Hrev_master [page 18] [Emergency Care Journal 2022; 18:10457] Emergency Care Journal 2022; volume 18:10457 Abstract We report an interesting clinical case of Acquired Haemophilia A (AHA) after a probable Loxosceles rufescens spider bite in a 73- year-old woman, admitted to an Emergency Department (ED) of Central Italy during April 2019. AHA is a rare disease, whose acute clinical manifestations are not widely known by most ED physi- cians; its prompt recognition and treatment are crucial to avoid fatal bleeding. In particular, the development of AHA after a violin spider bite (another rare and poorly characterized clinical condi- tion) has never been described. Therefore, our case report could provide useful insight into the understanding and treatment of such unusual and possibly life-threatening conditions. Introduction Loxosceles spp. spider poisoning is rare in Europe, although bites from L. rufescens1 have been increasingly reported from countries around the Mediterrean basin.2 The marked synanthropy of this species and its tendency to hide in shoes or clothes left out on the floor or stored in closets, rooftops or garages make its bite a frequent report when the spider is accidentally pressed against the skin while dressing or sleeping.3 L. rufescens bites may lead to a localized reaction (cutaneous loxoscelism) and, less commonly, to systemic symptoms (systemic loxoscelism).1 Acquired Haemophilia A (AHA) is a rare, potentially lethal bleeding disease, characterized by the development of neutralizing autoantibodies against of factor VIII (FVIII), resulting in an isolat- ed prolonged aPTT.4–7 Half the cases (around 50%) are idiopathic, while the remaining 50% are associated with other systemic disor- ders (cancer, autoimmune diseases, pregnancy and other condi- tions).5,6,8,9 The bleeding phenotype of AHA is variable, ranging from life-threatening bleeds to mild mucocutaneous/muscular bleeding or no bleeding.5,6,8,9 Literature for both systemic and cutaneous diseases is scarce and to our knowledge no case of AHA developed after L. rufescens bite has been reported. Case Report A 73-year-old woman was admitted to our Emergency Department (ED) in April 2019 with a 12-hour history of localized bruising and swelling on the dorsal side of the left hand. She was not taking antiplatelet or anticoagulant medicines and she denied any recent trauma, travel, new medication or recent fever. The day before admission, she took azithromycin (500 mg) as antibiotic prophylaxis before a dental intervention. The patient reported pre- vious administration of azithromycin without significant adverse events. The month before the ED admission, she had physio-kine- sitherapy for rheumatic polymyalgia. In addition, she had a history of hypertension currently treated with losartan 25 mg. She denied any known allergies to medications. On clinical examination the patient was in good conditions, vital signs were stable and within normal limits (blood pressure Correspondence: Caterina Zattera, Emergency Medicine Post-graduate Training Program, IRCCS Policlinico San Matteo Foundation, University of Pavia, P.le Golgi 19, 27100 Pavia, Italy. Tel.: 0382.5011 - Fax: 0382.503139 E-mail: caterina.zattera01@universitadipavia.it Key words: Acquired haemophilia A; spider bite; violin spider. Conflict of interests: The authors declare no conflict of interests. Availability of data and materials: All data underlying the findings are fully available. Ethics approval and consent to participate: No ethical committee approval was required for this case report by the Department, because this article does not contain any studies with human participants or ani- mals. Informed consent was obtained from the patient included in this study. Consent for publication: The patient gave her written consent to use her personal data for the publication of this case report and any accompany- ing images. Received for publication: 13 March 2022. Revision received: 18 May 2022. Accepted for publication: 19 May 2022. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2022 Licensee PAGEPress, Italy Emergency Care Journal 2022; 18:10457 doi:10.4081/ecj.2022.10457 Publisher's note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organiza- tions, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its man- ufacturer is not guaranteed or endorsed by the publisher. An unexpected turn of events: A rare case of Acquired Haemophilia A after a violin spider bite Caterina Zattera,1,2 Simona Luly,1 Alessandro Cipriano,1 Grazia Maria Luisa Rizzelli,1 Nadia Cecconi,3 Massimo Santini1 1U.O. Medicina d'Urgenza e Pronto Soccorso, Emergency Department, Azienda Ospedaliero-Universitaria Pisana, Pisa; 2Emergency Medicine Post-graduate Training Program, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia; 3Department of Clinical and Experimental Medicine, U.O. Hematology, University of Pisa, Pisa, Italy Non -co mmerc ial us e o nly 130/80 mmHg, heart rate 80 beats/min, respiratory rate 14 breaths/min and body temperature 36°C). She presented with an extensive and mildly painful hematoma on the dorsal left hand and forearm; peripheral pulse was present, and no other signs or symp- toms were revealed. A Complete Blood Count (CBC) and Comprehensive Metabolic Panel (CMP) were prescribed. The initial White Blood Count (WBC) count was 10.59 ×10³ cells/µL (n.r. 4.0-11.0×10³ cells/µL), Hb 12.4 g/dL (n.r. 11.5-16 g/dL), platelet count 225×10³ cells/µL (n.r. 140-450×10³ cells/µL), aPTT 44.5 sec (n.r. 25.1-36.5 sec), glucose 153 mg/dL (n.r. 74-109 mg/dL); other results were normal (Table 1). Angio-Computed Tomography (Angio-CT) of her left arm and orthopaedic consult were requested; paracetamol and tramadol with metoclopramide were administered to treat pain. Angio-CT did not detect any arterial or venous active bleeding, but it revealed oedema and bleeding in the sub-cutaneous tissues her left forearm. The orthopaedic consultant recommended a 24-hour observation, the repetition of blood tests the next day and suggest- ed to maintain elevation of the left arm. On later examination that day, the patient developed agitation and confusion; body tempera- ture was 37.5°C and she complained of nausea, vomiting and worsening pain of the left arm. Amoxicillin/clavulanic acid, indomethacin and metoclopramide were administered, and the patient was transferred to our Emergency Medicine Unit. The next day, the hematoma was increasing in size (Figure 1), and the pain worsened; the left radial pulse was still palpable, but she developed paraesthesia of the first three fingers of the left hand. Blood tests were repeated with the following results: WBC counts 9.8×10³ cells/µL, Hb 12.4 g/dL, platelet count 212×10³ cells/µL, aPTT 44.5 sec, other results including Creatine Kinase (CK) levels and myoglobin were within the normal limits. Case Report Table 1. Patient’s complete blood count and comprehensive metabolic panel at admission and during the recovery. Reference Range Day 1 Day 2 Day 3 Day 11 Hb (g/dL) 11.5 – 16.0 12.4 11.2 9.1 9.9 Hematocrit (%) 37.0 – 47.0 35.8 31.8 25.4 30.1 White-cell count (per mm³) 4.0 – 11.0 10.59 14.46 9.97 6.07 Neutrophils (per mm³) 1.8 – 7.0 7.67 10.5 9.68 3.37 Lymphocytes (per mm³) 0.9 – 4.5 1.99 2.88 0.2 1.72 Monocytes (per mm³) 0.1 – 1.2 0.86 1.03 0.08 0.84 Eosinophils (per mm³) < 0.7 0.06 0.03 0.01 0.13 Basophils (per mm³) < 0.2 0.01 0.02 0 0.01 Platelet count (per mm³) 140 - 450 225 277 138 212 Sodium (mEq/L) 135 - 145 140 141 138 144 Potassium (mEq/L) 3.5 – 5.1 3.95 3.56 2.61 4.55 Creatinine (mg/dL) 0.50 – 0.90 0.66 0.63 0.7 0.63 Lactate dehydrogenase, LDH (U/L) 135 - 214 - 210 264 257 Creatinine kinase, CK (U/L) < 170 - 83 529 33 Myoglobin (µg/L) 25 - 58 - 44 149 < 21 C-reactive protein, CRP (mg/dL) < 0.5 - 4.43 11.21 1.05 Procalcitonin (ng/mL) < 0.5 - 0.09 8.68 0.27 Prothrombin (%) 80 – 130 88 87 89 97 I.N.R. 0.87 – 1.12 1.09 1.09 1.08 1.02 aPTT (sec.) 25.1 – 36.5 44.5 51 36.7 58.3 aPTT ratio 0.84 – 1.22 1.55 1.78 1.28 1.91 Ddimer (mg/L) < 0.3 - 0.37 - - Fibrinogen (mg/dL) 200 – 400 - 493 - 357 Antithrombin (%) 83-128 - 83 - - *LAC Absent - - - Neg *aPTT Mix - - - - 31 aPTT Mix T+2 - 54.3 Anti-fVIII Ab (UB/mL) Absent - - - 9.0 *vWF:RiCof% 50 - 150 - - - 120 fVIII (%) 60 - 150 - - - 6.7 *(Lupus anticoagulant panel, LAC; Mixing test: aPTT incubated Mix, aPTT Mix; activity of the ristocetin cofactor – von Willebrand factor, vWF:RiCof%). [Emergency Care Journal 2022; 18:10457] [page 19] Figure 1. Hematoma of the left arm, respectively at day 3 and at discharge. Non -co mmerc ial us e o nly Suspecting a compartmental syndrome, a second orthopaedic con- sult was requested: in the absence of indication for surgical treat- ment, the consultant advised for watchful observation and repeat blood testing. On later examination that day, the patient’s clinical status worsened and a large hematoma of the neck appeared. CBC and CMP were repeated: WBC counts was 14.46×10³ cells/µL, Hb 11.2 g/dL, platelet count 277×10³ cells/µL, aPTT 51 sec, CRP 4.43 mg/dL (n.v.