Massive portal vein thrombosis due to platelet-activating PF4 antibodies without proximate heparin exposure, infection, or SARS-CoV-2 vaccination

Introduction: Immunothrombosis (IT) caused by platelet-activating IgG antibodies against platelet factor 4 (PF4) is a newly recognized catastrophic disorder characterized by thrombocytopenia, atypically located thrombosis, and profound elevation of plasma D-dimer [1]. Adenoviral infections or vaccination with viral vector vaccines may precede PF4-dependent IT, but absence of precipitating factors has also been reported. While intravenous immunoglobulins (IVIG) are efficacious in interrupting anti-PF4-mediated platelet activation, the natural course and optimal management of the disorder remain unclear.

Method: We present the clinical features, laboratory findings, management, and outcome of PF4-dependent IT in a previously healthy adult.

Results: A 23-year-old male presented with a 3-day history of severe abdominal pain and headache. He had no primary diseases, and there was no recent infection, vaccination, or heparin exposure. CT scanning revealed bilateral pulmonary embolism and extensive portal vein thrombosis reaching into the splenic and superior mesenteric veins ([Fig. 1]). The platelet count was 34/nL (150–370/nL) and the plasma D-dimer level was 37 mg/L (<0.5 mg/L). Because of suspected hepatic, splenic, and enteric ischemia, the patient underwent emergency TIPS placement and laparotomy with mesenteric thrombectomy and extensive small-bowel resection. Antithrombotic treatment consisted of acetylsalicylic acid and low-molecular-weight heparin (LMWH), which was switched to unfractionated heparin perioperatively. Based on a strongly positive IgG-specific ELISA for PF4/heparin antibodies the patient received IVIG 1 g/kg on 2 consecutive days, resulting in rapid normalization of platelet counts ([Fig. 2]). PF4-dependent IT was confirmed by a negative heparin-induced (HIPA), but a positive PF4-induced platelet activation (PIPA) test. Consistently, antibodies specifically recognized PF4 alone and not PF4/heparin complexes in a chemiluminescence assay. The subsequent course was complicated by acute liver and kidney injury, formation of a sub-hepatic hematoma, and recurrent ileostomy bleeding, requiring multiple surgical interventions. There was no evidence for progressive thrombosis. While PIPA and HIPA tests were negative at all subsequent examinations, the PF4/heparin IgG ELISA stayed strongly positive until the latest follow-up, 6 months after initial presentation. Platelet counts and plasma D-dimer levels were normal, and LMWH was switched to fondaparinux following improvement of renal function.

Fig. 1  At initial presentation (A), contrast-enhanced CT scanning revealed extensive portal vein thrombosis with complete vessel occlusion (arrow). Following TIPS placement, thrombectomy, IVIG administration, and therapeutic anticoagulation with UFH/LMWH, the compressed portal vein was perfused with regular contrast enhancement (B). Asterisk indicates sub-hepatic hematoma.

Fig. 2  Course of platelet counts following administration of IVIG 1 g/kg on days 1 and 2 (arrows).

Conclusion: IVIG induced rapid and sustained remission of PF4-dependent IT without the need for further immunosuppressive therapy. Long-term anticoagulation with heparin successfully controlled the coagulopathy with persistent platelet count increase and a remarkable reduction of the thrombotic burden. Further research is needed, however, to define the optimal first line therapy in patients with acute anti-PF4-related IT.

Publikationsverlauf

Artikel online veröffentlicht:
13. Februar 2025

• References

• 1 Schönborn L, Esteban O, Wesche J, Dobosz P, Broto M, Rovira Puig S, Fuhrmann J, Torres R, Serra J, Llevadot R, Palicio M, Wang J, Gordon T, Lindhoff-Last E, Hoffmann T, Alberio L, Langer F, Boehme C, Biguzzi E, Grosse L, Endres M, Liman T, Thiele T, Warkentin T, Greinacher A.. Anti-PF4 immunothrombosis without proximate heparin or adenovirus vector vaccine exposure. BLOOD 2023; 142 (26) 2305-2314