Recurrent Pediatric Cerebral Venous Sinus Thrombosis Due to Probable SERPINC1-related Antithrombin III Deficiency: A Case Report

To the Editor: Sir, the study by Canhao and colleagues made the important point that the most frequent cause of death in patients with cerebral venous thrombosis (CVT) is transtentorial herniation and that these patients may potentially have benefited from decompressive hemicraniectomy.1 We would like to corroborate this argument by providing evidence for a rise in intracranial pressure (ICP) preceding brain herniation and death in a patient with CVT. A 29-year-old pregnant woman who presented with confusion and vomiting was admitted to a district general hospital. A right-sided weakness developed within 2 days. A CT brain scan showed a left temporal hemorrhage without mass effect. Her Glasgow Coma Scale score dropped to 8/15; she was intubated and transferred to the neurocritical care …

This guideline was compiled according to the BSH process at [https://b-s-h.org.uk/media/16732/bsh-guidance-development-process-dec-5-18.pdf]. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. A literature search was carried out using the terms given in Appendix S1 until April 2021. Review of the manuscript was performed by the BSH Haemostasis and Thrombosis Task Force, the BSH Guidelines Committee and the sounding board of BSH. It was also placed on the members section of the BSH website for comment. It has also been reviewed by Royal College of Obstetricians and Gynaecologists, Royal College of Paediatrics and Child Health, Royal College of Physicians and Thrombosis UK, a patient-centred charity dedicated to promoting awareness, research and care of thrombosis; these organisations do not necessarily approve or endorse the contents. This guideline updates and widens the scope of the previous British Society for Haematology (BSH) Clinical guidelines for testing for heritable thrombophilia1 to include both heritable and acquired thrombophilia. The term thrombophilia is generally used to describe hereditary and/or acquired conditions associated with an increased predisposition to thrombosis. Heritable thrombophilia refers to genetic disorders of specific haemostatic proteins. These guidelines focus only on the factors that are identified from laboratory testing and therefore exclude disorders such as cancer, inflammatory conditions and obesity that are associated with thrombosis through multiple mechanisms. The most clearly defined heritable thrombophilias are the factor V Leiden (FVL) variant (F5 G1691A), the prothrombin gene variant (F2 G20210A), protein C (PC) deficiency, protein S (PS) deficiency, and antithrombin (AT) deficiency.2 Important acquired thrombophilias include the antiphospholipid syndrome (APS), paroxysmal nocturnal haemoglobinuria (PNH), myeloproliferative neoplasms (MPN) and the presence of a JAK2 mutation in the absence of an MPN phenotype. Pregnancy is a hypercoagulable state due partly to physiological changes in both the coagulation and fibrinolytic systems. Heritable and acquired thrombophilias can interact to further increase the risk of thrombosis, for example during pregnancy and the puerperium. As there is evidence that some thrombophilias may be associated with pregnancy failure and complications, testing for this purpose is included. Elevated levels of procoagulant factors may increase the risk of thrombosis but the relationship is not straightforward. First, part of the variance is genetic, and therefore lifelong, but some is acquired so that comorbidities such as obesity or inflammation confound the estimate of effect. Second, some factors, most notably factor V (FV), have anticoagulant effects that counterbalance a procoagulant effect from their elevation. A meta-analysis of 12 genome-wide association studies (GWAS) for venous thromboembolism (VTE) identified variants in F2, F5, F11, and FGG (encoding fibrinogen gamma chain) linked to thrombosis as well as non-O alleles of ABO which mediate their effect via elevation of von Willebrand factor (VWF) and secondarily factor VIII (FVIII).3 This approach does not detect rare variants with functional effects increasing thrombotic risk as reported in factor IX (F9), factor II (F2) and fibrinogen-alpha (FGA), fibrinogen-beta (FGB), and FGG.4-6 However, the relevance of these genetic variants to routine clinical practice is not clear at present. A phenotypic analysis was carried out as part of the Multiple Environmental and Genetic Assessment (MEGA) case–control study of VTE. After adjustment for age and sex, levels of factors II, X, IX, XI, VIII and fibrinogen all showed a positive association with risk of thrombosis. After additional correction for FVIII levels, only FIX and FXI retained significance with odds ratios (ORs) for levels >95th centile of 1.8 (95% confidence interval [CI]: 1.1–2.9) and 1.8 (1.1–3.0), respectively. In contrast, the OR for FVIII>95th centile was 16.0 (9.7–26.3) after correction for age, sex, and all the other coagulation factors.7 However, because of interacting heritable and acquired influences on FVIII activity, variability in levels over time, and as yet, lack of evidence of a role in the management of individuals with thrombosis or asymptomatic family members, routine testing for FVIII is not currently recommended. Despite results from animal studies, there remains no genetic or phenotypic8-10 evidence that variation in FXII is associated with thrombosis in humans.11 FXIII has a complex relationship with thrombosis due to interactions with other factors and the effects of genetic variants on FXIII activity assays. Genetic studies showed that the Val24Leu variant was associated with a reduced risk of venous thrombosis (OR: 0.85; 95% CI: 0.77–0.95).12, 13 The associations of PC, PS and AT deficiencies with increased risks of VTE are well-established.14 The degree of deficiency is variable and sensitive to assay type but in general thrombosis risk rises as soon the levels of protein C, S or AT fall below the normal range. In contrast, although tissue factor pathway inhibitor (TFPI), heparin cofactor II, and protein Z-dependent protease inhibitor (ZPI) and its cofactor, protein Z, are also natural anticoagulants, the clinical significance of genotypic or phenotypic variation in these is uncertain and testing for clinical purposes is not recommended. Guidelines on laboratory aspects of testing for deficiencies of natural anticoagulants have recently been published by the British Society for Haematology15 and the International Society on Thrombosis and Haemostasis.16-18 The risk of a first episode of VTE is increased around 15-fold in heterozygous AT deficiency.19 Overall, the risks are similar in those with type I and type II defects with the exception of most type II heparin binding defects, which appear to have a 4-fold lower risk.19 In contrast, homozygous heparin binding site defects appear to be associated with a high thrombotic risk.20 Further differences within antithrombin subtypes have also been observed.21 However, data on differences in risk between and within different subtypes are limited, and findings vary according to study design, the population being studied (family or non-family members), and whether all or only unprovoked venous thrombotic events were included in the analysis. In those with heterozygous PC or PS deficiency, the risk of a first episode of VTE is increased around 5–7-fold.19, 22, 23 There are no clinically useful differences in thrombotic risk between type I and type II PC deficiency15 and no clear evidence of a difference in risk between different subtypes of PS deficiency. These risks for heterozygous PC and PS deficiency are similar to or greater than those associated with FVL variant or F2 G20210A variant, but deficiencies of the natural anticoagulants are much less common (population prevalence of <0.5% for each deficiency), at least in those of European origin, and contribute relatively little to the population burden of VTE. Deficiencies of physiological anticoagulants interact with acquired risks and a transient provoking factor is present in approximately 50% of episodes of VTE in genetically predisposed individuals.24, 25 Since deficiencies of these natural anticoagulants are caused by multiple different genetic variants, clinical laboratory assessment is generally based on measurement of plasma activities or concentrations rather than molecular analysis.15 Acquired causes of deficiencies (Table 1) should always be considered before testing and when interpreting results as, if present, it may not be possible to reliably diagnose a heritable deficiency. Acquired problems include warfarin and the potential assay-dependent impact of direct oral anticoagulants (DOACs).15 When the decision has been made to test for deficiencies of physiological anticoagulants, this should be