To the best of the authors’ knowledge, this report presents the first case of VITT complicated by extended portomesenteric thrombosis and resulting in atraumatic splenic rupture, which made splenectomy as well as TIPS placement inevitable. This led to a challenging combination: On the one hand, bleeding complications due to hemorrhagic coagulopathy because of splenic rupture and vaccine-induced thrombopenia required administration of clotting agents. On the other, extended portomesenteric thrombosis and the risk of TIPS occlusion necessitated therapeutic anticoagulation and platelet inhibition. This was managed by a broad interdisciplinary approach, close intensive care monitoring, and effective coordination of all treatment measures: application of intravenous immune globulins, adequate anticoagulation in VITT, as well as administration of clotting agents for the treatment of hemorrhagic coagulopathy, an emergency splenectomy, and placement of a TIPS for thrombaspiration and thrombolysis.
Symptoms and risk factors of VITT
Most cases of VITT documented in literature presented clinically with the triad of significantly elevated D-dimers (up to five times the reference range), thrombocytopenia < 150,000/µl, and arterial and/or venous thrombosis (especially at unusual sites), as did our patient. Portomesenteric thrombosis has been described in VITT previously, but not as fulminant as presented in our case with atraumatic splenic rupture requiring TIPS insertion and emergent splenectomy. The triad of symptoms in VITT resembles HIT type II and the more rare spontaneous HIT without heparin exposure [
13]. As per the recommendations of international professional societies [
14‐
16], clinical trials of VITT presenting 4–48 days (median, 14) [
11] post vaccination, mostly after the first dose of vector vaccine, should raise suspicion of VITT and must be investigated accordingly [
12]. So far, there are no identifiable risk factors for VITT except the vaccination with recombinant adenoviral vector vaccines itself, with an age range of VITT from 18 to 79 years (median 48 years) and equal gender distribution [
17].
Pathophysiology of VITT
Vaccination with recombinant adenoviral vector vaccines can result in heparin-independent production of autoantibodies against PF4 [
11]. This PF4/polyanion complex resembles the PF4/heparin complex that is responsible for HIT type II and can therefore be found in VITT without any previous heparin exposure [
10]. The binding site of anti-PF4 antibodies of VITT patients is restricted to the heparin binding site of PF4 and can actually be inhibited by heparin [
13]. Due to the formation of this PF4/polyanion complex [
18], thrombocytes are activated and aggregate, leading to thrombophilia with the risk of thromboembolic events and consumption coagulopathy [
20]. As opposed to HIT type II, in VITT, bleeding events as in our case have been described frequently [
10,
19]. The existence of PF4/vaccine complexes does not necessary result in VITT [
20,
21]. Although a positive test with clinical symptoms increases the likelihood of this diagnosis, in some cases of VITT, PF4/vaccine complexes could not even be detected [
22‐
24]. In our case, antibodies against PF4/polyanion complexes could be identified by IgG-specific ELISA, and PF4-related platelet aggregation could be shown by the PIPA test.
Diagnosis of VITT
Laboratory signs of VITT are significantly elevated D-dimers (up to five times the reference range), thrombocytopenia < 150,000/µl, reduced fibrinogen levels, positive PF4 antibodies in HIT-ELISA, and positive functional platelet activation tests (PAT) such as PIPA and serotonin release assay (SRA) test. Radiographic or ultrasound imaging of an atypical thrombosis can be helpful in the diagnosis of VITT [
16,
25]. Atraumatic spontaneous splenic rupture is a rare phenomenon in VITT (with only one other case recorded) [
26]. The incidence of atraumatic splenic rupture in the general population is estimated to be around 0.1–0.5% [
27]. On suspicion of VITT, it is crucial to implement adequate tests. Studies have revealed that rapid HIT assays such as rapid immunoassays (RIA) or chemiluminescence immunoassays (CLIA) should be avoided as they present poor sensitivity (< 20%) for anti-PF4 antibodies compared with IgG-specific ELISA tests (> 99%) [
28,
29]. In our case, the rapid HIT screening test also presented a negative result, in contrast to the positive IgG-specific ELISA. Recommendations for the diagnosis of VITT include PAT such as PF4-SRA, SRA, or HIPA testing with sensitivity > 99% for VITT [
24,
25,
29]. Additionally, especially in case of a negative HIPA test, a PIPA test with sensitivity of > 99% should be performed [
29]. In our case, a positive PIPA test despite a negative HIPA test confirmed the diagnosis of VITT.