<0.50 mg/dL), procalcitonin 0.09 ng/mL (n.v.<0.50 ng/mL) and ISTH Disseminated Intravascular Coagulation (DIC) Score10 was calculated and ruled out DIC (see Table 1). While fur- ther questioning the relatives for additional information, a new anamnestic clue was revealed: the patient’s husband stated that the day before admission to our ED, the patient had removed an arach- nid from her arm while doing household chores. Based on this finding, a violin spider bite was suspected. Blood cultures were drawn and resulted negative, a laryngoscopy was negative for internal bleeding; therefore, linezolid and piperacillin/tazobactam along with 1 IU of Fresh Frozen Plasma (FFP) were administered. On the third day of admission the patient’s daughter found a live spider in the patient’s house and brought the specimen for proper identification. The emergency physician identified a spider of genus Loxosceles, with three pairs of eyes and a darker violin mark on the cephalothorax. Unfortunately, an entomologist was not available at our hospital to confirm the ED physician’s suspect. On the same day blood tests were repeated: WBC counts was 9.97 ×10³ cells/µL, Hb 9.1 g/dL, platelet count 138×10³ cells/µL, aPTT 38 sec (Table 1). The next days there was an improvement of the clinical status and blood exams; a contrast-enhanced-CT and mag- netic resonance imaging of the left arm were performed and revealed extended necrosis of the subcutaneous tissues of the left forearm. On day 8 the patient was discharged with the diagnosis of spontaneous hematoma of the left arm and multiple diffuse hematomas after a probable violin spider (L. rufescens) bite. She was in a good clinical status, vital parameters were stable, but blood exams and coagulation factors levels (FVIII, FIX, FXI) were prescribed because a persistent isolated aPTT prolongation (51.9 sec). On day 11 from the presentation of symptoms, blood test reports confirmed aPTT prolongation (54.9 sec; n.r. 25.1-36.5 sec) and revealed a FVIII deficiency (4.1%; n.r. 60-150%). The patient was admitted again to our ED and an emergency haematologic consult was requested. Tests were performed to clarify the cause of isolated aPTT elongation (see Table 1). Based on clinical and lab- oratory findings, the patient was sent to our ED with the diagnosis of Acquired Haemophilia A (AHA) and methylprednisolone at a dose of 1 mg/Kg was administered. After therapy was started, the patient was transferred in our Emergency Medicine Unit for the second time. During hospitalization, the immunotherapy with steroids was continued, total-body contrast-enhanced-CT and blood exams for tumour markers were performed; no signs of neo- plasia were found. Blood exams for monitoring the coagulation showed an improvement of aPTT values; the patient condition was good and vital parameters stable. On day 18, the patient was dis- charged with a diagnosis of AHA after probable L. rufescens bite, with the recommendation to continue steroid therapy per os (pred- nisone 25 mg QD) and she was referred to the haematological out- patient clinic specialized on coagulation disorders. Two months after hospital discharge, the patient was in good clinical conditions and there was an improvement in the laboratory exams (aPTT 38 sec, fVIII 120%, fVIII Ab negative). Based on haematological consulting, steroid therapy was progressively reduced and definitively stopped after four months; to our knowl- edge no relapse has been reported. Discussion Loxosceles spp. bites are rare, but literature about this argu- ment is growing.2 L. rufescens is the most common species in the Mediterrean basin and in Italy.1 To allow a correct diagnosis of a spider bite (defined as a documented spider bite, based on Rader’s classification),10,11 the spider must be observed biting, captured during or immediately after the bite, identified by an expert and the bite must cause symptoms typically associated with a spider of that species.1,11 In our case, the clinical features of the wound were indicative of Loxosceles rufescens bite (pain absent immediately after the spider bite and increasing over the course of a day, pro- gressive appearance of bruising and swelling);1,2,11–13 the localiza- tion of the bite was typical (arms and legs are the most commonly affected areas),1,2,11–13 the situation and the season were also consis- tent with Loxosceles spp. activity (spiders usually hide in dark cor- ners inside houses, between clothes and are active between April and October).11 Furthermore, Tuscany is an endemic area for L. rufescens. Unfortunately, the spider (as in many cases reported in literature)1,14 was not captured during or immediately after biting. We classified the wound as probable spider bite as per Rader’s cri- teria.1,11 Symptoms of Loxosceles bite could produce local or sys- temic signs, respectively called cutaneous and systemic lox- oscelism. Cutaneous loxoscelism is characterized by a local ery- thema and swelling, that can progress into ecchymosis and rarely can lead to necrosis and ulcer formation in a few days after the bite.1,2,13 Concerning cutaneous loxoscelism there are three possi- ble levels of severity: i) unremarkable: very little damage, self- healing; ii) mild reaction: redness, itching, slight lesion, self-heal- ing; iii) dermonecrotic: necrotic skin lesion, requiring medical and sometimes surgical treatment. This last condition, although very rare, is considered the most “characteristic” lesion of Loxosceles rufescens bites, which contributes in developing a clinical suspect. Among patients developing necrotic lesions, about two-thirds heal without complications.15 Systemic loxoscelism is a rarely and serious clinical condition in which malaise, fever, myalgias, nausea and vomiting are pre- sent, with or without acute haemolytic anemia, rhabdomyolisis, DIC and acute kidney disease.1,2,13 Systemic symptoms (malaise, low grade fever, nausea, vomiting, headache and mild leucocyto- sis), can also develop in patient with cutaneous loxoscelsim,1,2 as in our case. Moreover, almost one third of patients develop labora- tory evidence of cutaneous-haemolytic loxoscelism.2 This could explain the Hb reduction in our patient (Hb level decreased from 12.4 g/dL to 9.1 g/dL with mild increase of LDH level; haptoglobin level was not dosed), although it could have been caused also by the hematoma enlargement. We excluded AHA at a first evalua- tion, because the patient had a good response to FFP transfusion with a reduction of aPTT: this result ruled out AHA.4–6 Case Report Table 2. Hematological complications after violin spider bite after references.1,2,12,13 Clinical/laboratory findings Enzymes Involved Mild leukocytosis Immune System activation Haemolytic anemia Sphyngomyelinasis D aPTT prolongation Sphyngomyelinasis D, metalloproteases, hyaluronidases and serine proteases DIC - [page 20] [Emergency Care Journal 2022; 18:10457] Non -co mmerc ial us e o nly AHA is a rare autoimmune disease, characterized by low fVIII levels due to the presence of autoantibodies, resulting in mild to life-threatening mucocutaneous bleeding.4,5,9 Diagnosis is based on laboratory findings: isolated aPTT prolongation, without correc- tion in aPTT-mixing tests, low fVIII levels and the presence of fVIII inhibitors.4–6,8,9 Trasfusions of FFP during active bleeding in these patients are ineffective: in fact, the presence of fVIII inhibitors inactivates fVIII in FFP and the patient aPTT will not be corrected (no correction in mixing test, as seen in our case).5,6,16 In our opinion the initial prolongation of aPTT in our patient was due to L. rufescens poisoning, because aPTT value reduced after FFP infusion. Venom contains different toxins: sphyn- gomyelinasis D (responsible for the major dermatonecrotic symp- toms of loxoscelism and for the disruption of red blood cell mem- branes, resulting in hemolysis) and, among others, metalloproteas- es, hyaluronidases and serine proteases.12 In particular, these enzymes seem to interfere with blood coagulation because of thrombin-like, fibrinogenase and fibrinogen activating activities.12 For all these reasons, we attributed the initial aPTT prolongation and patient’s symptoms to Loxosceles’ venom and we excluded AHA at the time of the first diagnosis (Table 2 summarizes post- spider bite hematologic complications). Due to the persistent aPTT prolongation, we started to suspect a form of AHA and we requested lab tests that confirmed our sus- pects. In 50% of cases AHA is idiopathic, while the remnant 50% is caused by cancer, autoimmune diseases, pregnancy, drugs, der- matologic diseases and other conditions.5,6,8,16 Therefore, laborato- ry