performed only after 3 months of anticoagulation for acute thrombosis, as there is uncertainty over the validity of the results obtained earlier, leading to repeat testing and increased costs, and with there being no evidence that it influences acute management. Protein C activity Chromogenic assay Protein S Free protein S antigen Antithrombin activity Chromogenic assay Physiological reduction Neonates and children (different normal range from adults) Other causes of reduction Vitamin K antagonists (e.g., warfarin) Vitamin K deficiency Liver disease Disseminated intravascular coagulation Severe sepsis Artefactual increase DOACs or heparin if using clotting-based assay Artefactual decrease Factor V Leiden if using clotting-based assay Physiological reduction Neonates (Different normal range from adults) Pregnancy and puerperium Other causes of reduction Vitamin K antagonists (e.g., warfarin) Vitamin K deficiency Liver disease Nephrotic syndrome Disseminated intravascular coagulation Severe sepsis Recent thrombosis Oral oestrogen therapy (e.g., combined oral contraceptive pill or hormone therapy) Acute phase response Sickle cell disease Artefactual increase DOACs or heparin if using clotting-based assay. Artefactual decrease Factor V Leiden if using clotting-based assay Physiological reduction Neonates (Different normal range from adults) Late pregnancy, early postpartuma a James et al. 2014.176 Other causes of reduction Liver disease Disseminated intravascular coagulation Nephrotic syndrome Severe sepsis Recent thrombosis Heparin therapy L-asparaginase therapy Artefactual increase DOACs: Xa inhibitors – if using Xa-based assay Thrombin inhibitors – if using thrombin-based assay The FVL and F2 G20210A variants are the most commonly tested genetic variants predisposing to VTE.29 These are detected using polymerase chain reaction (PCR)-based methods. Their prevalence varies in populations of different ethnicity. For example, heterozygosity for FVL is present in about 5% of individuals of European descent but is rare or absent in peoples from sub-Saharan Africa, East Asia and indigenous populations of the Americas and Australia. Similarly, heterozygosity for the prothrombin gene variant is present in 1%–2% of Europeans and is rare or absent in other ethnic populations.30 The FVL variant abolishes a cleavage site for activated PC in factor V increasing procoagulant activity. The prothrombin gene variant is a point mutation (G20210A) in the 3′ untranslated region of the gene31 causing increased levels of prothrombin.32 These variants result in increased relative risks for first venous thrombosis of 5- and 3-fold, respectively.33 A large number of variants in other genes with a wide range of prevalences have been reported to confer an increased risk of thrombosis. These include variants of methylenetetrahydrofolate reductase (MTHFR), SERPINE1 (encoding plasminogen activator inhibitor type 1) (PAI-1) and factor XIII as well as variants linked to the quantitative changes in procoagulant factors discussed above.28 However, either their association with thrombosis is not convincingly consistent or their effect is too small to alter management and they should not be included in thrombophilia panels at present. Although it has been shown that multiple variants present in an individual can combine to identify a significant risk of recurrence,34 this requires validation and we do not yet know how and when to introduce this oligogenic model into practice. Paroxysmal nocturnal haemoglobinuria (PNH) and myeloproliferative neoplasms (MPN) are acquired genetic traits that increase the risk of thrombosis. PNH is an acquired clonal stem cell disorder characterised by the expansion of a population of blood cells deficient in glycosylphosphatidylinositol anchored proteins (GPI-AP) due to PIGA gene mutation resulting in a deficiency or absence of all GPI-anchored proteins including CD55 and CD59 on the cell surface. Absence of CD59 leads to chronic complement activation resulting in the classical clinical features of intravascular haemolysis and thrombosis.35 Up to 10% of patients with PNH will present with thrombosis. The neutrophil clone size correlates best with thrombosis risk and patients with a clone of over 50% have a cumulative 10-year incidence of thrombosis of 34.5% compared to 5.3% in those with a clone of <50%. MPNs are characterised by clonal expansion of an abnormal haematopoietic stem/progenitor cell and include polycythaemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). MPN or presence of a clone characterised by a JAK2 mutation in the absence of an MPN phenotype are associated with arterial and venous thromboses.36 The thromboses associated with PNH and MPN can occur anywhere in the venous or arterial systems but particularly in unusual sites for example, splanchnic vein thrombosis (SVT) (which includes portal vein (PVT), mesenteric vein (MVT) and splenic vein thrombosis, and the Budd–Chiari syndrome (BCS)) and cerebral venous sinus thrombosis (CVST).37, 38 In MPN, thrombosis often precedes disease recognition. Molecular abnormalities, primarily the V617F mutation in JAK2 exon 14, are found in 95% of PV (and an exon 12 mutation in most remaining patients) and in 60%–70% of ET and PMF patients.39 Isolated JAK2 mutations occur in approximately 0.1%–0.2% of the general population without an MPN phenotype and in 2.9%–5.6% of patients with CVST with no MPN phenotype40 (Table 2). A proportion of patients positive for JAK2 mutation with normal full blood count at presentation progressed into MPN during follow-up.41 Mutations of MPL exon 10 are present in about 5% of those with ET or PMF.42-44 In patients without JAK2 or MPL mutations, 67%–71% of those with ET and 56%–88% of those with PMF are positive for a calreticulin gene (CALR) mutation.45 In a study by Rumi et al. of 1235 consecutive patients diagnosed with ET or PV, the incidence of thrombosis associated with JAK2-mutated patients with ET and PV was similar; 7.1 and 10.5% respectively and was four times that of patients with ET and the CALR mutation (2.8%). The incidences of thrombosis associated with the JAK2 exon 12 and MPL mutations are not well documented due to the small number of patients with these mutations. Testing for JAK2, CALR, MPL variants in peripheral blood is sensitive and bone marrow samples are not required.39 Detailed guidance on assays used for detection of JAK2 mutations is available in separate guidelines.46 Diagnosis of PNH is based on flow cytometric analysis using antibodies directed against GPI-AP.47 The diagnosis of APS is dependent on the presence of at least one clinical feature (thrombosis or pregnancy morbidity) and at least one laboratory feature of antiphospholipid antibodies (aPL) which include lupus anticoagulant (LA), immunoglobulin (Ig) G or IgM anticardiolipin antibodies (aCL) or anti-β2-glycoprotein-I (anti-β2GPI) antibodies).48 The aPL need to be persistent, that is, present on two or more occasions at least 12 weeks apart.49 Of the three tests, a positive LA appears to be the most strongly associated with recurrent thrombosis, but individuals who are positive for all three assays ("triple positives") have the highest thrombotic risk.50-52 Although the BSH guidelines (2012) on the investigation and management of antiphospholipid syndrome stated that in patients with thrombosis, measuring IgM antibodies does not add useful information,53 both IgG and IgM aCL and anti-β2GPI are part of the international consensus on laboratory diagnostic criteria for APS.49 There is increasing evidence that IgM anticardiolipin and anti-β2GPI antibodies have a pathogenic role in patients with APS.54-57 In patients with thrombotic APS, uncertainties remain as to the recurrence risk in patients with an initial unprovoked, compared to provoked, VTE and in those with venous compared to an initial arterial thrombosis.58 There is increasing evidence that the recurrence risk of VTE provoked by minor risk factors is similar to that with unprovoked VTE.59, 60 Therefore, such patients may also benefit from extended anticoagulation therapy as in those with unprovoked VTE. As the presence of antiphospholipid antibodies may alter management including choice of antithrombotic therapy in these patients, it may be reasonable to test for antiphospholipid antibodies. Catastrophic APS (CAPS) is a rare, but potentially fatal, variant of APS characterised by sudden onset of extensive microvascular thrombosis at multiple sites leading to multiorgan failure.61 CAPS tends to occur usually in patients with triple positive APS. Recommendations on the timing of, and indications for, antiphospholipid antibody testing following venous or arterial thrombosis are provided in the Addendum to British Society for Haematology Guidelines on Investigation and Management of Antiphospholipid Syndrome (2020).62 