Prostaglandin-endoperoxide synthase-2 deletion affects the natural trafficking of Annexin A2 in monocytes and favours venous thrombosis in mice

2017 ◽  
Vol 117 (08) ◽  
pp. 1486-1497 ◽  
Author(s):  
Patrizia Amadio ◽  
Eva Tarantino ◽  
Leonardo Sandrini ◽  
Elena Tremoli ◽  
Silvia Barbieri
Keyword(s):  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Peritoneal Macrophages ◽  
Mutant Mice ◽  
Nuclear Accumulation ◽  
Prostaglandin Endoperoxide ◽  
Vein Thrombosis ◽  
Prostaglandin Endoperoxide Synthase

SummaryDeep-vein thrombosis (DVT) is a common condition that often leads to pulmonary thromboembolism (VTE) and death. The role of prostaglandin-endoperoxide synthase (PTGS)2 in arterial thrombosis has been well established, whereas its impact in venous thrombosis remains unclear. Here, we showed that PTGS2 deletion predisposes to venous thrombosis as suggested by greater clot firmness and clot elasticity, by higher plasma levels of functional fibrinogen, factor VIII and PAI-1 activity, and proved by bigger thrombi detected after inferior vena cava ligation (IVCL) compared to WT mice. PTGS2-/- thrombi have greater fibrin content, higher number of F4/80+, TF+ and ANXA2+ cells, and lower S100A10+ cells. Remarkably, monocyte depletion reduced thrombus size in mutant mice, suggesting an important role of PTGS2-/- monocytes in this experimental setting. Interestingly, PTGS2 deletion reduced membrane ANXA2, and total S100A10, promoted assembly of ANXA2/p50NF-kB complex and its nuclear accumulation, and induced TF in peritoneal macrophages, whereas ANXA2 silencing decreased dramatically TF. Finally, Carbaprostacyclin treatment prevented venous thrombus formation induced by IVCL in mutant mice, reduced the ANXA2 binding to p50NF-kB subunit and its nuclear trafficking, and decreased TF in PTGS2-/- macrophages. PTGS2 deletion, changing the natural distribution of ANXA2 in monocytes/macro-phages, increases TF expression and activity predisposing to venous thrombosis. Interestingly, Carbaprostacyclin treatment, inhibiting nuclear ANXA2 trafficking, controls monocyte TF activity and prevents DVT occurrence. Our data are of help in elucidating the mechanisms by which PTGS2 inhibition increases DVT risk, and suggest a new role for ANXA2 in venous thrombosis.Supplementary Material to this manuscript is available online at www.thrombosis-online.com.

scholarly journals Protective Effects of Kininogen-1 Gene Deficiency in Mouse Models of Venous Thrombosis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 289-289
Author(s):  
Aatira Vijay ◽  
Mohamad B Kassab ◽  
Young Jun Shim ◽  
Shadi Swaidani ◽  
Adam Mauskapf ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Continuous Light ◽  
Light Irradiation ◽  
Fluorescence Angiography ◽  
Contact Activation ◽  
Tail Vein ◽  
Platelet Accumulation

