Catheter Directed Thrombolytic Therapy for Pediatric Cerebral Sinus Vein Thrombosis

Background: Cerebral sinus vein thrombosis (CSVT) involves the thrombosis of the dural sinus and/or cerebral veins and it is considered a form of stroke. The estimated incidence of CSVT in children is 0.6 per 100,000 children per year. Poor outcomes, including death, happen in 9 to 29% of patients affected by CSVT. In addition, neurologic deficits, affecting primarily cognition and behavior, are seen in 50% of affected children. No randomized clinical trials have been conducted on pediatric CSVT so current guidelines for treatment have been extrapolated primarily from adult studies. Published guidelines by the American College of Chest Physicians, American Heart Association and American Society of Hematology, support the use of anticoagulation with unfractionated heparin (UFH) or low molecular weight heparin (LMWH). These same guidelines also suggest that catheter directed thrombolysis (CDT) with tissue plasminogen activator (tPA) and mechanical thrombectomy (MT) could be used when there has been clinical deterioration or no improvement (clot progression) despite anticoagulation. In all cases, these are based on uncontrolled case series and expert opinion. There is very little data on the safety and efficacy of CDT and/or MT for pediatric CSVT. Method: Pediatric patients with CSVT seen at Cook Children's Medical Center from January 1, 2008 to December 31, 2018 were identified by searching EMR using ICD-9 and ICD-10 codes. From this group, patients treated with MT and CDT in addition to anticoagulation were selected and reviewed. Results: Five children (4 to 14 y/o) were treated with MT and CDT after failing anticoagulation with UFH or LMWH. Diagnosis was made by MRI/MRV and all had CSVT of multiple sinuses. Four patients had more than one underlying disorders/factors that increased their risk for thrombosis including: Ulcerative Colitis in 2, severe anemia in 2, Systemic Lupus Erythematosus (SLE) in 1, use of oral contraceptives together with obesity and bacterial sepsis in 1. Two patients did have a thrombophilia: Protein S deficiency in 1 and Protein S and C deficiency in another. One patient with SLE had a positive hexagonal phase neutralization test but rest of evaluation was negative. Three patients had systemic bleeding prior initiation of UFH and MT/CDT. All children were treated with UFH, and due to clinical neurologic deterioration and/or worsening of imaging findings (4 comatose and 1 with persistent increased ICP), all underwent thromboaspiration and catheter directed infusion of tPA for 17 to 48 hours at a dose of 1 to 2 mg/hr. All patients continued anticoagulation with UFH during catheter directed tPA infusion and after the catheter was removed. All cases had partial resolution of the sinus vein thrombosis, although 1 had quick reocclusion. Post procedure bleeding happened in 1 patient who had also had an external ventricular drainage placed and developed parenchymal and intraventricular hemorrhage that led to discontinuation of tPA infusion, and 2 patients developed petechial brain hemorrhages. Four patients had great neurologic recovery and minimal deficits, but 1 had significant neurologic deficits. One patient died from lupus complications. (Table) Conclusion: Endovascular therapy including MT and CDT with tPA in conjunction with systemic UFH, may have a role in pediatric patients with CSVT who have deterioration despite initial anticoagulation. In our series, after procedures, all patients had partial resolution of their CSVT (but 1 had quick reocclusion) and 4 out of 5 patients had good neurologic outcomes despite bad predictor signs (coma, extensive CSVT). Further studies are needed to identify which patients would benefit from early endovascular treatment. Table Disclosures No relevant conflicts of interest to declare.

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Venous Thromboembolic Disease and Bone Marrow Transplant: A Remarkable Cause of Mortality and Morbidity — Potentially Preventable

Blood ◽

10.1182/blood-2018-99-113780 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5070-5070

Author(s):

Marta Rivas Luque ◽

Estefanía Morente Constantin ◽

Pablo Romero Garcia ◽

Maria Almudena Garcia-Ruiz ◽

Manuel Jurado

Keyword(s):