In asymptomatic individuals with triple positive antiphospholipid antibodies (mostly identified because of a prolonged activated partial thromboplastin time or presence of an autoimmune disorder), the incidence of first thrombotic events (which were equally distributed between venous and arterial thrombosis) was estimated to be 5% per year.52 Lower incidences of thrombosis of 1% and 0.5% annually respectively have been described in asymptomatic single antibody positive individuals and in women with the obstetric antiphospholipid syndrome.63, 64 In situations where the clinical utility of testing is not clear, testing is clearly not mandatory (clinical utility is defined as the ability of a test to improve clinical outcome). It is important that patients are counselled in advance of any decision on whether or not to undertake testing. This should include discussion of the aims of testing and how it might alter management decisions. What is the utility of identifying a heritable thrombophilic trait in a patient who has had a venous thrombotic event in modifying their future management or the management of asymptomatic family members? The relative risk of thrombophilic traits for recurrent VTE is less than that for a first episode of thrombosis because the comparator group is different. Moreover, the risk is managed differently, and no clinical trials have been undertaken. There are conflicting data on the association of FVL and F2 G20210A variants with risk of recurrence in the overall population of patients with VTE.33, 65 Observational data suggest that FVL Leiden but not F2 G20210A is associated with an increased risk of recurrence.33, 65 However, in a study with of 354 consecutive patients aged ≥65 years with a first unprovoked VTE, 9.0% of patients had FVL and 3.7% had a F2 G20210A variant.66 After adjustment for age, sex, and periods of anticoagulation as a time-varying covariate, at 3-year follow up neither the FVL (HR 0.98; 95% CI: 0.35–2.77) nor the F2 G20210A mutation (HR 1.15; 95% CI: 0.25–5.19) was associated with recurrent venous thromboembolism compared to controls.66 Patients with natural anticoagulant deficiencies were from studies from which for recurrent VTE after of for a first event were A meta-analysis of individuals with AT deficiency the odds of recurrence were increased with an recurrence risk without anticoagulant therapy of (95% CI: for and (95% CI: for VTE A further study in which AT was in on only one found the odds of recurrent VTE were increased (95% CI: in those with AT activity centile and (95% CI: in those with AT activities of In a study of the risk of recurrent VTE in patients who not anticoagulant was (95% CI: in those with PC deficiency and (95% CI: in those with PS In a the odds of recurrent VTE were increased (95% CI: in PC deficient patients and (95% CI: in those with PS deficiency 10 the of recurrence were and patients with FXI activity between the and or Patients with the highest factor VIII had a for recurrence of (95% CI: compared to those with FVIII In terms this to a recurrence of 5% per compared to per Although these effects are their utility is Clinical in with such as in patients, can identify those risk of recurrence is high to anticoagulation and which is not by the absence of a thrombophilic These factors also identify patients with risk of recurrence not in the presence of heritable thrombophilic There is no evidence that the presence of heritable thrombophilia influences the choice or the of anticoagulant therapy when thrombosis potentially in those with AT In AT deficiency, diagnosis specific which can be and can also of laboratory of this is a rare disorder and so routine testing is not in the absence of a family as two or more with For patients with a and/or family of thrombosis in the absence of a clear risk genetic analysis via is available as and should be combined with phenotypic testing where The of a genetic trait with the strength of the family The heritable thrombophilic traits follow with variable of FVIII and FXI have clear genetic but also significant acquired so the of being is less of a heritable trait in a family does not a risk of thrombosis high to anticoagulation and does not alter most However, some guidelines include of heritable thrombophilic traits in their risk assessment with a impact on Absence of that trait in a family their risk of thrombosis but does not it to normal and the utility of testing will on their and the of the VTE Overall, the recurrence risk for VTE is by the clinical (e.g., provoked with risk factors (e.g., and rather than the thrombophilia Therefore, when a patient is to have a heritable thrombophilic it may be reasonable to testing of when this will alter their management for example, deficiencies of PC, PS or AT deficiency in a of for FVL is not in women with a first degree relative with FVL but no of thrombosis or to combined oral contraceptive or oestrogen However, the of family of thrombosis, thrombophilia testing and risk of thrombosis of should be discussed with all women to whether they will alter their therapy and should be documented Investigation and management of thrombosis at unusual sites are discussed in BSH For thrombosis at unusual which often or conditions the testing for thrombophilia should be for patients with The association of MPN and PNH with thrombosis at unusual which includes splenic vein thrombosis and the has been in and these disorders should be tested for in the absence of a clear for the such as or of data from found that in of patients, splanchnic vein thrombosis the diagnosis of For the remaining patients, thrombosis at a of years after Diagnosis of PNH and MPN is important because these have specific in to anticoagulation to recurrent thrombosis. In a and meta-analysis of small studies to assess the prevalence of heritable thrombophilia in patients with and the prevalence of PC, and PS deficiencies were and in and and in respectively. three studies compared the prevalence of heritable thrombophilia between patients and The odds ratios of heritable PC and PS deficiencies for were (95% CI: (95% CI: and (95% CI: These studies are only for the first thrombotic event and the risk of recurrent events associated with heritable thrombophilia and thrombosis at unusual sites is not well but to be Therefore, the of testing for heritable thrombophilia is and testing should be considered only if the thrombotic event in the absence of a clear risk factor for the event at a age CVST is a rare for of all The of CVST patients will have an risk the most common of which are oral contraceptive and Other rare causes that can contribute to CVST include APS, MPN, chronic inflammatory and factors such as or CVST is reported in of patients with and around of patients with of patients diagnosed with CVST are found to have a JAK2 mutation with normal full blood count at (Table 2). CVST are reported in to of patients with However, it is not clear how of these patients had a normal full blood count at presentation with studies have shown the presence of aPL the risk of thrombosis at unusual sites such as and As the type and of anticoagulation are by the presence of antiphospholipid testing for these antibodies is in an BSH In the absence of a clear risk patients with CVST may need anticoagulation and routine testing for heritable thrombophilia is not There is no evidence to suggest an association of heritable thrombophilia with vein The pathogenic role of antiphospholipid antibodies in is A meta-analysis of studies showed that presence of antiphospholipid antibodies was associated with incidence of 95% CI: A more study that included consecutive patients with and also showed that antiphospholipid antibodies were more in than in 10% OR 95% CI: with patients more lupus anticoagulant or triple positive antiphospholipid antibody than Testing for aPL may be considered in patients without risk factors and no other for such as and as those with positive aPL be considered for There is conflicting evidence with to the presence and the strength of associations between FVL and F2 G20210A variant and arterial thrombosis. Although some studies a increased risk of in patients with FVL or F2 G20210A variants, this has not been in S1 on the association of the FVL or with These variants are common in the European population and will be found in patients with their presence a role for events is not and is to from these When significant associations have been these have been too to be of clinical significance and there are no clinical trials to suggest that management should be as a result of the presence of these heritable deficiencies of PC and PS are rare, studies with to assess potential associations with risk of arterial thrombosis are Overall, there is no evidence to an association between heritable thrombophilia and arterial thrombosis in a