Abstract Background- High molecular weight Kininogen (HK) is a nonenzymatic co-factor of the contact activation system. HK binds prekallikrein (PK) and FXI to surfaces in proximity to FXII, amplifying PK activation by FXIIa and the reciprocal activation of FXII by activated PK (PKa), as well as FXI activation of FXIIa. PKa cleavage of HK also liberates bradykinin-a proinflammatory and vasoactive nanopeptide. The aim of this study was to define the pro-thrombotic role of kininogen in venous thrombosis (VT) and to use in vivo serial analysis of thrombus development to understand the recruitment and retention of platelets in the growing thrombus in the absence and presence of kininogen. Methods- The development of VT in mice deficient in kininogen (mKng1-/-) was compared to that in their wild-type littermates. A femoral-saphenous stasis VT model was prepared by ligating both saphenous and femoral veins. Next VT formation, growth, and dissolution (n=3 for each group) was monitored using intravital microscopy (IVM) via a multichannel epifluorescence microscope (Nikon Eclipse 90i). To induce stasis VT, FITC-dextran (10 mg/kg, ex/em 488/520 nm) was injected retro-orbitally, and then continuous light irradiation (20x objective, 475nm/35nm) of the saphenous vein was applied for 5 minutes. FITC-dextran fluorescence angiography monitored thrombus formation and dissolution. Immediately after VT formation, platelet accumulation at the thrombus site was monitored in the Cy5 channel (630/38 nm) via injection of a GPIbβ antibody conjugated with Dylight-649 (150nmol/kg), over time. All images were identically windowed in each channel, and thrombus area was measured using NIH ImageJ software. To corroborate IVM studies, we also evaluated a complete stasis model of inferior vena cava (IVC) ligation (n=7-8 per group). Thrombi were harvested after 48 hours and thrombus weight and length were measured to estimate thrombus mass. FXI circulates in blood as a homodimer along with HK. We determined the effect of kininogen deficiency on FXI activity. FXI activity assay used a combination of inhibitors, serially, to monitor the cleavage of substrate specific to activated FXI and release of chromogen, as a function of FXI activity. Finally, to determine the effects of Kng1 deficiency on bleeding, tail vein bleeding times were also determined (n=8 per group). Results- In femoral-saphenous stasis VT, thrombus developed in both groups immediately following FITC-channel light irradiation. However, thrombus size was smaller in Kng1-/- as compared to WT (Figure 1). Results from serial IVM of VT indicated faster thrombus dissolution in the Kng1-/- group. Lower platelet signals, as shown at 2 and 6 hours in the Kng1-/- mice may be consistent with this hypothesis. Thrombus area analysis suggested decreased thrombus formation in the Kng1-/- animals, and temporal analysis indicated faster dissolution by 6 hours (Figure 2). IVC ligation results corroborated the findings of femoral-saphenous DVT model, demonstrating that thrombus weight was significantly lower in Kng1-/- mice as compared to WT (p<0.001, Figure 3). FXI activity was also decreased in the Kng1-/- group (p<0.10). Tail vein bleeding times, however, showed no increased bleeding in Kng1-/- mice. Conclusion- These initial results suggest a pro-thrombotic role of kininogen and a protective role of kininogen deficiency in two murine venous thrombosis models, without incurring a bleeding penalty. Thrombus dissolution was faster and platelet accumulation was inhibited in Kng1-/- mice. These findings suggest that targeting kininogen may provide a new approach to prevent and treat venous thrombosis. Figure 1 Figure 1. Disclosures McCrae: Dova, Novartis, Rigel, and Sanofi Genzyme: Consultancy; Sanofi, Novartis, Alexion, and Johnson & Johnson: Consultancy, Honoraria. Jaffer: Mercator, Inc.: Other: Sponsred research.

Abstract 36: Alpha 2-antiplasmin Prevents the Resolution of Deep Vein Thrombosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Satish Singh ◽  
Aiilyan K Houng ◽  
Samantha Howard ◽  
B Tyler Emerson ◽  
Guy L Reed
Keyword(s):  
Venous Thrombosis ◽  
Vena Cava ◽  
Relative Effect ◽  
Vein Thrombosis ◽  
Significant Difference ◽  
Tissue Plasminogen ◽  
Deep Vein ◽  
Metalloproteinase 9 ◽  
One Way Anova

