Management of Refractory Heparin-Induced Thrombocytopenia with Ivig, Plasma Exchange, and Rituximab: A Case Report

Background: Heparin-induced thrombocytopenia and thrombosis (HITT) is an immune response to heparin, forming antibodies against the heparin-platelet complex leading to platelet (PLT) activation and thrombin formation. We present a case of HITT refractory to anticoagulation (AC) with improvement following intravenous immunoglobulins (IVIg), plasma exchange (PLEX), and rituximab.

Case Presentation: A 62-year-old female presented with respiratory distress in the setting of severe aortic stenosis. Her initial bloodwork showed hemoglobin (HGB) 14.7 g/dL, PLTs 161,000/µL, international normalized ratio (INR) 1.4, and activated partial thromboplastin time (aPTT) 28.9s. Low molecular weight heparin (LMWH) was started for deep venous thrombosis (DVT) prevention. Coronary angiography was performed on day 2, for which 5000 units (u) of unfractionated heparin (UFH) was administered intra-procedurally; LMWH was continued until day 4. The patient underwent aortic valve replacement on day 6 with 25000u of UFH intraoperatively and 5000u UFH thrice daily thereafter. PLTs decreased to 78,000/µL post-operatively but recovered to 116,000/µL by day 10. She was discharged on day 11 off AC. On day 13, she returned with new left arm and right foot pain, swelling, and discoloration. Extremity ultrasounds revealed acute superficial and deep vein thromboses in all extremities. Investigation revealed PLTs 18,000/µL, HGB 8.5 g/dL, fibrinogen 137 mg/dL, positive serotonin release assay (SRA), and positive anti-platelet factor-4 (aPF4) assay. She was re-admitted for suspected HITT. Argatroban was started, and thrombectomy of her lower extremity was performed. Despite non-heparin based AC, a new thrombus developed in her intrahepatic vena cava on day 17. IVIg was initiated for 3 days, and AC was transitioned to bivalirudin. Persistently elevated d-dimer, low PLTs, low fibrinogen, positive SRAs and PF4 assays, and worsening of her clinical symptoms prompted unconventional treatment with PLEX for 5 days on day 19 and rituximab on day 25. PLEX was resumed for 3 days on day 29 due to decreasing platelets and rising D-dimer during its brief absence, with a subsequent rituximab dose administered on day 30. By day 33, venous recanalization was observed on extremity ultrasounds, platelets and fibrinogen normalized, and d-dimer decreased. The patient transitioned to long-term oral AC by discharge on day 37 and continued rituximab outpatient. aPF4 assays remained positive.

Discussion: First line heparin induced thrombocytopenia (HIT) management involves heparin elimination and a non-heparin based AC to prevent thromboembolic events while platelets recover, which typically occurs within three to seven days of heparin cessation. In severe refractory HIT, platelet recovery can take weeks with high risk of venous and arterial thromboembolisms, as reported by Ahmed et al (2007). Limited data exists to guide the management of patients who fail to respond to first line therapy. The use of IVIg was based on a small case series by Padmanabhan et al. (2017) that showed clinical resolution of HIT with IVIg (1g/kg). Both PLEX (Bavli et al (2021)) and Rituximab (Batra et al (2022)) have also been used in refractory cases; these therapies likely function by either mitigating the activity of, removing or preventing the formation of pathologic auto-antibodies. Combining these modalities therefore is reasonable, and this case describes a patient with severe refractory HITT who ultimately responded to this approach. It is not yet known why a subset of patients with HIT have severe presentations, as in this case, while other individuals exhibit milder manifestations. Additional research into the pathophysiology and management of this entity is needed.

Conclusion: There are no current guidelines for treating severe refractory HIT. Further investigation is necessary to assess the role of autoimmunity and immunosuppression in managing this life-threatening condition.

No relevant conflicts of interest to declare.

Rituximab was used off-label to treat refractory, likely autoimmune heparin-induced thrombocytopenia with thrombosis, and this was based off it's appropriate mechanism of action as well as previous case reports demonstrating success with its use. Intravenous immunoglobulins was used off-label to treat refractory, likely autoimmune heparin-induced thrombocytopenia with thrombosis, and this was based off it's appropriate mechanism of action as well as previous case reports demonstrating success with its use.