Combined Application of Ultrasound-Guided Percutaneous Drainage and Urokinase Lavage: An Economical and Effective Treatment for Muscle Hematomasin Hemophiliacs

1. AbstractAim:Aninitialattempttotreathemophiliachematomabyultrasound-guided intratumoral drainage combined with urokinase lavage after adequate supplementation of coagulation factors. Methods: With sufficient supplementation of coagulation factors, drainage tube was inserted into hematomas under the guidance of ultrasound. 30,000 units of urokinase were injected into the hematomas through drainage tube, the drainage tube was clampedfor6hoursandthendrainedfor2hours,thisprocesswas repeated twice a day. Results:After a-5-day and a-3-day treatment, the intermusclar hematomas in two patients basically disappeared, accompanied with compression symptoms relief. No obvious adverse reactions andseriouscomplicationswereobservedduringthetreatmentand follow-up. Conclusion:Ultrasound-guideddrainagecombinedwithurokinaselavageisasafe,effective,andminimallyinvasivetherapeutic strategy for intermuscular hematomas in hemophiliacs, avoid- ing potential complications of surgical resection and limiting the cost.

2. Introductioning episodes occur in muscles. If not treated in a timely manner, muscle hematoma in patients with hemophilia can lead to serious complications, such as nerve injury, osteofascial compartment syndrome, and even sepsis. The World Hemophilia Federation recommendshighdosecoagulationfactorreplacementtherapyfor managementofmusclehematomasinsuchcases[1].However,in China and other developing countries, most patients with hemophilia do not have sufficient access to coagulation factor replace- ment therapy due to economic constraints, resulting in a higher incidence of muscle hematoma and poorer prognosis. Ultrasound-guided percutaneous drainage is a fast, real-time, and well-tolerated procedure that can remove hematoma in a short time. However, for patients with hemophilia, repeated bleeding may cause organization and viscosity of hematomas, potentially lowering the success of evacuation. It is reported that urokinase can degrade the fibrin in the hematoma, making the sticky hema- toceles become thinner and easier to drain [2]. Hence, to improve the efficiency of drainage, we describe our initial attempt to treat muscle hematomas in hemophiliacs with ultrasound-guided per- cutaneous drainage and urokinase lavage after supplying enough coagulation factor.