Sir, Cerebral venous sinus thrombosis (CVST) primarily affects young and middle-aged population. It accounts for 0.5–1% of all strokes.[1] It has an annual incidence of 3–4/million population.[2] Due to its rarity, large population-based studies are sparse, although several case series have been reported from India.[3] Unlike arterial stroke, only one-third CVST patients present acutely. Nearly half have subacute CVST and one-fifth develop symptoms gradually over more than a month.[2] To date, no Indian studies has discussed differences in risk factors, clinical profile, neuroimaging findings, and outcome of acute, subacute, and chronic CVST. Herein, we have compared the same. This retrospective study involved CVST patients at a tertiary care hospital in North India from May 2018 to March 2020. All CVST patients aged ≥18 years were included. CVST was confirmed by brain magnetic resonance imaging (MRI) and MR venography (MRV) or computed tomography scan of brain venous sinuses (CTV). Patients with non-venous cerebral stroke and infection-related CVST were excluded. Demographic and clinical features including risk factors, obstetric history in females, neuroimaging findings, treatment, and outcome details were collected. In-hospital complications including need for decompressive craniectomy, intensive care unit (ICU) and mechanical ventilation were recorded. Modified Rankin Score (mRS) was used to assess neurological severity and outcome at discharge and 6-month follow-up, with a score of 0–1 defining "good functional outcome." We categorized patients in acute (<8 days), subacute (8–30 days) and chronic (>30 days) groups according to symptom duration at presentation. Hemoglobin <11 g/dl in pregnant, <12 g/dl in non-pregnant females and <13 g/dl in males was considered anemic.[4] Hyperhomocysteinemia was defined as plasma homocysteine level >15 μmol/L.[5] The analysis was done using Statistical Package for Social Sciences (SPSS) v28.0. Descriptive statistics was calculated. Chi-Square or Fisher's exact test was used to compare categorical variables. The 36 included patients were grouped into acute (n = 16;44.5%), subacute (n = 15;41.7%) and chronic (n = 5;13.9%) CVST [https://links.lww.com/AIAN/A52]. Mean age of patients was 31.94 years (range = 20–70), with 19 (52.8%) being males. [https://links.lww.com/AIAN/A53] shows risk factors and clinic-radiological profile of entire cohort. [https://links.lww.com/AIAN/A54] compares the risk factors, clinico-radiological profile, and outcome of CVST patients in the three groups. While proportion of acute and subacute CVST patients with obstetrical risk factors were comparable, it was absent in chronic CVST [Supplementary Table 2]. A comparable proportion in each group had anemia with iron deficiency and history of alcohol consumption. Alcohol consumption was more frequent in male patients (P = 0.09). Hyperhomocysteinemia was detected in 13 (36.1%) patients, with two showing methylenetetrahydrofolate reductase mutation. A significantly higher proportion of males had hyperhomocysteinemia (male: female = 52.6%:17.6%; P = 0.04). Amongst 5 (13.9%) patients with thrombophilia, antiphospholipid syndrome, Protein S, and Protein C deficiency was seen in 2 (5.6%), 2 (5.6%), and 1 (2.8%) patient, respectively [Supplementary Table 1]. Headache (88.9%), seizures (58.3%), altered sensorium (25%), and visual impairment (19.4%) were common presenting symptoms. While a similar proportion in all three groups reported headache, a significantly higher proportion of acute CVST patients manifested seizures (P = 0.048) [Supplementary Table 2]. Although a comparable proportion of patients in all three groups showed infarction on neuroimaging, a significantly higher proportion of acute CVST patients developed hemorrhagic infarction (P = 0.04). While superior sagittal sinus (SSS) and transverse sinus (TS) was involved in two-third patients, sigmoid sinus (SdS) was involved in 55.6% patients [Supplementary Table 1]. SSS was most commonly involved in acute, and TS in subacute and chronic CVST. Initial anticoagulation with either subcutaneous low-molecular-weight heparin (LMWH) (n = 31;86.1%) or intravenous heparin (n = 5;13.9%) was followed by oral anticoagulation. Two patients, one presenting acutely and another subacutely, underwent decompressive craniectomy, with the former failing to survive. Although subacute CVST had a higher median mRS at admission compared to acute and chronic CVST, 92% of all patients attained good functional outcome at 6 month. Two (5.5%) patients, both with acute CVST, could not survive [Supplementary Table 2]. Acute, subacute, and chronic CVST was seen in 44.5%, 41.7%, and 13.9% of our patients, respectively. The same was reported in 14.2%, 72.8%, and 12.3%, respectively, in a previous Indian study, where patients presenting within 48 hours of symptom onset were included in acute group.[6] Puerperal state, anemia, alcohol consumption, hyperhomocyteinemia, antiphospholipid syndrome, Protein S, and Protein C deficiency was seen in 25%, 25%, 19.4%, 36.1%, 5.6%, 5.6%, and 2.8% of our cases, respectively, with Narayan et al. reporting the same in 9.8%, 18.4%, 15.6%, 18.2%, 7.2%, 12.3%, and 9.1% patients, respectively.[6] Although, the risk factors were comparable in the three groups, alcohol consumption was seen in higher proportion of acute CVST. Post-partum state and anemia with iron deficiency was common in subacute CVST. Alcoholism has been reported in male CVST patients previously,[6] with dehydration, enhanced coagulability, and increased platelet reactivity likely precipitating acute CVST.[6] Subacute CVST in post-partum females appear related to a delay in seeking consultation due to lack of awareness in primary physicians and general population. Anemia with iron deficiency may result in thrombocytosis, reduced red blood cell deformability and increased viscosity, thereby contributing towards CVST.[7] Headache was the most common presenting symptom in all three CVST groups similar to previous reports.[689] Up to 50% of CVST patients develop seizures,[68910] and was seen in 58.3% of our patients. While most clinical features were comparable in the three groups, seizures manifested in a significantly higher proportion of acute CVST patients, probably related to increased parenchymal involvement, especially hemorrhagic infarction. Neuroimaging showed SSS and TS involvement in two-third patients and was comparable to 54.3% and 48% involvement, respectively, reported previously.[6] While SSS was most commonly involved sinus in acute, TS thrombosis was most frequent in subacute and chronic CVST. Since SSS is the primary drainage site for cortical veins and CSF, its blockage may result in early decompensation and appearance of clinical symptoms. Development of adequate collaterals and gradual compensation due to patent SSS might have delayed the symptoms despite TS involvement in subacute and chronic cases. Majority of patients (92%) reported a good functional outcome at 6-month. In-hospital mortality in 2 (5.6%) patients, both acute CVST, was comparable to 4–8% mortality in acute phase reported previously.[26] Single-center study, retrospective design, and small sample size are the major limitations of our study. Authors' contributions to the manuscript Dr. Desai I: Writing the first draft; data collection; statistics Dr. Tiwari A: Writing the first draft; review and critique Dr. Kumar M: Statistics; review and critique Dr. Singh J: Data collection; review and critique Dr. Dhar N: Data collection; review and critique Dr. Kumar N: Conception; design; writing the first draft; statistics; review and critique Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