Introduction: Deep venous thrombosis is a major cause of death and disability. Despite anticoagulation treatment, venous thrombi persist for months, causing chronic venous obstruction, inflammatory remodeling and post-thrombotic syndrome. The mechanisms responsible for impaired clearance of venous thrombi are poorly understood. Alpha 2-antiplasmin (a2AP) is the primary physiological inhibitor of plasmin and a key regulator of the fibrinolytic pathway. The role of a2AP in the resolution of venous thrombosis has not been determined. Hypothesis: We tested the hypothesis that a2AP prevents the resolution of experimental deep venous thrombi. Methods and Results: Thrombus resolution and content were examined in a2AP +/+ and a2AP -/- mice using a well-established, fibrinolytic-resistant, stasis model induced by ligation of the inferior vena cava (IVC). Thrombus weight and composition were determined after 7 days. Data was analyzed by one-way ANOVA with Neumann-Keul’s correction. Thrombus weight was reduced in a2AP -/- mice by >90% when compared to a2AP +/+ mice (p<0.001); there was no significant difference between a2AP -/- mice and shams. Histochemical and immunofluorescence staining showed significant reductions in IVC fibrin content, neutrophil recruitment and matrix metalloproteinase-9 expression in a2AP -/- mice (p<0.001) vs. a2AP +/+ mice. The relative effect of plasminogen activation and a2AP on resolution of preformed venous thrombi was examined in wild-type a2AP +/+ mice treated 24 h after IVC ligation with tissue plasminogen activator (TPA) (1.2 or 5 mg/kg) or a monoclonal antibody inactivating a2AP (10 mg/Kg). By comparison to 7 day old venous thrombi in untreated mice, treatment with TPA at 1.2 mg/kg or 5 mg/kg did not decrease thrombus size after 7 days. In contrast, a2AP inactivation significantly reduced thrombus weight vs. untreated and TPA-treated mice (p<0.01 to p<0.001). Conclusions: In experimental venous thrombosis, a2AP was required for the persistence of venous thrombi 7 days after formation. Venous thrombi resisted TPA, but were sensitive to resolution after a2AP inactivation. This suggests that a2AP may be responsible for the persistence of clinical venous thrombosis in humans.

ROLE OF PLATELETS IN EXPERIMENTAL THROMBOSIS INDUCED BY VENOUS STASIS

1987 ◽  
Author(s):  
A Bernat ◽  
E Vallée ◽  
J P Maffrand ◽  
J Gordon
Keyword(s):  
Platelet Count ◽  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Venous Stasis ◽  
Severe Thrombocytopenia ◽  
Antiplatelet Effect ◽  
Experimental Thrombosis ◽  
Dense Granules

Venous stasis in the rat, induced by ligature of the vena cava, provokes thrombosis. This venous thrombosis was initially believed to be platelet-independent because severe thrombocytopenia (95 % reduction in platelet count), aspirin and dipyridamole had little effect. However, the model responded to other platelet anti-aggregators, such as Ticlopidine and its analogue PCR 4099, although these compounds had no effect on coagulation, fibrinolysis or leucocyte functions (Thromb. Res. 37, 279-285, 1985). Both these drugs are known to exert their main antiplatelet effect against aggregation induced by ADP.The aim of the present study was to re-evaluate the role of platelets in this model of venous thrombosis. We have been able to show that :1) complete thrombocytopenia (99 %), achieved with an antiplatelet anti-serum, dramatically inhibited thrombus formation (by 84 % ; p < 0.01).2) partial transfusion of platelets (23 %) from control animals to these thrombocytopenic rats re-established the thrombosis.3) transfusion (under identical conditions) of platelets from rats treated with PCR 4099 had no effect.4) vena cava ligature in Fawn Hooded rats (deficient in platelet dense granules) induced less thrombosis (64 % of control ; p < 0.05).We conclude that this venous stasis model is platelet-dependent. Furthermore, because thrombus formation was reduced in normal rats treated with anti-aggregants acting selectively against ADP, and in rats lacking ADP in their platelet dense granules, it appears that ADP plays a major role in this model of thrombosis.

scholarly journals Cellular Fibronectin Promotes Deep Vein Thrombosis in Obese Mice

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Nirav Dhanesha ◽  
Manish Jain ◽  
Prakash Doddapattar ◽  
Anetta Undas ◽  
Anil K Chauhan
Keyword(s):  
Deep Vein Thrombosis ◽  
Venous Thrombosis ◽  
Conflicts Of Interest ◽  
Vena Cava ◽  
Significant Risk ◽  
Comorbid Condition ◽  
Vein Thrombosis ◽  
Deep Vein ◽  
Cellular Fibronectin

