Asymptomatic COVID-19-Associated Acquired Hemophilia A and Disseminated Intravascular Coagulation From a Bypassing Agent.

Acquired hemophilia A (AHA) is a clotting disorder characterized by the presence of neutralizing antibodies that inhibit factor VIII, resulting in increased bleeding risk. Known etiologies include malignancy, autoimmune conditions, graft-vs-host disease, and more recently coronavirus disease 2019 (COVID-19) infection. In this case report, we describe an 86-year-old female who was found to have AHA incidentally during preoperative workup for meningioma resection. She was subsequently found to have COVID-19 infection which was the likely cause of her development of AHA. She was treated with factor eight inhibitor bypassing agent (FEIBA) and recombinant factor VII (rVII) for a small hematoma on her right arm along with prednisone and cyclophosphamide. She then developed disseminated intravascular coagulation (DIC) initially secondary to FEIBA and subsequently rFVII. DIC resolved after these factor concentrates were withheld. The aim of this case report was to emphasize the importance of monitoring partial thromboplastin time (PTT) in patients with COVID-19 and proceeding with AHA workup if indicated. It is also imperative to know and understand the potentially life-threatening, albeit rare, adverse effects of DIC associated with the administration of factor concentrates, especially in the elderly population and withholding these factor concentrates once DIC is suspected.

Surgery with emicizumab prophylaxis for two paediatric patients with severe haemophilia A with inhibitors.

Emicizumab is a prophylaxis for patients with severe haemophilia A with and without inhibitor. Despite weekly administration of emicizumab, coagulation states stay below normal value and cannot be assessed by standard haemostasis tests. In our two patients, we used the thrombin-generation assay (endogenous thrombin potential and Peak) to monitor the patient's clotting status. Under emicizumab, it is necessary to add a bypassing agent (BPA) such as rFVIIa (Novoseven) to avoid bleeding before surgery. The BPA dosage was based on a thrombin-generation assay and collegial consultation.

Plant latex thrombin-like cysteine proteases alleviates bleeding by bypassing factor VIII in murine model.

Hemostasis is a tightly regulated process which maintains a fluid state of blood within the vasculature and provides thrombotic response upon tissue injury. Various scientific studies have implicated the role of plant latex proteases in hemostasis using in vitro experiments. However, in vivo models substantiate their role in hemostasis. Therefore, in the present study, the effect of plant latex thrombin-like proteases (PTLPs) on hemostasis was investigated systematically using mice tail bleeding as a preclinical model. In this direction, latex protease fractions (LPFs), which showed potent thrombin-like activity, were selected as they act directly on fibrinogen to form clot and quickly stop bleeding. Thrombin-like activity was exhibited mainly by cysteine proteases. Calotropis gigantea, Carica papaya, Jatropha curcas, Oxystelma esculentum, Tabernaemontana divaricata, and Vallaris solanacea LPFs and papain from C. papaya latex significantly reduced bleeding on a topical application in normal and aspirin administered mice. In addition, PTLPs accelerated the clotting of factor VIII deficient plasma, while, papain brought back the clotting time to normal levels acting like a bypassing agent. Further, papain failed to show activity in the presence of specific cysteine protease inhibitor iodoacetic acid; confirming protease role in all the activities exhibited. At the tested dose, PTLPs except C. gigantea did not show toxicity. Further, structural and sequence comparison between PTLPs and human thrombin revealed structural and sequence dissimilarity indicating their unique nature. The findings of the present study may open up a new avenue for considering PTLPs including papain in the treatment of bleeding wounds.

The efficacy of bypassing agents in surgery of hemophilia patients with inhibitors.