BACKGROUND: Cerebral venous thrombosis is a multifactorial and difficult-to-diagnose disease, complicated by venous stroke, intracerebral hemorrhage, progressive cerebral edema, dislocation syndrome, and even death. The broad variability of clinical symptoms and lack of pathognomonic manifestations complicate timely diagnosis of cerebral venous thrombosis. AIM: To identify significant risk factors for cerebral venous thrombosis and to evaluate the dynamics of neuroimaging findings at 1, 3, and 6 months after cerebral venous thrombosis onset in young and middle-aged patients with a history of COVID-19, comparing outcomes between those treated with direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs). METHODS: Young and middle-aged patients with a history of novel coronavirus infection (COVID-19) were examined and divided into two groups depending on the presence or absence of cerebral venous thrombosis. The main risk factors, structural features of the major arteries and cerebral venous sinuses, as well as the course of cerebral venous and sinus thrombosis during anticoagulant therapy (with direct oral anticoagulants and vitamin K antagonists) at 1, 3, and 6 months after the development of cerebral venous thrombosis were analyzed. RESULTS: We examined 120 young and middle-aged patients with COVID-19 divided into 2 groups: Group I – 70 patients who developed cerebral venous thrombosis during COVID-19 – 21 (30%) men and 49 (70%) women; Group II – 50 patients who had COVID-19 without cerebral venous thrombosis development – 27 (54%) men and 23 (46%) women. The main risk factor for developing cerebral venous thrombosis among women in the first group (with cerebral venous thrombosis during COVID-19) compared to the second group (patients who had COVID-19 without developing cerebral venous thrombosis) was the use of combined oral contraceptives: 22.9% and 4.0%, respectively (р = 0.001). Among group I patients, 32 (45.7%) cases of cerebral venous thrombosis were accompanied by the development of venous stroke: ischemic in 13 (18.6%) patients, hemorrhagic in 7 (10%), mixed (ischemic stroke with hemorrhagic infiltration) in 12 (17.1%) patients. In a comparative analysis of the variants of the structure of the cerebral arteries (absence of the posterior communicating arteries, pathological tortuosity of the internal carotid artery [ICA], trifurcation of the ICA, open arterial circle of Willis) and venous sinuses (presence of hypo-/aplasia), no statistically significant difference was detected. The analysis of the course of cerebral venous thrombosis during treatment with vitamin K antagonists (warfarin) and direct oral anticoagulants in 53 patients with cerebral venous thrombosis (age 41 ± 12 years) at 1,3, and 6 months after the development of cerebral venous thrombosis onset showed that with anticoagulants, recanalization was observed in 44 (83%) patients: complete – in 21 patients (47.7%), partial – in 23 (52.3%). Recanalization was absent in 9 (17.0%) cases. No recurrent cerebral venous thrombosis cases were observed among the study patients. CONCLUSION: Verification of cerebral venous thrombosis in the context of COVID-19 necessitates a detailed examination of risk factors, patient history, assessment of clinical manifestations, and comprehensive implementation of laboratory and instrumental, as well as neuroimaging diagnostic methods. Timely verification and immediate initiation of anticoagulant therapy ensure a relatively favorable prognosis for the disease course.