Treatment of VITT
The pathomechanism of VITT is not fully understood so far, so no direct treatment option is available yet. Management only focuses on treating complications of VITT such as thrombosis and consumption coagulopathy and reducing the amount and effect of circulating PF4 antibodies.
Due to the similarity of VITT to HIT type II, a potential interaction with heparin cannot be excluded. Pending further data, the use of heparin in VITT should be avoided to prevent any possible interaction. Anticoagulation should be performed with nonheparin anticoagulant agents instead, such as danaparoid, argatroban, fondaparinux, or direct oral anticoagulants [
30]. Before suspicion of VITT was raised, our patient also received heparin. Whether this had harmful effects remains unclear [
3]. After suspicion of VITT, anticoagulation was established with argatroban, a direct thrombin inhibitor with a short plasma half-lifetime, as the patient remained hemodynamically unstable and coagulopathic. The dose of argatroban was monitored by rotation thrombelastometry (ROTEM, Werfen GmbH, Germany) as studies have revealed that aPTT is a suboptimal marker for dosing direct thrombin inhibitors [
31‐
34].
Owing to bleeding complications, our patient required massive transfusion, which in general should be avoided in VITT whenever possible. In particular, platelet transfusions increase the risk of antibody-mediated platelet activation and coagulopathy [
30].
As our patient stabilized hemodynamically and his thrombocyte count recovered, anticoagulation could be switched to fondaparinux subcutaneously for the general ward and to an oral anti-Xa inhibitor (apixaban) at discharge to the rehabilitation clinic. Current recommendations for patients suffering from VITT include continuation of therapeutic anticoagulation for at least 3 months [
5,
15].
Another treatment option for VITT is the application of IVIG [
8,
22,
35], which blocks circulating PF4 antibodies from interacting with the FcγRIIa receptor on the surface of platelets, thereby avoiding platelet activation [
3,
5,
11,
36]. However, IVIG therapy itself is associated with a risk of thrombosis in up to 13% when used among patients with autoimmune disorders [
37]. Our patient was treated with IVIG (2 × 1 g/kg Octagam). Whether this may have aggravated his thrombosis, requiring radiographically assisted re-thrombectomy, remains unclear.
The use of steroids can be considered in the management of VITT, especially in case of delayed availability or unsuccessful treatment with IVIG and plasma exchange (PLEX) [
5]. Corticosteroids potentially increase the thrombocyte count faster than IVIG alone in other settings of autoantibody-mediated thrombocytopenia [
38]. Our patient initially received a dose of intravenous corticosteroids (500 mg prednisone). The use of alternative immunosuppressants (rituximab or eculizumab, for example) can be considered in cases of VITT refractory to therapy, but evidence for this treatment is lacking so far [
15,
16].
Furthermore plasma exchange (PLEX), preferably against plasma rather than albumin, could represent an alternative option for reducing the amount of circulating PF4/vaccine complexes and correcting hypofibrinogenemia [
17]. PLEX was discussed but rejected in our management of VITT as IVIG therapy seemed to be effective.
In our patient, portomesenteric thrombosis was too extensive to be treated conservatively. TIPS insertion was crucial for the successful management of VITT to reduce venous congestion and perform thrombaspiration/thrombolysis via the TIPS catheter [
9,
39]. Klinger
et al. [
40] analyzed the safety and benefit of transjugular thrombolysis with or without TIPS in 17 patients with noncirrhotic, nonmalignant portal vein thrombosis. The study could show a high recanalization rate of 94.1% with no major complications. The 1- and 2-year follow-up examination of these patients revealed portal vein patency rates of 88.2%. Transjugular thrombolysis with or without TIPS seems to be a safe and effective measure in acute, noncirrhotic, nonmalignant portal vein thrombosis. This is especially the case in patients presenting with bowel infarction and a low chance of revascularization with systemic anticoagulation, as was the case in our patient. A systematic review of the risks and benefit of thrombolysis and TIPS insertion in VITT-induced portal vein thrombosis is currently lacking, as there is only one other case documented so far, where TIPS insertion and thrombolysis was beneficial in the treatment of VITT [
39]. Our patient is the first to be documented with VITT-induced atraumatic splenic rupture requiring splenectomy, TIPS insertion, and thrombolysis for successful management.