10.4081/btvb.2022.44
Aortic arch thrombosis represents a severe condition which usually requires surgical treatment in specialized centers. Treatments described in literature are mostly surgery or sodium heparin infusion. Here we describe an off-label use of alteplase in aortic arch thrombosis in a patient in whom sodium heparin treatment failed and surgery was not possible due to the site of thrombus. We report the case of a 34-year-old postpartum patient who was admitted to our hospital for aortic arch thrombosis. She had no genetic disorders for hypercoagulability, only a family history for ischemic cerebrovascular accident. As treatment with sodium heparin failed and surgery was not possible due to the site of thrombus, she received a low-dose, ultra-slow-flow treatment with alteplase for 75 hours with successful removal of the thrombus. No side effects from alteplase were observed. Considering the safety and efficacy in this patient, as well as the easiness by which it can be reproduced in the majority of clinical settings, this treatment may be a viable option in cases of aortic arch thrombosis when conventional treatments are not applicable or available.
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Marisa De Feo
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Bleeding, Thrombosis and Vascular Biology
thrombosis
Successful treatment of aortic arch mural thrombosis with low-dose, ultra-slow-flow thrombolysis: a case report and literature review
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Bleed Thromb Vascul Biol
Marisa De Feo
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10.4081/btvb.2022.44
Department of Cardio-Thoracic Sciences, University of Campania "Luigi Vanvitelli," Naples
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Özkan M, Gündüz S, Gürsoy OM, et al. Ultraslow thrombolytic therapy: A novel strategy in the management of PROsthetic MEchanical valve Thrombosis and the prEdictors of outcomE: The Ultra-slow PROMETEE trial. Am Heart J 2015;170:409-18.
Successful treatment of aortic arch mural thrombosis with low-dose, ultra-slow-flow thrombolysis: a case report and literature review
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1
                                                                                                                     CASE REPORT

Successful treatment of aortic arch mural thrombosis with low-dose,
ultra-slow-flow thrombolysis: a case report and literature review
Rosina Albisinni,1 Tommaso Marrazzo,2 Arta Karruli,2 Sabrina Manduca,3 Giuseppe Nobile,4 Nicola Galdieri,5
Marisa De Feo6
1
  Unit of Infectious and Transplant Medicine, AORN Ospedali dei Colli-Monaldi Hospital, Naples, Italy; 2Department of Precision
Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy; 3Unit of Ecocardiography and Endovascular Therapy, AORN
Ospedali dei Colli-Monaldi Hospital, Naples, Italy; 4Unit of Vascular Surgery, AORN Ospedali dei Colli-Monaldi Hospital, Naples,
Italy; 5Unit of Cardiac Anesthesia and Intensive Care, AORN Ospedali dei Colli-Monaldi Hospital, Naples, Italy; 6Department of
Cardio-Thoracic Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy



ABSTRACT
    Aortic arch thrombosis represents a severe condition which usually requires surgical treatment in specialized centers. Treatments
described in literature are mostly surgery or sodium heparin infusion. Here we describe an off-label use of alteplase in aortic arch
thrombosis in a patient in whom sodium heparin treatment failed and surgery was not possible due to the site of thrombus. We report




                                                                                               ly
the case of a 34-year-old postpartum patient who was admitted to our hospital for aortic arch thrombosis. She had no genetic disorders
for hypercoagulability, only a family history for ischemic cerebrovascular accident. As treatment with sodium heparin failed and




                                                                                       on
surgery was not possible due to the site of thrombus, she received a low-dose, ultra-slow-flow treatment with alteplase for 75 hours
with successful removal of the thrombus. No side effects from alteplase were observed. Considering the safety and efficacy in this pa-
tient, as well as the easiness by which it can be reproduced in the majority of clinical settings, this treatment may be a viable option




                                                                                 e
in cases of aortic arch thrombosis when conventional treatments are not applicable or available.
                                                                            us
                                                                            al
  Correspondence: Rosina Albisinni, Ospedale Monaldi, Piazzale Et-           INTRODUCTION
                                                         ci

  tore Ruggieri, 80131 Napoli, Italy.
  Tel: +39.0817064154                                                            Aortic arch thrombosis is a rare disease, with only a
                                                       er


  E-mail rosa.albisinni@ospedalideicolli.it                                  few cases described in literature mostly in patients with
                                                                             no major risk factors such as atherosclerosis, trauma,
                                                      m



  Key words: Low-dose ultra-slow-flow, Thrombolysis, Alteplase,
  Aortic arch, Thrombosis.                                                   aneurism, hypercoagulable state,1,2 few cases with essen-
                                          om