Objective: Obesity is a significant risk factor for deep vein thrombosis (DVT). The mechanisms of increased DVT in preexisting comorbid condition of obesity remain poorly understood. Cellular fibronectin containing extra domain A (Fn-EDA), an endogenous ligand for toll-like-receptor 4 (TLR4), is known to contribute to thrombo-inflammation in the experimental models. However, the role of Fn-EDA in modulation of venous thrombosis in context of obesity is not elucidated yet. Approach and Results: We found that cellular Fn-EDA levels were significantly elevated in plasma of venous thromboembolism (VTE) patients that positively correlated with body mass index (BMI). To investigate whether Fn-EDA promotes venous thrombosis in obese condition, WT and Fn-EDA-/- mice were either fed a control or high-fat diet (HF-diet) for 12-weeks. DVT was induced by inferior vena cava stenosis and evaluated after 48 hours. We found that HF diet-fed WT mice exhibited increased DVT susceptibility compared with control diet-fed WT mice. In contrast, HF-fed Fn-EDA-/- mice exhibited significantly reduced thrombus weight and decreased incidence (%) of DVT compared with HF-fed WT mice that was concomitant with improved blood flow, reduced neutrophil content and citrullinated histone H3-positive cells (a marker of NETosis) in IVC thrombus. Exogenous Fn-EDA potentiated NETosis in neutrophils stimulated with thrombin-activated platelets via TLR4. Genetic deletion of TLR4 in Fn-EDAfl/fl mice, which constitutively express Fn-EDA, reduced DVT compared with Fn-EDAfl/fl mice. Conclusion: These results demonstrate a previously unknown role of Fn-EDA in the modulation of DVT, which may be an important mechanism promoting DVT in the setting of obesity. Figure Disclosures No relevant conflicts of interest to declare.

Inflammatory Monocyte Counts Determine Venous Blood Clot Formation and Resolution

2021 ◽  
Author(s):  
Fatemeh Shahneh ◽  
Hans Christian Probst ◽  
Sabine C. Wiesmann ◽  
Noelia A-Gonzalez ◽  
Wolfram Ruf ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Inferior Vena Cava ◽  
Tissue Factor ◽  
Inferior Vena ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Wild Type ◽  
Vein Thrombosis ◽  
Deep Vein

Background: Monocytes are thought to be involved in venous thrombosis but the role of individual monocyte subpopulations on thrombus formation, clot inflammation, and degradation is an important unresolved issue. We investigate the role of inflammatory Ly6C hi monocytes in deep vein thrombosis and their potential therapeutic impact. Methods: Frequencies and compositions of blood monocytes were analyzed by flow cytometry in CCR2 −/− (C-C chemokine receptor type 2) and wild-type mice of different ages and after treatment with the NR4A1 (nuclear receptor group 4 family A member 1, Nur77) agonist CnsB (cytosporone B). TF (tissue factor) sufficient and deficient Ly6C hi monocytes were adoptively transferred into aged CCR2 − /− mice. Thrombus formation and size were followed by ultrasound over a 3-week period after surgical reduction of blood flow (stenosis) in the inferior vena cava. Results: Reduced numbers of peripheral monocytes in aged (>30 w) CCR2 −/− mice are accompanied by reduced thrombus formation after inferior vena cava ligation. Reducing the number of inflammatory Ly6C hi monocytes in wild-type mice by CsnB treatment before ligation, similarly suspends clotting, while later treatment (d1 or d4) reduces thrombus growth and accelerates resolution. We describe how changes in inflammatory monocyte numbers affect the gradual differentiation of monocytes in thrombi and show that only tissue factor-competent Ly6C hi monocytes restore thrombosis in aged CCR2 − /− mice. Conclusions: We conclude that the number of inflammatory Ly6C hi monocytes controls deep vein thrombosis formation, growth, and resolution and can be therapeutically manipulated with a NR4A1 agonist at all disease stages.

scholarly journals PREVENTION AND TREATMENT OF VENOUS THROMBOSIS AND THROMBOEMBOLISM IN SURGICAL TREATMENT PELVIC NEOPLASMS

2020 ◽  
pp. 74-80
Author(s):  
A. V. Chikin
Keyword(s):  
Surgical Treatment ◽  
Venous Thrombosis ◽  
Vena Cava ◽  
Fold Increase ◽  
Initial State ◽  
Pelvic Neoplasms ◽  
Surgical Interventions ◽  
Vein Thrombosis ◽  
Prevention And Treatment ◽  
Before And After

