Cerebral venous thrombosis in patients with autoimmune disease, hematonosis or coronavirus disease 2019: Many familiar faces and some strangers

Abstract Background Cerebral venous thrombosis, a rare stroke, is characterized by neurological dysfunction caused by bleeding and/or infarction resulting from venous sinus thrombosis, the so‐called venous stroke. Current guidelines recommend anticoagulants as first‐line therapy in the treatment of venous stroke. With complicated causes of cerebral venous thrombosis, treatment is difficult, especially when combined with autoimmune diseases, blood diseases, and even COVID‐19. Aims This review summarizes the pathophysiological mechanisms, epidemiology, diagnosis, treatment, and clinical prognosis of cerebral venous thrombosis combined with autoimmune diseases, blood diseases, or infectious diseases such as COVID‐19. Conclusion A systematic understanding of particular risk factors that should not be neglected when unconventional cerebral venous thrombosis occurs and for a scientific understanding of pathophysiological mechanisms, clinical diagnosis, and treatment, thus contributing to knowledge on special types of venous stroke.


| INTRODUC TI ON
Cerebral venous thrombosis (CVT), including thrombosis of the cerebral veins and dural sinuses, is a peculiar cerebrovascular disorder of current interest, partly because of the significant morbidity associated with disorder. 1-3 CVT is a complicated stroke subtype, accounting for 0.5%-1% of all strokes, with a median diagnostic delay of 7 days, and the rate of missed diagnosis is 73%. [4][5][6] Thus, CVT is a special stroke subtype that should not be ignored.
Anticoagulation therapy, such as subcutaneous low-molecularweight heparin (LMWH) or new oral anticoagulants, has been regarded as the first-line treatment for CVT. 7 Patients with CVT who receive substandard anticoagulant therapy often have a good outcome. 8,9 However, at least 13% of all patients with CVT die or become severely handicapped. 10,11 Previous studies have identified blood stasis, endothelial cell damage or damage to the vessel wall, and hypercoagulation (Virchow's triad) as the three main elements of thrombosis. 12 At present, it is well established that changes in the Virchow's triad can lead to the occurrence of CVT. For instance, endothelial cell damage in which collagen fibers under the endothelium are exposed activates platelets and coagulation factor XII and initiates the endogenous coagulation system; simultaneously, the damaged endothelial cells release a large amount of tissue factor, which activates coagulation factor VII and can also activate the exogenous coagulation system to induce the formation and even recurrence of thrombus. 10,13 Therefore, the combination of anticoagulation and etiological treatment is the key therapy, but the risk factors and causes of CVT are complicated and diverse, such as sex-specific factors (use of estrogen-progesterone, puerperium, oral contraceptives, pregnancy), hereditary thrombophilia factors (protein C, S or antithrombin III deficiency), acquired thrombophilia factors (antiphospholipid syndrome, nephrotic syndrome, hyperhomocysteinemia), and other risk factors (anemia, infections). 14 These diverse causative factors/etiologies pose a challenge for the clinical management of CVT, especially when combined with autoimmune diseases, hematological disorders, and even COVID-19. [15][16][17] Thus, the purpose of this study was to review the pathophysiological mechanisms and clinical features of special types of venous stroke and to provide guidance for further research on the pathophysiological mechanisms, clinical diagnosis, and treatment of special types of venous stroke.

| Venous stroke in patients with Behçet's disease
Behçet's disease (BD) is a systemic variable vessel vasculitis with an unknown etiology that involves the venous and arterial systems. 18,19 BD is one of the leading causes of venous stroke in Mediterranean and Middle Eastern countries. 20 The pathogenesis of CVT in BD is not fully clear. 21 The likely cause of CVT in BD patients is venous inflammation-induced endothelial dysfunction and abnormal activation of coagulation function. 22 Assessment of a multicenter cohort from the United States showed that the proportion of venous stroke patients with BD was approximately 1%. 11 Furthermore, an international study on cerebral vein and dural sinus thrombosis (ISCVT) achieved the same results. 10 BD patients with venous stroke tended to be younger and predominantly male. 23 Thrombosis was detected mostly in the transverse sinus in BD complicated with venous stroke. 24 In a retrospective case-control study of 840 BD patients, 21 were diagnosed with venous stroke, as reported by Shi et al., 22 and the transverse sinus was found to be the most frequently affected site, followed by the superior sagittal sinus, sigmoid sinus, and straight sinus. Venous stroke-BD patients typically present with vasculitis such as trilogy of BD and intracranial hypertension syndrome, with headache being the primary symptom. 25 In the VENOST study, 1144 patients with venous stroke were enrolled from 35 centers, and 9.4% of patients were shown to have BD. 26 Headache accounted for 92.6% of the reported symptoms, followed by visual field defects (38%), nausea or vomiting (25.9%), cranial nerve palsy (14.8%), focal neurologic deficits (8.73%), epileptic seizures (7.4%) and altered consciousness (4.6%). Symptom onset in venous stroke-BD patients corresponded to the subacute form. 27 Venous inflammation-induced endothelial dysfunction and abnormal activation of coagulation function may be the mechanism of thrombosis. Systemic anticoagulation is the standard treatment for venous stroke. 14 Anticoagulation therapy is a recommended treatment for venous stroke, involving the intravenous administration of heparin or LMWH. 14,28 Following the acute phase of venous stroke, a minimum duration of 3-6 months of warfarin administration with a target international normalized ratio (INR) range of 2-3 is advised. 14,29 In cases where the patient exhibits intolerance to warfarin, alternative oral anticoagulants, such as rivaroxaban and dabigatran, may be deemed as viable options. 30 Based on a cohort of 64 patients with BD-associated venous stroke, Saadoun et al. 31 concluded that compared to anticoagulation alone, the addition of immunosuppressive therapy did not affect either the neurological outcome or thrombosis recurrence risk.
To date, there has yet to be a consensus on whether a combined treatment of immunosuppressive agents and anticoagulation is preferable to anticoagulation or immunosuppressive therapy alone for venous stroke in BD patients. 20