                                                                             tial thrombocytosis and malignancies,3-6 and as conse-
  Contributions: The Authors contributed equally.                            quence of atherosclerosis in different sites of aorta.7
                                                                             Pregnant women are at high risk for developing venous
  Conflict of interest: The Authors declare no potential conflict of
                                    -c




  interest.                                                                  thromboembolic events and aortic dissection or rupture.8-
                                                                             10
                                                                                However, arterial thrombosis is not a common manifes-
                           on




  Funding: None.                                                             tation during pregnancy or postpartum period.9
                                                                                 As this disease is fatal, the first line of treatment is sur-
  Ethical approval and consent to participate: The patient gave con-
                     N




  sent to this treatment after she was explained the impossibility/fail-
                                                                             gery as described in a previous case report,11 also in 21 pa-
  ure of other treatment options.                                            tients in a cohort of 38 patients with thrombus in ascendant
                                                                             or aortic arch and in 88 patients in a meta-analysis study of
  Received for publication: 15 June 2022.                                    200 patients.1,2 In patients with thrombus located in the aor-
  Revision received: 29 July 2022.                                           tic arch, surgery was the most common treatment.2 Persis-
  Accepted for publication: 15 September 2022.
                                                                             tency after treatment was higher in anticoagulant group
  Publisher’s note: All claims expressed in this article are solely those    compared to surgery group (26.4% vs 5.7%).1 As this dis-
  of the authors and do not necessarily represent those of their affili-     ease is rare in postpartum patients with no major risk factors
  ated organizations, or those of the publisher, the editors and the re-     for arterial thrombosis, no data regarding treatment in such
  viewers. Any product that may be evaluated in this article or claim        patients in particular when surgery, a first line treatment
  that may be made by its manufacturer is not guaranteed or endorsed
  by the publisher.                                                          can’t be performed or is not efficient, exists in literature.
                                                                             Here we describe a case of aortic arch thrombosis in a post-
  ©
   Copyright: the Author(s), 2022                                            partum female treated with alteplase.
  Licensee PAGEPress, Italy
  Bleeding, Thrombosis and Vascular Biology 2022; 1:44
  doi:10.4081/btvb.2022.44
                                                                             CASE REPORT
  This work is licensed under a Creative Commons Attribution-
  NonCommercial 4.0 International License (CC BY-NC 4.0).                       A 34-year-old woman diagnosed with critical ischemia
                                                                             of left upper limb, was transferred to our hospital,

                                              Bleeding, Thrombosis and Vascular Biology 2022; 1:44
2                                                        R. Albisinni et al.




Monaldi Hospital from the Emergency Unit of another                   weighing 3,700 grams and underwent post-surgery antico-
hospital in April 2021, where she was admitted for the                agulant therapy with low-molecular-weight heparin which
onset of severe pain. She had a recent medical history of             lasted only for 10 days. The patient also reported a family
giving birth to a deceased fetus 2 weeks ago. The left arm            history of arterial thrombosis (she reported ischemic ictal
appeared cold and cyanotic, radial pulse was not appre-               episode and persistent motor aphasia of the father at the age
ciable and the humeral one was hyposphygmic. The motor                of 30). The patient had a Body mass index of 35, hypothy-
capacity was preserved, however, burdened by intense                  roidism in sub-optimal medical therapy; the study of coag-
painful symptoms. The patient who was alert and collab-               ulation factors associated with thrombosis such as natural
orating, was subjected to chest angiography and subse-                anticoagulant showed normal C and S coagulation Proteins,
quently to selective angiography of the upper limb. The               Antitrombin III, absent heparin-induced platelet antibody,
Computed Tomography angiogram showed a thrombus in                    lupus anticoagulant, anticardiolipin antibodies and anti
the aortic arch between the origin of the left carotid artery         Beta-2 glycoprotein I. There was only a slight alteration of
and the left subclavian artery with a preserved flow and              homocysteine, increased D-Dimer and significant mixed
without signs of aortic dissection; echo-color-Doppler of             dyslipidemia (Table 1).
the left upper limb evidenced occlusion of the humeral bi-                Genetic mutations associated with thrombophilia such
furcation with preserved mobility and sensitivity of the              as FV Leiden G1691A and FII G20210A were absent.




                                                                                              ly
left hand. After consultation with a vascular surgeon spe-            Only MTHFR C667T in homozygosity was present.