Extensive cerebral venous sinus thrombosis with hemorrhagic venous infarction as the initial presentation of acute myeloid leukemia: A case report.

Dear Sir: Cerebral venous thrombosis (CVT) is a rare variety of cerebrovascular disease that can occur at any age and generally has a favorable outcome. However, poor outcome in CVT has been documented [1]. It is caused by a wide range of etiologies, polycythemia is one among them. Polycythemia is a myeloproliferative disorder that is caused by a variety of etiologies [2]. The occurrence of malignant CVT as a presenting manifestation of polycythemia has not been reported so far. Here, we report a 58-year-old man, who presented with status epilepticus and had mixed density lesion in left fronto-parietal region, which rapidly progressed within 24 hours to cause transtentorial herniation, requiring decompressive surgery. A 58-year-old man was brought with history of 2 episodes of generalized tonic-clonic seizures (GTCS) with no regaining of consciousness in between the episodes of 1 day duration. There was preceding history of holocranial headache with vomiting 1 day prior, which lasted for 2 hours and subsided with analgesics. He did not have fever or loose stools. In the emergency room, he had 1 more episode of GTCS. He was a smoker and used to consume alcohol. On examination, he was stuporous. Pupils were equal but reacting sluggishly to light. There was bilateral papilledema. Gaze preference to left was present. Motor examination showed paucity of movement in right upper and lower limb with right plantar extensor response. Hematological investigations revealed high hemoglobin (Hb) level (22 g/dL) and a hematocrit of 57.5%. Total leukocyte and platelets counts were normal. Renal, hepatic and thyroid function tests, serum electrolytes were normal. Computed tomography (CT) brain at admission showed mixed density lesion in left fronto-parietal region with hemispheric edema and anterior inter-hemispheric fissure bleed (Figure 1). Magnetic resonance venography (MRV) brain showed non-visualization of left transverse, sigmoid sinuses and internal jugular vein (Figure 2). Serum homocysteine, protein C, S, anti-thrombin III and factor V leiden levels were normal. Anti-phospholipid and anti-nuclear antibodies were negative. Serum erythropoietin level was normal and JAK2 mutation was negative. Abdominal ultrasonography was normal. Therapeutic phlebotomy was carried out. He was started on heparin anticoagulation and anti-edema measures (mannitol, oral glycerol). Figure 1. Non-contrast CT brain (A) & (B) at time of admission shows bleed in anterior interhemispheric fissure (red arrow) (A); (B) hemorrhagic lesion in left fronto-parietal region with hemispheric edema; (C) At 12 hours after admission shows increase ... Figure 2. MRV brain (A) & (B) showing non-visualization of left transverse, sigmoid sinuses and left internal jugular vein. His sensorium remained the same and repeat CT brain after 12 hours revealed increase in the size of the lesion with mass effect. Anti-edema measure was intensified and was put on ventilator for hyperventilation. He developed pupillary asymmetry within the next 12 hours. Repeat CT brain showed worsening of lesion with mass effect and midline shift suggestive of trans-tentorial herniation (Figure 1). Patient was taken up for emergency decompressive craniectomy. There was no improvement in sensorium following surgery. Post operative Hb level was 16 g/dL. Within the next 24 hours, his Hb level rose to 21 g/dL. Therapeutic phlebotomy was carried out. The expertise for endovascular intervention was not available. Patient succumbed to illness within 36 hours of surgery. A wide range of etiologies have been implicated in the causation of CVT. Hypercoagulable disorders, like factor V Leiden mutation, presence of anticardiolipin antibody, antithrombin gene mutation and myeloproliferative neoplasms like polycythemia vera and essential thrombocythemia are one among them [2,3]. Thrombosis is a serious complication of polycythemia and can lead to death in up to 8.3% of patients as reported by Ferro et al. [4]. Polycythemia can be primary (caused mainly by mutation in the JAK2 gene) or secondary [5]. Chronic hypoxia causes secondary polycythemia by increasing serum erythropoietin levels leading to excess production of erythrocytes from the bone marrow [6]. Polycythemia causes stasis of blood that result in hyperviscosity leading to the development of thrombosis. Thrombosis of cerebral veins or sinuses results in raised venular and capillary pressure. As local venous pressure rises, there is decrease in cerebral perfusion causing ischemic injury and cytotoxic edema. Along with cytotoxic edema, disruption of the blood-brain barrier leads to vasogenic edema, and venous and capillary rupture culminates in parenchymal hemorrhage. Thrombosis of cerebral sinuses impairs CSF absorption, leading to increased intracranial pressure. Consequently, increased intracranial pressure worsens venular and capillary hypertension and contributes to parenchymal hemorrhage and vasogenic and cytotoxic edema [7]. CVT has a favorable outcome with timely diagnosis and intervention. However, unfavorable outcome do occur. Factors related to acute mortality in CVT includes advanced age, disturbed consciousness, focal neurological deficits, recurrent seizures, and hemorrhagic infarct [8]. In the prospective International Study on CVT (ISCVT) cohort of 624 patients, death occurred in 8% and moderate to severe disability in 5.1% of patients, despite the use of anticoagulant treatment [4]. Transtentorial herniation is the most frequent cause of death. Endovascular treatment appears to be reasonably safe and can be considered in severe cases that do not respond to heparin therapy. However, impending transtentorial herniation does not benefit from endovascular thrombolysis and needs cranial decompressive surgery. But, Coutinho et al. [9] reported successful treatment of CVT with impending herniation with decompressive hemicraniectomy followed by endovascular thrombosuction. Malignant CVT refers to supratentorial cortical lesions attributable to superficial venous system thrombosis with or without sinus involvement; with clinical or radiological signs of transtentorial herniation; either at onset or after worsening despite anticoagulation [10]. In a series by Theaudin et al. [10] regarding the performance of decompressive surgery in malignant CVT, none of the 12 patients with malignant CVT had polycythemia as a risk factor. The only identifiable risk factor for CVT in our patient was polycythemia. Even though JAK2 mutation results were negative, primary polycythemia cannot be ruled out as 20% of cases of polycythemia vera possess a negative JAK2 mutation, and serum erythropoietin levels were normal. Bone marrow studies could not be done in view of poor general condition. The possible etiology for polycythemia may be smoking. Smoker’s polycythemia presenting as CVT is uncommon, and there is a paucity of evidence suggesting such an association. Smoker’s polycythemia is diagnosed after exclusion of other causes of primary polycythemia, such as JAK2 mutation and erythropoietin level. Polycythemia is one of the causes for occurrence of the CVT. However, the occurrence of malignant CVT in association with polycythemia has not been reported so far.

