH0.1 IU/mL UFH0.3 IU/mL UFH100 IU/mL UFHAnti-PF4/H EIA-IgG (normal, <0.45 U)Anti-PF4/polyvinyl sulfonate EIA-IgG/A/M (normal, <0.40 U)
1 (62, male) 
Day 0 100 100 100 1.821 1.011 
Day 14 12 61 0.651 0.481 
2 (54, female) 
Day 0 81 100 100 2.731§ 2.084 
Day 28 81 100 1.625§ 1.734 

Neither patient had lab evidence of microangiopathy, vasculitis, or antiphospholipid antibodies (not shown).

*

For both patients, reactivity in both EIAs was inhibited >50% by 100 IU/mL heparin (not shown).

For both patients, reactivity was inhibited to 0% serotonin-release at 0.3 IU/mL heparin by Fcγ receptor-blocking monoclonal antibody (not shown).

Day 0 represents day of stroke admission, with blood sample obtained before giving any heparin.

§

Performed at 1/200 dilution (final), rather than usual 1/50 dilution.

For patient 2, subsequent results in the IgG/A/M EIA were 0.946 (day 100) and 0.246 (day 240).

Discussion

These cases further support spontaneous HIT as an unusual explanation for acute arterial stroke and thrombocytopenia. One patient had preceding orthopedic surgery, an event previously reported with spontaneous HIT (Thromb Haemost 2013;109:669-75). The strong serum-dependent platelet activation at 0 IU/mL heparin helps to explain how thrombocytopenia and thrombosis can occur in a patient not receiving heparin. RECOMMENDATION. Based on the serological findings of these and previous cases, we propose that a definitive diagnosis of spontaneous HIT syndrome should be based upon all of the following criteria: thrombocytopenia, thrombosis, lack of proximate heparin exposure, strong-positive PF4-dependent immunoassay(s), and a strong-positive platelet activation assay featuring both heparin-dependent (e.g., high heparin neutralization) and heparin-independent platelet activation (at 0 IU/mL heparin).

Disclosures:

Warkentin:Pfizer Canada: Honoraria; Paringenix: Consultancy; Immucor GTI Diagnostics: Research Funding; WL Gore: Consultancy; GSK: Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.