                                                                                       on
cialist, the patient underwent endarterectomy with inef-                  Ninety-six hours after surgery, a parenteral anticoag-
fective distal revascularization of the hand and digital              ulant therapy with warfarin initiated and she was re-
compartment. A few hours after the first surgery, due to              assessed in terms of radiological exams with a CT




                                                                                  e
the pain, reduced mobility and sensitivity of the hand and            angiography scan and a trans-esophageal echocardiogra-
the lack of the humeral pulse and the distal left radial and
ulnar pulses, worsened by the absence of vascularization
                                                                               us
                                                                      phy showing the thrombus in the aortic arch unchanged
                                                                      (dimension 1.3×3.2 cm) (Figure 1).
                                                                          Ten days after vascular surgery and anticoagulant
of the palmar and dorsal arch of the hand, we proceeded
                                                                     al
to new fogartization treatment followed by infusion of r-             treatment start, due to the high risk for new embolic
                                                       ci

TPa (Alteplase) 2 mg per hour over the next 24 h. After               events, and in consideration of impossibility of carrying
12 hours, despite the continuous infusion of thrombolytic,            out cardiac surgery for the removal of the thrombus in the
                                                     er


we detected the presence of tension in the muscle lodges              aortic arch, also in the absence of therapeutic alternatives
                                                                      and on the basis of the data in the literature describing the
                                                    m



of the forearm and hypothermic hand (retained mobility
and sensitivity) and therefore acute compartment syn-                 use of r-TPA (alteplase) thrombolytic treatment on throm-
                                           om




drome of the forearm and radiocarpal joint and fingers                bosis of cardiac prostheses also reported in pregnant sub-
was diagnosed.                                                        jects, thrombolysis treatment was initiated with a
    The appearance of the compartment syndrome is an in-              "low-dose, ultra-slow-infusion" protocol [25 mg in 25
                                     -c




direct sign of partial effectiveness of a revascularization at        hours repeatable up to 5 times starting when the values of
                                                                      international normalized ratio (INR) are ≤1.7]. The patient
                              on




least in the forearm area. However, due to the appearance
of bleeding from the site of entry of the infusion catheter,
thrombolysis was suspended, and coagulation was re-eval-
                         N




uated in consideration of the need to perform fasciotomy.
The patient underwent a new fogartization with arterial
revascularization of the humeral artery and ulnar artery
with removal of thromboembolic material in both sites. De-
compression of the volar area of the forearm was performed
by extending the incision from the elbow to the wrist on
the volar side of the forearm, also evacuating a small col-
lection of blood and fluid from the muscle area.
    48 hours after surgery, anticoagulation therapy with
enoxaparin sodium 10000 UI every 12 h was started, and
72 hours after surgery acetylsalicylic acid at a dose of 300
mg per day was introduced.
    After a few days, the surgical wound was treated with
Vacuum Assisted Closure therapy (VAC therapy, -120
mmHg) to facilitate healing by secondary intention.
    In anamnesis about two weeks before this episode, the             Figure 1. Trans-esophageal echocardiography showing aortic
                                                                      arch mural thrombus before thrombolysis treatment.
patient gave birth by caesarean section to a deceased fetus

                                      Bleeding, Thrombosis and Vascular Biology 2022; 1:44
                     Successful treatment of aortic arch mural thrombosis with low-dose, ultra-slow-flow thrombolysis                 3



gave consent to this treatment after she was explained the                bosis as it satisfies the three elements of Virchow’s triad
impossibility/failure of other treatments options.                        specifically hypercoagulability, venous stasis and endothe-
    She underwent a total of 75-hours therapy with a total                lial damage.13 Major changes in coagulation parameters are
dose of 75 mg of alteplase. No adverse event from this                    fibrinogen increase, resistance to activated protein C and
treatment was observed. Trans-esophageal echocardiog-                     increase of fibrinolytic inhibitors levels.14 However, these
raphy performed after treatment, showed no residue of the                 changes in pregnancy are associated more with venous
previously presented thrombotic formation.                                thrombosis as arterial ones are very rare in pregnancy.9 The
    At discharge, due to the patient's high body weight, she              patient apart from family history of cerebrovascular acci-
had indication for anticoagulant therapy with Vitamin K                   dent did not have other major risk factors for arterial throm-
antagonists (VKA) (INR target 2.5-3) and acetylsalicylic                  bosis described in literature such as atherosclerosis,
acid at a dose of 300 mg per day. The literature regarding                thrombocytosis, prothrombin alteration, deficit of antico-
therapy with new Direct Oral Anticoagulants in obese pa-                  agulant protein C, S, deficit of antithrombin, presence of
tients suggest preferring treatment with VKA because of                   anticardiolipin antibodies or genetic disorders of coagula-
the lack of available safety and efficacy data. The wound                 tion factors such as FV G1691A, FII G20210A.15
on the left arm was periodically medicated and after a few                     The preferred treatment for arterial thrombosis is sur-
days it healed. At 90 days follow up the patient continued                gery compared to medical treatment. Surgery leads to




                                                                                              ly
treatment with VKA with INR range 2-3, and acetylsali-                    lower rate of complications such as limb amputation and




                                                                                       on
cylic acid. No recurrent event is observed until now.                     lower rate of recurrence.1 However, in this case, throm-
                                                                          bosis removal surgery was not possible due to the anatom-
                                                                          ical site of thrombus and possible side effects of