3. Methods decreased muscle function of the right knee caused by repeated bleeding.Threeweekslater,hefeltprogressiveswollenintheright leg,accompaniedbyhyposensationfromtherightlegtofootdorsum.Ultrasoundexaminationrevealedaheterogeneousechomass on the lateral muscles of right calf, which was 17 * 8 * 7cm in size approximately. Based on clinical manifestation and ultrasonographic features, it was concluded that the motion disorder and sensory disturbance of the patient's right leg was caused by compression from the heterogeneous intramuscular mass. To explore thecompositionofthemass,a2.4mlbolusofcontrastagent(SonoVue®, Bracco, Milano, Italy) was then injected into the elbow vein. Circular hyperenhancement was observed in the periphery while no enhancement was found in the central space, suggesting that the mass was a hematoma with no obvious granulation tissue and neovascularization formed inside (Figure S1). Therefore, we tried to drain the muscular hematoma under the guidance of ultrasound. After supplementing 1500 IU of recombinant human coagulate factorVIII, a 16G puncture needle was successfully inserted into the hematomaunder the guidance of ultrasound, while no hematocele could be drained out. Then a 0.038-inch wire was placed into the hematoma through the needle, followed by inserting a 12F drainage tube. However, there was still no hematocele drawn out due to viscosity of the content. Urokinase lavage was thenperformedbasedonthelackofobviousgranulationtissueor neovascularization within the hematoma on CEUS. To make the viscous hematocele become diluted and easy to drain out, 30,000 IU of urokinase were dissolved in physiological saline(20 ml) andinjectedintothehematomathroughdrainagetube.Thedrain- age tube was clamped for 6 hours in order to increase thrombo- lytic effect of the urokinase and then drained for 2 hours, these procedures repeated twice a day. To maintain factor VIII activity above 30%during thisprocedure, thepatient wasprescribed with prothrombin complex twice daily for 25 IU/kg. Ultrasound was adopted to monitor the change of muscle hematoma. Subject B, a 27-year-old man with severe hemophilia A felt his right forearm swollen gradually two weeks ago.Aweek later, the patient felt numbness in the right thumb, index finger and middle finger, occasionally accompanied with movement disorders. Ultrasonography revealed a polycystic hematoma in the flexor of theforearm.Thehematomawaslocatedbetweenulna,radius,and median nerve with an approximate size about 10.5*3.5*3.2cm, compressing the median nerve, which was swollen and thickened underultrasounddetection.Afterinjecting2.4mlbolusofcontrast agent into elbow vein, no-enhanced area was found inside the hematoma under CEUS evaluation (Figure S2). In order to relieve the compression on the median nerve, a 14F drainage tube with several side-hole was placed along the long axis of the hematoma to penetratethreemaincapsulesunder ultrasound guidance.After supplement of coagulation factor (20 IU/kg, twice a day), 20 mL salinesolutioncontaining30,000IUofurokinasewasinjectedvia a drainage tube, the drainage tube was clamped for 6 hours and then drained for 2 hours (repeated twice a day). Subject C, a 12-year-old boy with severe hemophilia A felt pain in the right hip joint accompanied with limited mobility. A wide range of heterogeneous echo mass was observed in his right iliopsoas muscle under ultrasound detection. However, since CEUS evaluationrevealedanunevenhyperenhancementinthemasswith scattered no-enhanced areas, suggesting that the mass might be a hematoma with abundant granulation tissue and neovascularization formed inside (Fig. S3), it was not suitable for urokinase lavage treatment in this case. Hence, the patient underwent surgery to remove the hematoma. ThisstudywasapprovedbytheEthicsCommitteeofourhospital. Written informed consent was obtained from all patients before conventional ultrasound and CEUS examinations.

4. ResultsIn subjectA, the hematoma gradually shrank in volume (volume isestimatedbasedonlength*width*height*0.52)underultrasound detectionduringthefive-daytreatment.Threemonthslater,norecurrence of the muscle hematoma was observed under ultrasound examination, and the function of the lower limbs had gradually recovered. (Fig.1) Three days after the procedure, the hematoma in subject B basically disappeared confirmed by ultrasound. The patient gradually recovered from movement disorder and sensation disturbance in the right forearm. Four months later, no recurrence of the muscle hematoma was observed (Figure 2). theflexoroftheforearm(LongAxissectionofhematoma,A).Thehema- toma was located between median nerve (*), radius and ulna (ShortAxis sectionofhematoma,B).Threedaysafterdrainageandurokinaselavage, ultrasonography showed that the hematoma had nearly disappeared (C). Hematoma did not recur at the 4-month follow-up after treatment (D).