Summary. Venous thromboembolic complications — a collective concept that combines thrombosis of the saphenous and deep veins, as well as pulmonary thromboembolism. In the clinical practice of a doctor of any specialty, especially surgical, the possibility of timely diagnosis, treatment and preventive measures for deep vein thrombosis and pulmonary embolism are extremely important. Purpose. To study the most informative measures for the prevention and treatment of venous thrombosis and thromboembolism in the surgical treatment of pelvic neoplasms. Materials and methods. The analysis of the results of the examination and treatment of 112 patients observed for tumors of the pelvic organs and tumors of the retroperitoneal space is presented. Results and discussion. When studying the initial state of the hemostasis system in 48 patients, a significant shortening of activated partial thromboplastin time (APTT), a 1.5-fold increase in the concentration of fibrinogen, which indicates activation of the procoagulant link, as well as an increase in platelet aggregation by 20.0 %, were established. Studies of the hemostatic system showed that surgical interventions and injuries contribute to increased hypercoagulation. Conclusions. The most informative methods for determining thrombosis in the system of the inferior vena cava and the optimal examination algorithm are: ultrasonic dynamic angioscanning, determination of the amount of D-dimer, computer, magnetic resonance bolus venography and retrograde ileocavagography. The use of unfractionated and low molecular weight heparins effectively prevents the development of thrombosis and thromboembolism before and after surgery and does not cause bleeding. Nonspecific and specific prophylaxis of venous thrombosis and embolism allowed a 2.8-fold reduction in their number in patients of the main group.

Abstract 54: Peptidylarginine Deiminase 4-dependent Generation of Neutrophil Extracellular Traps is Crucial for Deep Vein Thrombosis in Mice

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Kimberly Martinod ◽  
Melanie Demers ◽  
Tobias A Fuchs ◽  
Siu Ling Wong ◽  
Alexander Brill ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Peptidylarginine Deiminase ◽  
Wild Type ◽  
Chromatin Decondensation ◽  
Peptidylarginine Deiminase 4 ◽  
Vein Thrombosis ◽  
Deep Vein ◽  
Deficient Mice

Introduction Histone hypercitrullination by the enzyme peptidylarginine deiminase 4 (PAD4) leads to nuclear chromatin decondensation that is needed for neutrophil extracellular trap (NET) formation. NETs consist of chromatin and granule proteins that are released into the extracellular environment. NETs were shown to be involved in thrombosis by promoting coagulation and platelet adhesion and were identified in the thrombus scaffold in animal models of deep vein thrombosis (DVT). Objective Whether NETs are involved in the pathogenesis of DVT or whether they are merely a consequence of neutrophil recruitment to the thrombus is unknown. We hypothesized that NET formation would be impaired in PAD4-deficient mice during deep vein thrombosis and that this may affect thrombus formation and/or stability. Methods PAD4-deficient mice are incapable of citrullinating histones and therefore fail to decondense chromatin during NETosis. We performed the inferior vena cava stenosis model of DVT in wild-type or PAD4-/- mice. Intravital microscopy was done to assess leukocyte vessel wall interaction in PAD4 deficiency. Results We induced NET formation in isolated peripheral blood mouse neutrophils with ionomycin and found that PAD4-/- neutrophils had a complete inability to produce NETs (WT, 20.65±2.61% NETs; PAD4-/-, not detected. n=4). Leukocyte-endothelial interactions in PAD4-/- mice were not impaired upon induction of systemic Weibel-Palade body release (WT, 55.2±11.8; PAD4-/-, 62.0±17.5 cells/min, n=5-6). In the DVT model, while a majority (9/10) of wild-type mice formed a thrombus 48 hours after stenosis, only 1 of 11 PAD4-/- mice formed a thrombus. Thrombus formation could be rescued by infusions of isolated WT bone marrow neutrophils into PAD4-/- mice, and extracellular H3Cit+ areas were seen within these thrombi. This data suggests that neutrophil PAD4 was essential for thrombus formation in deep veins. Conclusion NETs comprise a crucial part of the pathologic thrombus scaffold, and here we report that the lack of NETs inhibits pathological thrombosis. Chromatin decondensation initiated by PAD4 in neutrophils is a key player in the formation of deep vein thrombi and targeting neutrophil histone modification could be a new way to prevent DVT.

scholarly journals Importance of platelets in experimental venous thrombosis in the rat