| Venous stroke in patients with antiphospholipid syndrome
Antiphospholipid syndrome (APS) is a systemic and noninflammatory autoimmune disease characterized by arterial and venous thrombosis and circulating antiphospholipid antibodies. 45 APS is generally secondary to SLE but can also occur idiopathically. APS patients with venous stroke as the initial presentation is rare. 46 The mechanism is still not clear, but it has been speculated that antiphospholipids activate endothelial cells, platelets, and monocytes, promoting the prethrombotic state. 47 Furthermore, anti-β2GP-1 antibodies and complement activation play an essential role in thromboembolism. 47 In the ISCVT study of 624 patients, 5.9% had APS as the underlying cause of venous stroke. 10 Venous stroke is a rare manifestation in APS patients. Studies published in the literature are scarce and primarily comprise case reports or short case series; thus, there is a paucity of extensive epidemiological studies on venous stroke in APS patients.
Jerez-Lienas et al. 15 indicated, in a series of 27 patients and a review of the literature, that venous stroke was located in the transverse and sigmoid sinuses in 73% of patients, superior sagittal sinus in 55%, straight sinus and deep venous system in 10% and cortical veins in 14%. Sixty percent of patients had extensive thrombosis affecting multiple sinuses. 15 APS with venous stroke as the earliest presentation was initially described in 2008. 48 The predominant forms of clinical presentation are acute and subacute, with headaches being the most prevalent symptom reported in 74% of published cases. 15,49 In a single-center study of the management of venous stroke patients with APS by Shen et al., 50 local endovascular thrombolysis, endovascular mechanical thrombectomy, and internal jugular vein stenting were utilized in patients who suffered from anticoagulant inefficacy, with satisfying outcomes. Glucocorticoids and intravenous immunoglobulin and/or plasma exchange therapy are applied in catastrophic APS-associated venous stroke, which is characterized by microvascular thrombosis resulting in multiorgan failure. 51,52 Upon hospital discharge, 78% of patients had a complete resolution of the symptoms or mild symptoms (mRS = 0-1), 4% of patients recovered partially and maintained autonomy (mRS = 2), 10% of patients sustained mild to moderate impairments (mRS = 3-5), and 6% of patients died during hospitalization (mRS = 6). 15 During 6 and 12 months of follow-up, the mRS remained favorable, with the remaining symptoms disappearing. 15,53

| Venous stroke in patients with Sjogren's syndrome
Sjogren's syndrome (SS) is a chronic systemic autoimmune disorder characterized by mononuclear cell infiltration in the salivary and lacrimal glands, whereby most characteristic symptoms consist of sicca syndrome, including xerostomia and dry eye-xerophthalmia, but can involve multiple organs. 54,55 SS is occasionally accompanied by neurological disorders, and reports of SS leading to venous stroke are rare. 56,57 The pathogenetic mechanisms responsible for venous stroke involvement in patients with SS likewise remain unclear. 58 Based on existing case reports and literature reviews, thrombosis was observed mostly in the transverse sinus in patients with SS accompanied by venous stroke. 57,[59][60][61][62] In addition, the straight sinus, vein of Galen, left middle cerebral vein, and inferior sagittal sinus can be involved. 57 Given the heterogeneity in manifestations, the unique clinical characteristics of venous stroke in SS patients remain obscure. Immunosuppressive agents are combined with anticoagulant therapy to treat SS-associated venous stroke. 61 The anticoagulation therapy was administered in accordance with the international standard. 14 However, without the credibility of large relevant clinical trials, the application of hydroxychloroquine is based on empirical data. 60 Previous reports indicate that SS-induced venous stroke patients have a favorable prognosis. 57 Following 3-5 years of follow-up, patients had no clinical or radiological relapse and fully recovered. 61