Vaccine‐induced Immune Thrombocytopenia and Thrombosis (VITT)

Local fibrinolysis in cerebral venous thrombosis

Intracranial haemorrhage with a twist

Surgical treatment of refractory and extensive cerebral venous sinus thrombosis (CVST) has limited applications. Here, we describe an open, direct sinus thrombectomy in the early phase of extensive CVST. A 49-year-old man with extensive CVST that occurred after the coronavirus disease 2019 (COVID-19) vaccination and affected the drainage of the Labbé vein presented with clinical deterioration and left temporal hemorrhagic infarction. Since the patient had extensive CVST, we determined that systemic anticoagulation and endovascular treatment were not suitable treatment options. Therefore, we decided on an emergency surgical treatment and performed direct surgical thrombectomy. We followed extended suboccipital approach and made multiple incisions on the sinuses, exposing the posterior superior sagittal sinus to the transverse sigmoid junction. Consequently, the clinical condition of the patient dramatically improved, resulting in a favorable outcome with a modified Rankin scale score of 0. Performing emergency open surgical thrombectomy was a technically feasible treatment option that recanalize obstructed sinuses. Importantly, the patient recovered with a good clinical outcome. Early maximal surgical thrombectomy can be an effective and lifesaving method to treat extensive CVST with hemorrhagic infarction.

Objective To explore the clinical efficacy and long-term outcomes of anticoagulants therapy in pediatric cerebral venous sinus thrombosis (CVST). Methods 58 CVST children aged 1 month to 16 years received an standardized anticoagulant therapy of low molecular weight heparin, warfarin and urokinase.Initial and follow-up neuroimages were evaluated for associated intracranial hemorrhage, thrombus propagation rate and long-term quality-of-life.And clinical outcome was assessed by the modified Rankin scale (mRS). Results Among them, 38/58 received anticoagulants at diagnosis.Major anticoagulation-associated hemorrhage occurred in 5.3% (2/38) and clinical outcome was favorable.Early follow-up imaging demonstrated thrombus propagation in 5/58 children (1/38 with and 4/20 without anticoagulation[P=0.023]). Five deaths were associated with CVST (1 with anticoagulation). The decreasing rate of mortality in CVST with anticoagulation was 25%-30%.Clinical outcomes of death and long-term worse prognosis were unfavorable in 22%(11/50). The clinical risk factors of long-term outcomes were full-term infant (OR[odd ratio]0.12, P=0.045), neuroimaging of multiple lesions (OR 15.16, P=0.042) and anticoagulation (OR 0.007, P=0.024). Initial intracranial hypertension was associated with neonatal asphyxia (OR 0.35, P=0.025), neuroimaging of multiple lesion (OR 8.73, P=0.048) and onset time (OR 0.89, P=0.003). Furthermore anticoagulation was probably helpful for CVST children in controlling subacute intracranial pressure (P=0.048). Conclusions In pediatric CVST with mild intracranial hemorrhage, anticoagulation is both safe and effective.And it may reduce the rate of mortality, enhance quality-of-life and improve long-term outcomes. Key words: Cranium; Venous sinus; Thrombosis; Comparative Study