5. DiscussionThe most widely accepted treatment for muscular hematoma in patientswithhemophiliaiscoagulationfactorreplacementtherapy [1].However,thelong-termuseandhighdoseofcoagulationfac- tors is unaffordable for many patients with hemophilia in China. In addition, this treatment does not immediately reduce the sizeof the hematoma. Ultrasound-guided percutaneous drainage is a low-cost, minimally invasive method for the treatment of musclehematomainpatientswithhemophilia,butitseffectiveness is questionable due to few case reports that muscle hematomas caused by repeated bleeding are too viscous to be drained effectively[2-4].Withthecapabilityofdegradingfibrininbloodclots, urokinase has been reported for its effectiveness on intracavitary lavage to dissolve hematoma with viscous content such as intraranialhematoma,subduralhematoma,retroperitonealhematoma [5-7].Therefore, we first attempted to perform ultrasound-guided drainagecombinedwithurokinaselavagetotreatmuscularhemaomas in patients with hemophilia. In subject A, about 400 IU/kg of coagulation factor in total was used during the treatment. According to the reports, for muscle hematomasofsimilarsize,thecoagulationfactordoseusedinreplacementtherapyalonewasashighas3000-4000IU/kg,andthe duration of treatment lasts for more than 20 days.Typically, such caseswillundergosurgerytoremovethehugehematoma.Incases of muscle hematoma causing peripheral neuropathy and loss of function, the principle of surgery is extensive fasciotomy, which will lead to massive trauma and may result in sequelae, such as scar contracture. In comparison with coagulation factor replacementtherapyandsurgery,ultrasound-guideddrainagecombined with urokinase lavage is a feasible option in patients with hemophilia under poorer economic conditions due to its excellent performance in evacuating huge muscle hematoma in a minimally invasivemanner,aswellasreducingthecoagulationfactordosage and treatment costs. InsubjectB,althoughthemusclehematomawasrelativelysmall, itwasurgenttoremovethehematomainordertorelievethecompression of median nerve. However, in this case, surgical operationismoretraumaticandhasahigherriskofcomplicationssuch as bleeding and infection during and after surgery.Therefore, the patient underwent the procedure of ultrasound-guided drainage combinedwithurokinaselavageandthehematomashrunksignificantly in a-three-day treatment. Additionally,itisworthnotingthatusingurokinaseonhematomas with abundant granulation tissue and neovascularization formed inside is inappropriate in order to avoid the risk of hemorrhage caused by the entry of urokinase into the circulatory system [5]. Therefore, the hematoma in subject C did not receive urokinase lavagetreatmentforpotentialriskofbleeding.Furthermore,urokinasecanbeusedtodissolveacute(1-14days)andsubacutethrom- bosis or hematoma (15-28 days) effectively [8]. Fortunately, the formation time of hematoma in the first two cases is within four weeks. In addition, no obvious granulation tissue and neovascularization were formed inside the hematoma under CEUS evaluation,whichmakesitmoresuitabletodissolvethehematomawith urokinase. According to some studies, local lavage of urokinase is at lower risk of inducing recurrent bleeding and hyperfibrinolysis compared withintravenousthrombolysis[9].However,sincethehemophiliacscomewithpoorcoagulationfunctioninmostcases,itwasrecommendedto maintaincoagulationfactorlevelsabove30% during treatmentinbothpatientsaccordingtotheperioperativeguidelines forhemophiliainordertopreventrebleedingduringtreatment.In contrast to systemic thrombolytic therapy, which requires a high dose of urokinase to dissolve the thrombus and restore the pateny of blood flow, the therapeutic goal of urokinase lavage is to reduce the viscosity of the hematoma until it can be discharged through the drainage tube. Therefore, the dosage of urokinase in thetreatmentprocesswaslimitedwithlongerefficienttimedueto safetyconcerns.Inthefirsttwocases,thedosageofurokinasewas 60,000IU/day,whichwasmuchlowerthanthedosageofsystem- ic thrombolysis (600,000-800,000 IU/day). Under the treatment, the hematoma was drained smoothly, and there were no signs of rebleeding in the next three-month follow-up observation. These casesshowedthattheuseoflow-doseurokinaseforintramuscular lavage of hematoma under conditions of coagulation factor supplementation is both safe

6. ConclusionUltrasound-guideddrainagecombinedwithurokinaselavageisa minimally invasive therapeutic strategy for intermuscular hema - tomas in patients with hemophilia. The procedure can relieve the pressure from the hematoma immediately, shorten the treatment period, and limit the total cost with immediate results. Howev -er, further optimization is required to determine the appropriate amount and efficient time of urokinase lavage for hematomas of different sizes at various sites. In addition, there were only few cases in this study, and the follow -up time was relatively short. Further large -scale clinical studies with long -term follow -up are needed to verify the safety and efficacy of this method for treat - ment of muscle hematoma in patients with hemophilia.

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Richard ME1.Combined Application of Ultrasound-Guided Percutaneous Drainage and Urokinase Lavage: An Economical and Effective Treatment for Muscle Hematomasin Hemophiliacs. Annals of Clinical and Medical Case Reports 2022