tests and imaging exams were performed to find the hidden cause of AHA: haematological or solid tumour, autoimmune dis- eases, infective diseases and other causes were excluded. Due to the close temporal relationship between spider bite and AHA man- ifestations, in our opinion the most probable cause that triggered the production of fVIII autoantibodies has been the violin spider’s poisoning. To confirm our hypothesis it would have been interesting to characterize the anti fVIII antibodies: an IgM positivity could have confirmed the acute development of AHA. Unfortunately antibodies characterization was not requested at the time. Despite this, the absence of pre-existing aPTT alterations, the exclusion of secondary pathologies and the consequentiality of the two events supports our hypothesis. The patient was treated with corticosteroids at immunosup- pressive dose with complete remission of the symptoms in six months.4,5,17 The rapid response to corticosteroid therapy could be explained by the secondary nature of the event: the spider bite may have caused the formation of anti-venom antibodies that cross- reacted with fVIII. The absence of relapses in the following months, with the tapering of the steroid therapy, seems to confirm our hypothesis. Conclusions Here, we described a case wherein a patient developed AHA induced by a probable violin spider’s bite. Albeit rare, AHA is a potentially life-threatening condition. Emergency physicians must consider AHA in the range of bleeding differential diagnosis and be aware of the possible systemic complications following a spider bite, in order to provide prompt treatment and avoid potentially preventable life-threatening haemorrhages. References 1. Nentwig W, Pantini P, Vetter RS. Distribution and medical aspects of Loxosceles rufescens, one of the most invasive spi- ders of the world (Araneae: Sicariidae). Toxicon 2017;132:19- 28. 2. Jerusalem K, Salavert M. Probable cutaneous loxoscelism with mild systemic symptoms : A case report from Spain. Toxicon 2018;156:7-12. 3. Fusto G, Bennardo L, Duca ED, et al. Spider bites of medical significance in the Mediterranean area: misdiagnosis, clinical features and management. J Venom Anim Toxins Incl Trop Dis 2020;26:e20190100. 4. Charlebois J, Rivard GÉ, St-Louis J. Management of acquired hemophilia A: Review of current evidence. Transfus Apher Sci 2018;57:717-20. 5. Franchini M, Vaglio S, Marano G, et al. Acquired hemophilia A: a review of recent data and new therapeutic options. Hematology 2017;22:514-20. 6. Collins P, Baudo F, Huth-Kühne A, et al. Consensus recom- mendations for the diagnosis and treatment of acquired hemophilia A. BMC Res Notes 2010;3:161. 7. Huth-Kühne A, Baudo F, Collins P, et al. International recom- mendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica 2009;94:566-75. 8. Kessler CM, Knöbl P. Acquired haemophilia: an overview for clinical practice. Eur J Haematol 2015;95:36-44. 9. Baudo F, Collins P, Huth-ku A. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. Blood 2012;120:39-46. 10. Di Nisio M, Baudo F, Cosmi B, et al. Diagnosis and treatment of disseminated intravascular coagulation: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 2012;129:e177-84. 11. Rader RK, Stoecker WV, Malters JM, et al. Seasonality of brown recluse populations is reflected by numbers of brown recluse envenomations. Toxicon 2012;60:1-3. 12. Helena L, Trevisan-silva D, Pereira V, et al. Recent advances in the understanding of brown spider venoms: From the biolo- gy of spiders to the molecular mechanisms of toxins. Toxicon 2014;83:91-120. 13. Planas E, Zobel-thropp PA, Ribera C, Binford G. Not as docile as it looks? Loxosceles venom variation and loxoscelism in the Mediterranean Basin and the Canary Islands. Toxicon 2015;93:11-19. 14. Stuber M, Nentwig W. How informative are case studies of spider bites in the medical literature ? Toxicon 2016;114:40-4. 15. Pauli I, Puka J, Gubert IC, Minozzo JC. The efficacy of antivenom in loxoscelism treatment. Toxicon 2006;48:123-37. 16. Collins PW, Chalmers E, Hart D, et al. Diagnosis and manage- ment of acquired coagulation inhibitors: a guideline from UKHCDO. Br J Haematol 2013;162:758-73. 17. Collins PW, Hirsch S, Baglin TP, et al. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors’ Organisation. Blood 2007;109:1870-7. Case Report [Emergency Care Journal 2022; 18:10457] [page 21] Non -co mmerc ial us e o nly