Background and Purpose: Increasing concern of cerebral venous thrombosis due to treatable and curable causes of stroke. The diagnosis of cerebral venous sinus thrombosis is challenged due to nonspecific clinical symptomatology. Patients may present at an emergency room with a variety of neurological conditions such as severe headache, weakness, seizure, etc. Neuroimaging, particularly noncontrast cranial computed tomography (NCCT), is an investigation of choice in differentiation and triage the patients for further treatment. CT is sensitive in the detection of acute thrombosis or blood clots in all regions of the body. We hypothesize that NCCT might be sensitive to diagnose cerebral venous thrombosis immediately. Materials and Methods: Retrospectively review the electronic database of our patients, there are 27 patients with cerebral sinus venous thrombosis (SVT) and 4 patients with cerebral deep venous thrombosis (DVT). Other 79 patients present with clinically diagnosed cerebral venous thrombosis but the final result can exclude cerebral venous thrombosis. We use MR imaging and CT venography as the gold standard. Independently reviewed by two neuroradiologists for CT direct sign and CT indirect signs that suggest SVT or DVT. CT direct signs for SVT and DVT are the presence of hyperdensity in the sinus venous or deep venous system (cord sign, attenuated vein sign) and CT indirect signs are the changes in brain parenchyma (brain edema, hemorrhagic infarction). Results: Sensitivity and specificity of NCCT in detection attenuated vein sign and diagnosis DVT are 75% and 100% whereas the sensitivity and specificity of NCCT in detection cord sign and diagnosis SVT are 43.8% and 99.7% as respectively. Conclusions: NCCT might not sensitive in detection of SVT without CT direct sign which needs further investigation. However, NCCT might beneficial for emergency conditions such as DVT patients, cortical vein thrombosis and also in SVT patients with the positive CT direct sign.

Cerebral venous sinus thrombosis (CVST) is a rare but potentially life-threatening cause of stroke. Several risk factors have been identified including hypercoagulable state, malignancy, use of oral contraceptives, pregnancy, head injury, infection, and prothrombotic states such as heparin-induced thrombocytopenia (HIT). HIT is a prothrombotic state leading to thrombosis in several distinct locations including CVST requiring prompt discontinuation of heparin and initiation of nonheparin anticoagulation to prevent catastrophic consequences. Very rarely, HIT can complicate the ongoing CVST leading to worsening thrombosis and clinical deterioration. We here report an exceedingly rare case of CVST complicated by HIT in a 22-year-old female patient who showed remarkable clinical improvement after discontinuation of heparin and initiation of argatroban.

In 1825, Ribes described a case of a 45-year old man who died after a 6-month history of epilepsy, seizures and delirium. The autopsy examination revealed thrombosis of the superior sagittal sinus, the left lateral sinus and a cortical vein in the parietal region. This was probably the first detailed description of extensive cerebral venous sinus thrombosis (CVST). Since then, the literature describing this disease has comprised of case reports, series and some newer prospective studies, including recent reviews and guidelines (statement) on the diagnosis and management of CVST (Siddiqui & Kamal, 2006; Stam, 2005; Saposnik et al, 2011; Brown & Thore, 2011). The cerebral venous sinus thrombosis is a challenging condition and it is most common than previously thought. CVST accounts for 0.5% to 1.0% of all strokes and usually affects young individuals. Important advances have been made in the understanding of the pathophysiology of this vascular disorder. The diagnosis of CVST is still frequently overlooked or delayed as a result of the wide spectrum of clinical symptoms and the often sub-acute or lingering onset. Patients with CVST commonly present with headache, although some develop a focal neurological deficit, decreased level of consciousness, seizures, or intracranial hypertension without focal neurological signs. Uncommonly, an insidious onset may create a diagnostic challenge. The main problem of this disorder is that it is very often unrecognised at initial presentation. In particular, a prothrombotic factor or a direct cause is identified in approximately 66% of the CVST patients (a list of most important causal and risk factors are listed in Table 1). Cerebral venous thrombosis is more common in women than men, with a female to male ratio of 3:1 (cited in Ferro & Canhao, 2011). The imbalance may be due to the increased risk of CVST associated with pregnancy and puerperium and with oral contraceptives. The female predominance in CVST is found in young adults, but not in children or older adults.

Aims & Objectives: Bilateral Cerebral Venous Thrombosis (CVT) is a rare clinical presentation in the adolescent population and therefore offers a diagnostic challenge. The purpose of reporting this case is that the novel use of EMT in an adolescent with bilateral CVT has not been reported before and should be considered in as an emergent therapeutic adjunct in a similar case presentation. Methods: We present the case of a 17 year old boy who presented as non-traumatic coma and was found to have bilateral CVT on MRI. He subsequently underwent endovacular mechanical thrombectomy (EMT) Results: Case Presentation: We report a case of a 17 year old boy who presented as non-traumatic coma. Further imaging revealed extensive cerebral venous sinus thrombosis with hemorrhagic venous infarction in bilateral parietal lobes. Examination revealed a drowsy child. Hemodynamics were within the normal range. However, a detailed neurological examination revealed anisocoric pupils, increased tone in all four extremities and upgoing planters; He was started on Enoxaprin (1mg/kg SC Q12hourly); This was not an easy decision since the patient also had a hemorrhagic conversion in the infarct. There was no significant clinical improvement despite initiation of anticoagulation. A multidisciplinary decision led by neurology, hematology, and critical care decided on an emergent endovascular mechanical thrombectomy. Aspiration thrombectomy in the Superior sagittal sinus was performed and the enoxaparin was later switched to rivoroxaban. The patient showed dramatic clinical improvement. He regained consciousness with restoration of motor function.Conclusions: Endovascular mechanical thrombectomy is a safe therapeutic consideration of failed medical management for bilateral CVT.