                                                                               e
DISCUSSION                                                                anesthetics risk due to obesity. After an unsuccessful treat-
    This case presentation shows the efficacy and safety of
low-dose, ultra-slow flow treatment in a postpartum patient
                                                                        usment with sodium heparin, we opted for an off-label treat-
                                                                          ment with alteplase with low-dose, ultra-slow-flow
                                                                          protocol, normally used in cardiac valve thrombosis,16,17
                                                                 al
following cesarian section. In literature limited data regard-
ing treatment with parenteral anticoagulants in postpartum                which resulted successful. Low-dose ultra-slow flow in-
                                                     ci

patients exists, with one case report describing a throm-                 fusion of tissue-type plasminogen activator was associ-
                                                   er


bophilic postpartum patient treated with sodium heparin.12                ated with low rate of nonfatal complications and mortality
Pregnancy is a high-risk condition for developing throm-                  with a success rate of 90% in 114 patients with prosthetic
                                                  m
                                          om




Table 1. Hematochemical and coagulation parameters.
Parameter                                                                Hospital admission                     Post thrombolysis
                                    -c




Red blood cells, cells/µL                                                    3.290.000                              3.220.000
                            on




Hemoglobin, g/dl                                                                10.2                                    8.9
Platelet count, cells/µL                                                      388.000                               472.000
International normalized ratio                                                  0.96                                    1.06
                     N




Activated partial thromboplastin time, sec                                       30                                     31
Fibrinogen, mg/d Ddimer, ng/ml                                                560/868                               451/208
C reactive protein, mg/dl                                                       9.16                                    1.2
Antitrombin III, %                                                              130                                     105
Creatinine, mg/dl                                                               1.07                                    0.7
Aspartate aminotransferase/Alanine aminotransferase, UI/L                      14/18                                 14/27
Total bilirubin/Direct bilirubin, mg/dl                                       0.23/0.10                             0.5/0.14
Creatine kinase, UI/L                                                            46                                     21
Protein C, %                                                                    130                                     NA
Factor VIII, %                                                                  266                                     NA
Resistance to activated Protein C                                               2.24                                    NA
Protein S, %                                                                     71                                     NA
Lupus anticoagulant                                                             1.24                                    NA
Antibodies anticardiolipin                                                     Absent                                   NA
Anti B2 glycoprotein                                                           Absent                                   NA
Homocystein, µmol/L                                                              20                                     NA


                                             Bleeding, Thrombosis and Vascular Biology 2022; 1:44
4                                                         R. Albisinni et al.




valve thrombosis with 120 different episodes between                    7. Laperche T, Laurian C, Roudaut R, Steg PG. Mobile throm-
2009 and 2013 in PROMETE TRIAL.18                                          boses of the aortic arch without aortic debris. A trans-
   Regarding pregnant patients with thrombosis, an 8-                      esophageal echocardiographic finding associated with
year timeline study on 24 patients with 25 pregnancies                     unexplained arterial embolism. The Filiale Echocardiogra-
                                                                           phie de la Société Française de Cardiologie. Circulation
and 28 prosthetic valve thrombosis episodes treated with
                                                                           1997;96:288-94.
low dose ultra-slow flow t-PA showed that all episodes                  8. Heit JA, Kobbervig CE, James AH, et al. Trends in the inci-
were treated successfully with only 2 episodes having                      dence of venous thromboembolism during pregnancy or
bleeding as side effect.17                                                 postpartum: a 30-year population-based study. Ann Intern
                                                                           Med 2005;143:697-706.
                                                                        9. Walker ID. Venous and arterial thrombosis during preg-
CONCLUSIONS                                                                nancy: epidemiology. Semin Vasc Med 2003;3:25-32.
                                                                       10. Kamel H, Roman MJ, Pitcher A, Devereux RB. Pregnancy
    Considering the safety and the efficacy of this treat-                 and the Risk of Aortic Dissection or Rupture: A Cohort-
ment in this patient, as well as the ease with which it can                Crossover Analysis. Circulation 2016;134:527-33.
be reproduced in the majority of clinical settings, we sug-            11. Alaeddini J, Ilercil A, Shirani J. Thoraco-abdominal aortic
gest considering this treatment as an option in cases of                   thrombosis and superior mesenteric artery embolism. Tex




                                                                                                 ly
aortic arch thrombosis when conventional treatments are                    Heart Inst J 2000;27:318-9.
not applicable or available.                                           12. Bohîltea RE, Turcan N, Muresian H, et al. Postpartum Aortic




                                                                                         on
                                                                           Bifurcation Thrombosis on the Background of Throm-
                                                                           bophilic Disorder. Maedica (Bucur) 2016;11:241-4.
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                                       Bleeding, Thrombosis and Vascular Biology 2022; 1:44
