Complex Regional Pain Syndrome (Crps) in a Hemophilia Child with Inhibitor: A Rare Interactable Cause of Joint Pains

Introduction: Joint bleeding is the main cause of joint pain in hemophilia patients and can lead to chronic joint disease which also happens to be one of the significant causes of disability and joint pain in these patients. Furthermore, ComplexRegional Pain Syndrome (CRPS), despite being a very rare complication, should be considered in cases of persistent intractable pain, especially in the pediatric group. Clinical symptoms in CRPS include severe chronic pain, edema, and decreased range of motion. CRPS management is critical to allowing the function and ability of the joint to restore. Method(s): This study aims to report a hemophilia case with intractable pain and his underlying diagnosis. A 14-year-old severe hemophilia A patient with high titer/responder inhibitor was on on-demand treatment by Bypassing Agents (BPAs). Result(s): During the disease course, his right knee became a target joint due to recurrent bleedings. Consequently, he underwent Radiosynoviorthesis (RSO) and treatment with BPAs. After three days of improving, he got an increasing fever and severe right knee pain. The COVID-19 test result was negative, but Staph. Aureus was found in the synovial fluid, and treatment began with Vancomycin and Rifampin. After several days, his condition and laboratory markers were improved, However, intractable disabling pain remained constant regardless of augmented combination therapy with FEIBA and rFVIIa. Parallelly, morphine was prescribed due to the Pain Management counseling. However, the pain began to rise as the morphine dosage declined. As a result, CRPS proposed to be the leading cause of pain, and after several prolonged special physiotherapy sessions, pain reduced significantly, only one BPA was continued and he was ambulated again. Discussion/Conclusion: The current case indicates that CRPS is a rare complication in patients with bleeding disorders which has been reported rarely till now. Nonetheless, it should be considered a diagnosis in complicated patients with recurrent hemarthrosis due to its debilitating and destructive nature.

Anticoagulants: dose control methods and inhibitors

These days, anticoagulants are in great demand. They are used as a prophylaxis for thromboembolic complications in various diseases and conditions in general therapeutic practice, cardiology, neurology, as well as obstetrics to manage high-risk pregnancies. The relevance of anticoagulants competent use has come to the fore in connection with the emergence of a new disease – COVID-19 and its serious complications such as developing thrombotic storm, in which the timely applied anticoagulant therapy is the key to the success of therapy. The risk of bleeding should be considered when using any anticoagulant. Age, impaired renal function and concomitant use of antiplatelet agents are common risk factors for bleeding. Moreover, only vitamin K antagonists and heparin have specific antidotes – vitamin K and protamine, respectively. Inhibitors of other anticoagulants are universal presented as inactivated or activated prothrombin complex concentrate and recombinant factor VIIa. Hemodialysis effectively reduces dabigatran concentration, activated charcoal is effective in the case of recent oral administration of lipophilic drugs. Research on new antidotes of currently available anticoagulants is under way, similar to testing of new types of anticoagulants that are sufficiently effective in preventing and treating thromboembolic complications with minimal risk of hemorrhagic. The main contraindication to anticoagulants use is the doctor's ignorance of the mechanisms of drug action and opportunities for suppressing its effect.

Safe and effective administration of multiple recombinant factors on VA-ECMO via post-oxygenator pigtail during acute massive pulmonary hemorrhage