BACKGROUND: Inhibitory antibodies to factor VIII (FVIII) or IX (FIX) are important issues when managing patients with hemophilia A or B. Advances in bypassing agents such as recombinant activated FVII (rFVIIa) and activated prothrombin complex concentrates (APCC) have enabled the aggressive management of hemophilia with inhibitors during emergency or elective surgery. This study provides an updated evaluation of the safety and effectiveness of bypassing agents in treating perioperative bleeding. METHODS: We reviewed the records of hemophilia patients with inhibitors who underwent surgery between May 2008 and July 2014 using bypassing agents or high-dose FVIII concentrates at a single center. RESULTS: In total, 36 surgeries (24 orthopedic, 12 other) were conducted in 18 hemophilia patients with inhibitors. The median inhibitor titer at surgery was 14 (range, 0.7-1,900) Bethesda units. Most patients had high-responding inhibitors. In total, 25 patients received APCC, 9 with rFVIIa initially. In most cases, bleeding stopped or was well controlled; however, bleeding in 6 patients was controlled using sequential bypassing therapy. Hemostatic efficacy of bypassing agents in various surgeries, based on the final patient outcome, was 94.4% (34/36). Among 5 emergency surgeries, 2 deaths occurred. CONCLUSION: Good control of hemostasis can be achieved using bypassing agents in hemophilia patients with inhibitors who are undergoing surgery. Thorough planning is needed before elective surgery and more active and aggressive management may be needed for emergency surgery. Use of bypassing agents can facilitate safe and successful surgeries in hemophilia patients with inhibitors.

Prophylaxis in real life scenarios.

Prophylaxis has become the standard mantra of care for those individuals with severe haemophilia A and B. Primary prophylaxis is advocated to prevent the occurrence of symptomatic acute spontaneous haemarthroses and to preserve joint structure and function. Typically, twice or thrice weekly infusions of factor VIII or IX concentrates are integral to this treatment approach. Secondary prophylaxis is initiated after the relentless cycle of progressive joint damage has been triggered by prior haemarthroses and is intended to preserve existing joint health by preventing additional spontaneous bleeding events. Event-driven prophylaxis involves the administration of clotting factor concentrates to prevent acute traumatic bleeds, which are anticipated to occur in association with surgical or physical trauma. This regimen enhances the effectiveness of primary or secondary prophylaxis protocols or on-demand approaches to replacement therapy. Besides the marked reduction in the so-called annual bleed rate, prophylaxis regimens frequently increase personal self-confidence to embark on a more active and physical lifestyle; however, in reality, prophylaxis must be individualized in accordance with bleeding phenotypes, with the unique pharmacokinetic profile of administered replacement clotting factor concentrates, with the specific clinical scenario, and with the degree of intensity anticipated for any physical activity. The introduction of extended half-life replacement products will also influence how these prophylaxis regimens will be accomplished. The following scenarios will discuss how prophylaxis regimens can be implemented to protect the individual from developing spontaneous and activity-induced acute bleeding complications and to maintain an improved quality of life.

Role of prothrombin complex concentrate in perioperative coagulation therapy.

Prothrombin complex concentrate (PCC) is a term to describe pharmacological products that contain lyophilized, human plasma-derived vitamin K-dependent factors (F), FII, FVII, FIX, FX, and various amounts of proteins C and S. PCCs can be rapidly reconstituted in a small volume (20 ml for about 500 international units (IU)) at bedside and administered regardless of the patient's blood type. PCCs are categorized as 4-factor PCC if they contain therapeutic amounts of FVII, and 3-factor PCC when FVII content is low. In addition, activated PCC which contains activated FVII and FX with prothrombin is available for factor VIII bypassing therapy in hemophilia patients with inhibitors. Currently, 4-factor PCC is approved for the management of bleeding in patients taking warfarin, but there has been increasing use of various PCCs in the treatment of acquired perioperative coagulopathy unrelated to warfarin therapy and in the management of bleeding due to novel oral anticoagulants. There is also an ongoing controversy about plasma transfusion and its potential hazards including transfusion-related lung injury (TRALI). Early fixed ratio plasma transfusion has been implemented in many trauma centers in the USA, whereas fibrinogen concentrate and PCC are preferred over plasma transfusion in some European centers. In this review, the rationales for including PCCs in the perioperative hemostatic management will be discussed in conjunction with plasma transfusion.