| Venous stroke in patients with inflammatory bowel disease
Inflammatory bowel diseases (IBDs) are distinguished by persistent inflammation of the gastrointestinal tract, the underlying cause of which remains unidentified. 63 The incidence of venous stroke in patients with IBD is estimated to range from 0.5% to 7.5%. 64  The co-occurrence of autoimmune disease and venous stroke warrants consideration of a differential diagnosis of cerebral venous thrombosis when a patient presents with symptoms indicative of brain damage. Currently, there is no universally accepted treatment protocol for such patients, nor is there a consensus on the optimal interdisciplinary approach ( Table 1).

| Venous stroke in patients with myeloproliferative neoplasms
Myeloproliferative neoplasms (MPNs) are a group of diseases, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), with an increased proliferation of one or more subtypes of myeloid cells. 74,75 PV and ET are associated with venous stroke. 76 MPNs are also associated with the risk of venous stroke recurrence. 77 Venous stroke occurs in approximately 1% of patients with MPNs. 78 In a joint analysis of two large databases, 27 patients were found to be diagnosed with venous stroke in a series of 706 MPN patients, and nine venous stroke patients were analyzed in a cohort of 2143 MPN patients, suggesting an association TA B L E 1 The epidemiology, circulating and imaging biomarkers, disease characteristics, treatment and prognosis of venous stroke in patients with autoimmune diseases.

| Venous stroke in patients with leukemia
Leukemias also be complicated by venous stroke. 82  Cerebral infarction most commonly occurs at, or shortly after, the diagnosis of APL or ALL is venous stroke. 82

| Venous stroke in APL patients
The occurrence of venous stroke in APL patients is extremely rare; only a few cases have been reported in the literature. 89,[93][94][95] Treatment with all-trans retinoic acid (ATRA) is the primary cause of venous stroke in APL patients. 96 The pathophysiology of coagulopathy in APL is complex. 97 In addition to several exogenous factors, the most compelling pathogenic mechanism probably involves leukemic cells, 98 which release multiple mediators that can influence blood coagulation through the following mechanisms: (1) high expression of two procoagulant factors by APL cells, namely, tissue factor (TF), which triggers a cascade of coagulation by forming a potent procoagulant complex with factor VII and cell membrane phospholipids, and cancer procoagulant, which activates factor X directly in the absence of activated factor VII 99 ; (2) deficiencies in fibrinogen and increases in fibrin degradation products and D-dimers, which indicate hyperfibrinolysis 100 ; (3) activation of the endothelium by adhering to APL cells resulting in clotting activation, leukocyte aggregation, hyperfibrinolysis, and thrombin generation 101 ; and (4) extracellular trap cell death, which induces excess thrombin production, fibrin deposition, hyperfibrinolysis, and endothelial damage. 102 The mechanism of venous stroke associated with APL has not yet been completely elucidated.  89 If venous stroke is refractory to medical treatment or progresses to cerebral edema or hemorrhage, venous sinus thrombectomy may be essential. 89 There was no recurrence of venous stroke or other complications from anticoagulation following treatment with ATRA and early anticoagulation.

| Venous stroke in ALL patients
Venous stroke is more frequent in patients with ALL than in those with other malignancies. 104 The cumulative incidence of venous stroke in ALL patients was 1.4%-6.2%. 105  procedure, is an alternative to anticoagulation in the case of severe venous stroke. 125 Resuming asparaginase treatment might be considered after the stabilization of venous stroke, but the evidence regarding the safety of this option is minimal. 122

| Venous stroke in patients with multiple myeloma
Multiple myeloma (MM) remains an incurable hematologic malignancy with clonal plasma cell proliferation and the production of monoclonal immunoglobulins. 126 increased P-selectin, and the accumulation of activated protein C resistance, which can result in hypercoagulability. [131][132][133] The coexistence of venous stroke and MM is rare. The spectrum of neurologic complications of MM-associated venous stroke and related conditions is complex, primary headaches. 126,130 Immunomodulatory drugs such as lenalidomide, thalidomide, and pomalidomide are widely used in MM and may be associated with an increased risk of venous thromboembolism. [134][135][136] Consequently, thromboprophylactic therapy is mandatory, along with immunomodulatory therapy, either with aspirin for patients at low risk of thromboembolism or LMWH for those with higher risk. 137  Anticoagulation therapy is the primary treatment for venous stroke and consists of intravenous unfractionated heparin or subcutaneous LMWH. 154 Eculizumab is recommended within 24 h of the onset of acute thrombosis to reduce the extent of the thrombus and prevent thrombotic recurrence. 155 Thrombocytopenia requiring platelet transfusion is necessary to increase the platelet concentration to a target of beyond 30-50,000/L before anticoagulation is initiated. 82 The outcome of venous stroke is worse in patients with PNH-related venous stroke than in those with other causes of venous stroke, primarily due to new venous thrombotic events. 142 The study by Meppiel et al. 142 highlights that patients with venous stroke have inferior long-term survival compared to patients without thrombosis and noncerebral thrombosis. However, the treatment and prognosis of venous stroke in PNH patients are debated and must be assessed in large long-term studies.