Introduction: Massive bleeding on extracorporeal membrane oxygenation (ECMO) is associated with multiple coagulation defects, including depletion of coagulation factors and development of acquired von Willebrand syndrome (AVWS). The use of recombinant factors, in particular recombinant activated factor VII (rFVIIa, Novoseven), to treat severe refractory hemorrhage in ECMO has been described. However, the use of multiple recombinant factors has been avoided in large part due to concern for circuit complications and thrombosis. Here, we describe the safe and effective administration of rFVIIa and recombinant von Willebrand factor complex (vWF/ FVIII, Humate-P) via post-oxygenator pigtail catheter on VA-ECMO for the treatment of massive pulmonary hemorrhage. Case Description: A 21-month-old (13.4 kg) girl with a recent history of COVID-19 infection presented to an outside hospital with parainfluenza bronchiolitis resulting in acute refractory hypoxemic respiratory failure (oxygenation index 58), refractory septic shock, and myocardial dysfunction. She was cannulated to VA-ECMO and subsequently diagnosed with necrotizing pneumonia from Pseudomonas and herpes simplex infections. Her course was complicated by a large left-sided pneumatocele and bronchopleural fistula requiring multiple chest tubes. She also had right mainstem bronchus obstruction from necrotic airway debris and complete right lung atelectasis. She was noted to have prolonged episodes of mucosal and cutaneous bleeding (oropharynx, chest tube insertion sites, peripheral IV insertion sites) associated with absent high molecular weight von Willebrand multimers consistent with AVWS. Tranexamic acid infusion was initiated and bivalirudin anticoagulation was discontinued. VA-ECMO flows were escalated to 140-160 ml/kg/min to maintain circuit integrity and meet high patient metabolic demand in the absence of anticoagulation. On ECMO day 26, she underwent bronchoscopy to clear necrotic debris from her airway to assist with lung recruitment. The procedure was notable for mucosal bleeding requiring topical epinephrine and rFVIIa. Post-procedure, she developed acute hemorrhage from her right mainstem bronchus, resulting in significant hemothorax (estimated 950 ml) with mediastinal shift, increased venous pressures, desaturation and decreased ECMO blood flow rate, necessitating massive transfusion of 2,050 ml (150 ml/kg) of packed red blood cells, platelets, plasma and cryoprecipitate. An airway blocker was placed in the mid-trachea to control bleeding. In addition to transfusion of appropriate blood products and continuation of tranexamic acid infusion, she was given both rFVIIa (100mcg/kg) and vWF-FVIII (70 units vWF/kg loading dose on the day of hemorrhage, followed by 40 units vWF/kg every 12 hours for 3 additional doses). Both products were administered over 10 minutes through a post-oxygenator pigtail to allow the product to circulate throughout the patient prior to entering the ECMO circuit. The circuit was closely monitored during administration and no changes to circuit integrity were noted in the subsequent hours while hemostasis was achieved. The ECMO circuit remained without thrombosis for 9 days after the bleeding event. Discussion: Balancing anticoagulation and hemostasis is a central challenge in maintaining ECMO support, especially given the prevalence of acquired coagulopathies such as AVWS. For our patient, AVWS contributed to mucosal bleeding necessitating cessation of anticoagulation and utilization of a high ECMO blood flow strategy to minimize circuit clot burden. This was further complicated by absent native lung function and minimal myocardial function, resulting in complete dependence on ECMO. An acute massive pulmonary hemorrhage was treated with multiple recombinant factors (rFVIIa and vWF/FVIII), that are often avoided on ECMO. To minimize clotting risk to the circuit and to maximize transit of these factors to our patient, we added a post-oxygenator pigtail for administration. While this approach was the result of extreme circumstances, th use of a post-oxygenator pigtail for administration of recombinant factors may represent a viable strategy for refractory hemorrhage while on ECMO.

A VERY COMPLICATED COURSE after VAGINAL DELIVERY in TYPE 3 von WILLEBRAND DISEASE with ALLOANTIBODIES to von WILLEBRAND FACTOR and FACTOR VIII