Blood ◽  
1992 ◽  
Vol 80 (9) ◽  
pp. 2281-2286 ◽  
Author(s):  
JM Herbert ◽  
A Bernat ◽  
JP Maffrand
Keyword(s):  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Progressive Increase ◽  
High Dose ◽  
Experimental Conditions ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Tissue Thromboplastin ◽  
Dose Dependent

Abstract Venous thrombosis was induced by ligature of the inferior vena cava in rats whose blood was made hypercoagulable by intravenous (IV) administration of tissue thromboplastin. From a dose-response showing that the administration of increasing doses of tissue thromboplastin resulted in a subsequent progressive increase of thrombus weight, two concentrations of tissue thromboplastin were chosen: a high dose (550 microL/kg, IV) where thrombus formation was optimal and a concentration (7 microL/kg, IV) where tissue thromboplastin-hypercoagulability was intermediate. In both experimental conditions, leukopenia provoked by a myelotoxic drug did not influence the development of venous thrombosis. However, after thrombocytopenia induced by an antiplatelet antiserum, a dramatic decrease in thrombus formation was observed in animals that had been pre-challenged with the lower dose of tissue thromboplastin, whereas decrease in platelet count did not affect venous thrombosis under high thrombogenic challenge. When administered orally 2 hours before thrombosis induction, the ticlopidine analogue clopidogrel showed dose-dependent inhibition of thrombus formation in animals that were pre-challenged with a low dose of tissue thromboplastin (ED50 = 7.9 +/- 1.5 mg/kg, orally) but remained ineffective against high tissue thromboplastin-induced venous thrombosis. We further determined the effect of heparin and hirudin, and showed that both of these drugs exhibited a more potent antithrombotic activity after injection of the lower dose of tissue thromboplastin than after injection of a high dose of tissue thromboplastin. Therefore, using our model of stasis and hypercoagulability, platelet activation played a major role in the development of venous thrombosis when the thrombogenitic stimulus was mild.

scholarly journals Venous Thrombosis in Acquired Hemophilia: The Complex Management of Competing Pathologies

TH Open ◽  
2019 ◽  
Vol 03 (04) ◽  
pp. e325-e330 ◽  
Author(s):  
Manu Chhabra ◽  
Zhen Wan Stephanie Hii ◽  
Joseph Rajendran ◽  
Kuperan Ponnudurai ◽  
Bingwen Eugene Fan
Keyword(s):  
Venous Thrombosis ◽  
Vena Cava ◽  
Cost Effective ◽  
Major Surgery ◽  
High Dose ◽  
Acquired Hemophilia ◽  
Vein Thrombosis ◽  
Associated Conditions ◽  
Activated Prothrombin Complex Concentrates ◽  
Deep Vein

Abstract Introduction Venous thrombosis is rare in the setting of factor VIII (FVIII) deficiency. Cases of deep vein thrombosis (DVT) have been described in hemophiliacs after recent major surgery, or in association with the administration of FVIII concentrate and activated prothrombin complex concentrates, but occurrence of spontaneous DVT is even more uncommon. Aim We describe the challenging management of extensive DVT in a patient with acquired hemophilia A with concurrent hemorrhagic manifestations and review similar published cases. Methods We summarize a series of 10 cases with the following demographics: 6 males and 4 females; median age at presentation of 65 (21–80); mean inhibitor titer of 68.5 Bethesda Units (BU 1.9 to BU 350). Results Four cases were idiopathic and six had associated conditions (cancer [two cases], recent pregnancy [two cases], and recent surgery [two cases]). Three cases had an inferior vena cava filter inserted for acute lower limb DVT/pulmonary embolism. Inhibitor eradication was achieved with high-dose steroids with or without cyclophosphamide, and adjunct Rituximab administration was used in three cases. One patient received concurrent therapeutic plasma exchange (TPE). Inhibitor eradication was fastest with concurrent TPE at 6 days (range: 6–733 days). The 30-day survival was 90%. Conclusions There was adequate response of inhibitors to immunosuppression with steroids and cyclophosphamide therapy. For more refractory disease, Rituximab is emerging as a beneficial and cost-effective adjunct with better rates of complete remission, and the threshold for its use may be lowered in this complex cohort with dual competing pathologies.

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