| Venous stroke in patients with thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura (TTP) is a severe, rare, and relapsing life-threatening thrombotic microangiopathy characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, and ischemic end-organ damage resulting from microvascular platelet-rich thrombi. 156,157 TTP is a disorder resulting from genetic or acquired severe deficiency of plasma ADAMTS13, a metalloprotease that cleaves endothelium-derived ultralarge von Willebrand factor (vWF), leading to unrestrained adhesion of the vWF multimers to platelets and microthrombi formation, resulting in thrombocytopenia and microangiopathic hemolytic anemia. [158][159][160][161] The predominant form of TTP is acquired immune-mediated TTP. 162 TTP is an infrequent cause of stroke among young adults. 163 Thrombotic thrombocytopenic purpura-associated venous stroke has rarely been reported. The treatment of TTP combined with venous stroke is mainly based on the treatment of the primary disease. As standard therapy, plasma exchange is used combined with immunosuppression with rituximab, cyclophosphamide, steroids, or vincristine. [164][165][166] Caplacizumab, a humanized immunoglobulin fragment that recognizes vWF, has recently been found to reduce thromboembolic events, stroke, and death in patients with TTP following plasma exchange and immunosuppression. bound to heparin. 183 Nascent PF4-HIT-IgG complexes recruit additional heparin-dependent HIT antibodies, forming multimolecular immune complexes and causing platelets to be activated, paradoxically, which can lead to CVT. 183,184 The development of venous stroke secondary to HIT is a rare occurrence documented in relatively few publications. 185 The  188,189 Nevertheless, more studies are needed to examine the efficacy of fondaparinux. Another standard treatment is intravenous immunoglobulin, which is often prescribed in combination with direct thrombin inhibitors and is especially effective in cases of autoimmune HIT-associated venous stroke. 178,190 However, the prognosis of venous stroke in HIT patients is inferior to that in patients with other risk factors. [191][192][193] Venous strokes frequently occur in individuals with hematolog-  Table 2).

| INFEC TI ON AND VACCINATI ON A SSO CIATED WITH VENOUS S TROKE
With the emergence of the COVID-19 pandemic, infection and vaccination have been associated with an increase in venous stroke, which has been raising concerns. 194,195  The treatment of COVID-19 VITT is centered on three key goals. 215 First, thrombosis must be prevented by anticoagulation.
Anticoagulation with nonheparin anticoagulants is the recommended treatment. Profound thrombocytopenia is not in conflict with anticoagulation. 216 Patients with COVID-19 VITT experiencing thrombotic complications are generally recommended a three-month course of therapy. If thrombocytopenia persists, further anticoagulation may be necessary, although the patient should be re-evaluated for thrombocytopenia. 213 Second, autoimmune process modulation is required to prevent the activation of further platelets. Intravenous immunoglobulins should be administered in conjunction with nonheparin anticoagulants, owing to improved platelet count and recovery in COVID-19 VITT by inhibiting serum-induced platelet activation. [217][218][219] George et al. 220 described the successful treatment of a patient with COVID-19 VITT and venous stroke using steroids, intravenous immunoglobulins, and bivalirudin. Patients with severe thrombocytopenia refractory to anticoagulation and intravenous immunoglobulin therapy may benefit from plasma exchange. 221 Therapeutic plasma exchange is an extracorporeal therapy that is not currently recommended for routine use for the treatment of COVID-19 VITT. 212 Third, COVID-19 VITT-specific complications should be addressed.
One of the most potentially deadly complications of COVID-19 VITT is major bleeding, particularly intracranial bleeding. Therefore, a transfusion to correct hypofibrinogenemia should be administered to patients with fibrinogen levels below 1.5 g/L. 215  Venous stroke is a rare but serious complication that can arised from both infection and vaccination. Infections in the craniofacial region, as well as vaccination, have the potential to cause venous stroke, which cannot be disregarded.

| CON CLUS ION
As a particular type of stroke, venous stroke is usually regarded with favorable outcomes and is primarily prevalent among young and middle-aged patients. However, some important risk factors, such as autoimmune diseases, hematological disorders., and even

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare no conflict of interest with respect to the present review study.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.