Introduction: Delivery in type 3 VWD with alloantibodies, a rare clinical entity with few treatment options, is a very high-risk situation. Methods: Case report Results: A 28 yo patient with type 3 VWD and alloantibodies to VWF and FVIII became pregnant after extensive preconceptional counselling. Previous ITI was unsuccessful and complicated by anaphylaxis. The pregnancy was complicated by a mild COVID-19 infection in the 2nd trimester, but otherwise uncomplicated. Delivery was induced at 38 4/7 weeks with prostaglandin and rFVIIa (NovoSeven®) started when in active labor. After a rapid vaginal delivery and afterbirth, manual placental removal was performed and a Bakri balloon inserted for ongoing bleeding despite rFVIIa 90μg/kg every 2h. As bleeding still continued, plasma-derived VWF was infused with initial excellent recovery and successful embolization of the aa uterinae was performed. Another infusion of VWF to prevent rebleeding resulted in minimal recovery and an allergic reaction despite prednisolone and clemastine. Rebleeding did not occur and patient was discharged at day 8. At day 12 she was readmitted because of endometritis followed by vaginal bleeding unresponsive to rFVIIa. Re-embolization was performed and off label emicizumab started to prevent rebleeding. A loading dose of 6mg/kg on day 1 and 3mg/kg on day 2 was given, followed by 3mg/kg EOW from the 2nd week onwards. As the infection was uncontrolled by broadspectrum antibiotics, hysterectomy was performed at dag 29, again complicated by diffuse bleeding requiring direct intra-abdominal packing and rFVIIa 90μg/kg every 2 hours in addition to emicizumab. A week after unpacking, asymptomatic pulmonary embolisms and thrombosis of the left v iliaca were discovered on CT. rFVIIa was stopped, prophylactic LMWH started and a third embolization performed when bleeding reoccurred. Two months after delivery she was discharged with low dose LMWH, emicizumab and antibiotics because of an intra-abdominal abcess. Discussion/Conclusion: Delivery in patients with severe bleeding disorders in the presence of alloantibodies is a high-risk situation. Emicizumab was partially helpful in maintaining hemostatic control. Besides bleeding, postpartum patients receiving intensive correction of coagulation and especially with additional risk factors like surgery and infection, are also at risk for thrombotic events.

Acquired Hemophilia-Treated with Rituximaband Emicizumab-A Case Report

Introduction: Acquired haemophilia A is a rare bleeding disordercaused due to autoantibodies against Factor VIII. As this is a rareentity, there are no randomized prospective trials to guide therapy.Aims &Objectives: We are herewith presenting a case report of anelderly gentleman diagnosed with Acquired haemophilia A andtreated with Rituximab and Emicizumab.Materials &Methods: 84 years old male, presented with extensiveecchymotic patches over his extremities associated with swelling ofbilateral lower limbs and left upper limb in April 2021. His arterialand venous Doppler showed subcutaneous edema without anythrombus. He had severe anemia with isolated prolonged aPTT (68.3;INR 0.9) with no previous history of bleeding disorder. Patient was aknown hypertensive on treatment for 7 years. Mixing studies doneshowed correction-(aPTT-82 s;post 1:1 mix with pooled normalplasma aPTT-34.7 s). Factor VIII and IX levels sent showed severefactor VIII deficiency (levels <1%)%. Factor VIII inhibitor level-1.8BU/ml(low titre). PETCT, Von willebrand antigen,ANA profile-normal. Hence, he was diagnosed with Acquired haemophilia A and wastreated with FFP, rfVIIa along with Azathioprine and Rituximab. Healso developed hematoma in the tongue and new onset swelling intothe right upper limb-he was given FEIBA 2000 units for 2 days.Result: He received 3 cycles of Rituximab (375 mg/m2) and one doseof Emicizumab (210 mg). After 2 doses of Rituximab, repeat inhibitor titres sent was 5.2 BU and F VIII levels-4%.After one dose ofEmicizumab, aPTT normalized to 24 s.Few days later, he developedfever, altered sensorium and hypotension;he was found to be COVIDpositive. His condition deteriorated in spite of mechanical ventilationand he died of cardiac arrest after 6 days of COVID treatment.Conclusions: As most of the Acquired haemophilia patients areelderly, their comorbidities and medications, influence the initialclinical presentation. The current management is based on rFVIIa,APCC, recombinant porcine FVIII and immunosuppressive therapy.Emicizumab (approved for congenital haemophilia) has been usedeffectively in acquired haemophilia A as per few case reports.However, effectiveness of Emicizumab in our patient could not bedetermined as he unfortunately succumbed to COVID infection.