Medical History ◽

Conflicts Of Interest ◽

Protein S ◽

Marrow Transplant ◽

Morbidity And Mortality ◽

Hematopoietic Stem ◽

Mortality And Morbidity ◽

Vein Thrombosis ◽

Venous Thromboembolic ◽

Hemorrhagic Risk

Abstract Thrombotic events are frequent in patients undergoing HSCT, being an important cause of morbidity and mortality. The highest incidence occurs three months after the transplant. There are several risk factors, which add to those already known for VTE: neoplasia, central venous catheters, immobilization, chemotherapy, infections, GVHD. In the series described, the frequencies are variable, between 0.5 and 23.5%, with an overall incidence of 5%. In patients with GVHD, this incidence increases, with up to 35% of events. METHODS A retrospective observational study that includes patients transplanted in our Unit between 2014 and 2017 has been conducted, with the objective of analyzing the incidence of VTE peri-TPH. Likewise, we have analyzed if it is associated to catheter, presence of CVRF, if there was a known medical history of thrombophilia, number of platelets at time of thrombosis, the heparin used and whether anticoagulation was maintained indefinitely or not. RESULTS Out of the 235 patients included in our series, 130 underwent an autologous transplant and 105 an allogeneic transplant. 18 thrombotic events occurred (9 men and 9 women, aged between 18 and 65 years), which means 7.5% (14 occurred between days 0-100, 12 in patients undergoing autologous hematopoietic stem cell transplantation). Three of them had thromboembolism and the rest deep vein thrombosis, 4 of which with catheter. The platelet count at the time of the event ranges from 21 to 409,000 / mm3. Regarding the heparin used, 2 were treated with Tinzaparin and the rest with Bemiparin. Only 1 of the patients presented prior VTE. Among the patients, there were some with CVRF and others without relevant medical history. Just in one patient, a family thrombophilia study had been performed prior to his hematological diagnosis, resulting in a deficit of protein S. In 8 of the patients, anticoagulation was maintained indefinitely with LMWH in the post-transplant period. CONCLUSIONS Our incidence approaches the literature, albeit the series of published cases are heterogeneous and with variable differences. Although the incidence of thrombosis in these patients is a cause of marked morbidity and mortality, the risk of bleeding also increases, therefore routine prophylaxis is not recommended in all patients. We must undergo an exhaustive analysis of the data to identify individually which patients may be candidates for prophylaxis, with the aim of reducing the incidence without raising the hemorrhagic risk of our patients. Disclosures No relevant conflicts of interest to declare.

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A Case Series: The Novel Use of Emapalumab and Ruxolitinib in Acquired Malignancy-Associated HLH in Pediatric Patients

Blood ◽

10.1182/blood-2020-142862 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 31-31

Author(s):

Kenny Hung Vo ◽

Jong Chung ◽

Arun Ranjan Panigrahi

Keyword(s):

Induction Chemotherapy ◽

Pediatric Patients ◽

Conflicts Of Interest ◽

Case Series ◽

The Novel ◽

Ifn Gamma ◽

Novel Therapeutics ◽

Genetic Components ◽

Organ System Failure ◽

Concurrent Processes

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory syndrome that is classified into primary and acquired forms. Primary-HLH has genetic components related to defects in cytotoxic T and NK cells. The acquired form of HLH is classified based on the underlying triggers of immune dysregulation through malignancy, infections, and/or autoimmune processes. The standard of care is established with etoposide and dexamethasone, but there are currently no guidelines for refractory HLH or cases with confounding presentations with infection or malignancy. We describe cases of malignancy-associated HLH (m-HLH) in pediatric patients to discuss the intricacies in the initial diagnostic considerations, the balance of therapeutic regimens and their toxicities, and the novel use of emapalumab and ruxolitinib in refractory patients. We discuss a 16-year-old female with NK/T-cell lymphoma of the nasopharynx who presented in septic shock with pancytopenia and DIC. Diagnostic considerations included progressive lymphoma, bacteremia, and EBV viremia as possible explanations for her shock physiology. HLH was a consideration on admission given her presentation, but she did not meet criteria until HD#7 with ferritin of 740ng/mL (ref 10-291ng/mL), soluble IL-2 receptor (CD25) of 10,600pg/mL (ref <1033pg/mL), sCD163 of 5,636ng/mL (ref 387-1,785ng/mL) and an abnormal NK cell function. Standard treatment with etoposide and dexamethasone showed minimal effect, as did the introduction of rituximab. Gemcitabine and oxaliplatin were started as treatment for her lymphoma as the driver of her HLH, but she developed acute decompensation with hemodynamic instability and multi-organ system failure. Her systemic inflammation worsened as evidenced by a rise in her ferritin to 15,462ng/mL and sIL-2 receptor to 28,700pg/mL. Her CXCL9, a downstream chemokine and marker of IFN-gamma activity shown to be elevated in HLH, had a dramatic increase to 106,918 pg/mL (ref <121pg/mL). A decision to hold treatment for her lymphoma was made to reduce toxicities and better manage her HLH. Compassionate use of emapalumab, an IFN-gamma inhibitor indicated in primary HLH, led to dampening of her systemic inflammatory processes with resolution of fevers and signs of recovery of her hepatobiliary, renal, and gastrointestinal systems. We also describe a 17-year-old male who presented with T-ALL and bacteremia who developed HLH during induction-chemotherapy with complications from bacterial sepsis and fulminant fungemia. He represented a diagnostic conundrum throughout his induction chemotherapy with persistent fevers despite appropriate treatment and improvement of his bacteremia and fungemia. It was not until HD#50 that he met criteria for HLH with the addition of a ferritin level of 6,073ng/mL. He had limited response to treatment and had multi-system toxicities from the therapies for his HLH, ALL, and fungemia that necessitated frequent adjustments to his treatment plans. The treatment for his HLH was not standard given the toxicities. Etoposide was never in consideration given concerns for myelosuppression and dexamethasone was not given at full doses due to intolerance but was given over a prolonged duration of months. His course included a waxing and waning response to a combination of steroids and IVIG with recurrent admissions for presumed HLH flares. A trial of ruxolitinib, a JAK inhibitor, demonstrated response with stabilization of his hyperinflammatory state. Although not curative, as evidenced by his persistent hyperferritinemia, the use of ruxolitinib has allowed him to better tolerate his chemotherapy and improve his overall quality of life with a decrease in frequency of flares and hospitalizations. These cases highlight the intricacies of the management of m-HLH in pediatric patients with the spectrum of disease severity and complex diagnostic evaluations one must consider at presentation. Due to the toxicity of treatment options for often concurrent processes of malignancy, infection, and HLH, novel therapeutics such as emapalumab and ruxolitinib are required and should be evaluated in larger studies. Furthermore, guidelines for the management of pediatric m-HLH are required with inclusion of adjustments to standard therapy based on toxicity, inciting factors, concurrent processes, and the incorporation of novel therapeutics to achieve improved outcomes. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Ruxolitinib and emapalumab for refractory acquired HLH in Pediatric patients.

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A Case of Hereditary Protein S Deficiency Presenting with Cerebral Sinus Venous Thrombosis and Deep Vein Thrombosis at High Altitude

Acta Haematologica ◽

10.1159/000126200 ◽

2008 ◽

Vol 119 (3) ◽

pp. 158-161 ◽

Cited By ~ 13

Author(s):

Velu Nair ◽

A.K. Mohapatro ◽

M. Sreedhar ◽

I.K. Indrajeet ◽

A.K. Tewari ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Venous Thrombosis ◽

Protein S ◽

Protein S Deficiency ◽

Vein Thrombosis ◽

S Deficiency ◽

Cerebral Sinus Venous Thrombosis ◽

Cerebral Sinus ◽

Deep Vein ◽

Sinus Venous Thrombosis

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The Prevalence of May Thurner Syndrome in Children with Ileo-Femoral Deep Vein Thrombosis- Does It Take 2 to Tango?

Blood ◽

10.1182/blood-2021-152442 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4263-4263

Author(s):

Divya Subburaj ◽

Pamala Cox ◽

Victoria E. Price ◽

Ketan Kulkarni

Keyword(s):

Risk Factor ◽

Deep Vein Thrombosis ◽

Pediatric Patients ◽

Conflicts Of Interest ◽

Anticoagulation Therapy ◽

Venous Stasis ◽

Thrombotic Risk ◽

Vein Thrombosis ◽

Catheter Directed Thrombolysis ◽

Deep Vein

Abstract Introduction: May-Thurner syndrome (MTS) is characterised by compression of the left external iliac vein by overriding right common iliac artery resulting in venous stasis. It carries a higher risk of left iliofemoral deep vein thrombosis (DVT), however the prevalence and management guidelines are unclear in pediatrics. We reviewed the prevalence of MTS in children diagnosed with left iliofemoral DVT at our center, associated prothrombotic risk factors and their clinical outcomes. Methods: This is a retrospective audit of pediatric patients (<18 years) with left iliofemoral DVT treated at the IWK Health Center from January 1 2008 to December 31 2020. Results: Twelve pediatric patients with left iliofemoral DVT were identified at our center and all patients except one had MRV/CTV during their course of anticoagulation to evaluate for MTS. MTS was diagnosed on imaging in 8 of the eleven evaluable patients with DVT and one patient had an incidental diagnosis of MTS with no DVT. The median age at diagnosis of MTS was 15 years (13-16), male:female ratio of 1:8. The overall prevalence rate was of MTS was 72.72% (8/11) in patients with left iliofemoral DVT. All patients with iliofemoral DVT and MTS had at least one other prothrombotic risk factor- initiation of estrogen containing contraceptive pills in the preceding 3 months of the DVT (n=5), inherited thrombophilia (n=2) and obesity (n=2). All patients with MTS were referred to vascular surgery. Only one patient required catheter directed thrombolysis and stenting at presentation of DVT, the remaining 7 patients were managed with anticoagulation alone. Complete (n=1) or partial (n=7) resolution of the thrombus was seen in all 8 patients. Median duration of follow up was 3 years. Recurrent DVT was seen in 1 patient and two patients came off anticoagulation at 6 months post therapy. Post thrombotic syndrome was seen in 4 patients, mild in 3 and moderate in 1; as per modified Villalta score. Conclusion: We observed a high prevalence of MTS in patients with left iliofemoral DVT which may be due our screening approachwith upfront radiographic evaluation for MTS in all patients with left iliofemoral DVT. A second pro-thrombotic risk factor was identified in all patients, which raises the possibility of a "two hit theory" for the occurrence of DVT in MTS. Compared to published adult studies, majority of our pediatric patients were managed conservatively with anticoagulation therapy alone. Disclosures No relevant conflicts of interest to declare.

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Special Conditions in Venous Thrombembolism – Case Series

PRILOZI ◽

10.2478/prilozi-2019-0021 ◽

2019 ◽

Vol 40 (2) ◽

pp. 103-111

Author(s):

Marijan Bosevski ◽

Irena Mitevska ◽

Marica Pavkovic ◽

Milka Klincheva ◽

Emilija Trajkovska Lazarova ◽

...

Keyword(s):

Randomized Clinical Trials ◽

Real Life ◽

Case Series ◽

Vascular Diseases ◽

The Elderly ◽

Hospital Death ◽

High Risk Population ◽

Vein Thrombosis ◽

Cancer Associated Thrombosis ◽

Deep Vein

Abstract Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a preventable cause of in-hospital death, and one of the most prevalent vascular diseases. There is a lack of knowledge with regards to contemporary presentation, management, and outcomes of patients with VTE. Many clinically important subgroups (including the elderly, those with recent bleeding, renal insufficiency, disseminated malignancy or pregnant patients) have been under-represented in randomized clinical trials. We still need information from real life data (as example RIETE). The paper presents case series with VTE in special conditions, including cancer associated thrombosis, malignant homeopathies, as well in high risk population.

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Head Trauma Is the Major Risk Factor for Cerebral Sinus-Vein Thrombosis

Blood ◽

10.1182/blood.v126.23.1108.1108 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1108-1108

Author(s):

Ornit Giladi ◽

David Steinberg ◽

Kobi Peleg ◽

David Tanne ◽

Adi Givon ◽

...

Keyword(s):

Risk Factors ◽

Risk Factor ◽

Head Trauma ◽

Trauma Registry ◽

Conflicts Of Interest ◽

Medical Center ◽

Control Group ◽

Vein Thrombosis ◽

National Trauma ◽

Cerebral Sinus

Abstract Cerebral sinus vein thrombosis (CSVT) is a rare disease with significant neurological sequellae and high mortality rate. Incidence of CSVT diagnosis in the western world has increased despite the reduced occurrence of infectious sinus thrombosis related to otitis media and mastoiditis. The objective of this study was to identify risk factors that may explain the predisposition to the site specific thrombosis based on patients from a single tertiary medical center. The study included 90 consecutive patients aged 15 and up that were diagnosed with acute CSVT from January 2002 to September 2014 at the Sheba Medical Center. As a control group we used the data extracted from the national trauma registry for the years 2012 and 2013 and from Maccabi Healthcare Services, the second largest health care maintenance organization (HMO) in Israel. Trauma history up to one month prior to diagnosis of CVST was found in 13 (14%) patients (10 men and 3 women). Six patients had skull fractures, the others had blunt trauma. Data from the national trauma registry were used to compute annual age and gender specific head trauma rates. The overall SMR was 941 (p < 0.0001); the separate results for men and women were 1206 and 543, respectively. Another important risk factor was infections confined to the head and neck in 7% of the cases and brain tumor in 8%. At the time of CVST, 23 of 50 (46%) women had a hormonal risk factor. The SMR for OC use was 1.63 (p=0.0298). Prothrombotic polymorphisms were detected in 16 of 63 (25.4%) patients who were tested for factor V Leiden and prothrombin G20210A mutation (OR=3.47, p=0.002) in comparison to 49% in DVT patients (OR=9.95, p<0.0001). In 29 of 90 patients at least one of the risk factors for atherosclerosis (hypertension, diabetes or hypercholesterolemia) was discerned but this was very close to the expected number adjusted for sex and age and SMR was 0.98. None of the risk factors correlated with severity of disease and outcome. These data suggest that search for CVST in patients with recent trauma and headache even after intact head CT is required. The other risk factors, such as hormone related and prothrombotic polymorphisms, were not specific just for CVST and the latter play a lesser role in CVST than in DVT. Disclosures No relevant conflicts of interest to declare.

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Protein S As a Potential Treatment for FIX-Derived Deep Vein Thrombosis

Blood ◽

10.1182/blood.v126.23.2277.2277 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2277-2277

Author(s):

Vijaya Satish Sekhar Pilli ◽

Willium Plautz ◽

Rinku Majumder ◽

Paolo Simioni

Keyword(s):

Deep Vein Thrombosis ◽

Thrombin Generation ◽

Conflicts Of Interest ◽

Ex Vivo ◽

Protein S ◽

Factor Ix ◽

Wild Type ◽

Vein Thrombosis ◽

Deep Vein

Abstract Background: Every year, 0.1-0.2% of the USA population experiences deep vein thrombosis (DVT). Two causes of DVT are increased Factor IX (FIX) levels and hyperactivating mutations in FIX (FIX Padua variant- R338L and Malmo variant T148A). In principle, inhibition of activated FIX (FIXa) should alleviate DVT. Previous in vitro studies demonstrated that the anticoagulant Protein S (PS) inhibits the intrinsic pathway mediated by wild type FIXa, making PS an attractive candidate to treat DVT. Aims: To establish Protein S as a remedy for FIX-mediated DVT/Padua/Malmo Methods: Anisotropy, clotting assays, thrombin generation assays, co-localization, co-immunoprecipitation, and bleeding assays. Results: We further explored the physiological relevance of the PS-FIXa interaction and PS-mediated inhibition of FIXa by ex vivo (co-immunoprecipitation) and in vivo (co-localization) studies. Because PS can inhibit FIXa in vivo, we used competitive, direct anisotropy assays and co-immunoprecipitation assays to measure the efficiency PS and hyperactive FIXa (R338L) interaction. Interestingly, the results demonstrated that FIXa R338L has lost its affinity towards PS compared with wild type FIXa. The same finding was obtained by ex vivo thrombin generation assays and FXa generation assays supplemented with various concentrations of PS. Thus, to be inhibited, hyperactive FIX requires a greater amount of PS compared with wild type FIXa. We are further confirming this finding with mouse models. Conclusion: Addition of PS to plasma inhibits both wild type and R338L FIXa and extends clotting time. Previous studies showed that the addition of PS has no significant negative effects. Thus, we conclude that PS supplementation potentially constitutes a novel and effective treatment for FIX-mediated DVT. Disclosures No relevant conflicts of interest to declare.

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