Advance Publication

Circulation Journal REVIEW doi: 10.1253/circj.CJ-20-0078

Electrophysiological Procedures in Patients With Disorders ― A Systemic Review ―

Bartosz Krzowski, MD; Paweł Balsam, MD, PhD; Michał Peller, MD, PhD; Piotr Lodziński, MD, PhD; Marcin Grabowski, MD, PhD; Joanna Drozd-Sokołowska, MD, PhD; Grzegorz Basak, MD, PhD; Monika Gawałko, MD; Grzegorz Opolski, MD, PhD; Jedrzej Kosiuk, MD, PhD

Catheter ablation (CA) is considered first-line treatment for many patients with symptomatic arrhythmias. Indications for CA are constantly increasing, as is the number of procedures. Although CA is nowadays regarded a safe procedure, there is a risk of com- plications, including both - and -related events. Several factors contribute to periprocedural risk; of these, patient coagulation status is of considerable clinical relevance. In this context, even a simple procedure poses a considerable challenge in a patient with coagulation disorder. However, the level of evidence regarding CA in patients with coagulation disorders is very low. Neither experts’ recommendations nor clinical guidelines have been presented so far. The aim of this article is to analyze potential procedure-related risks and provide clinicians with useful information and practical suggestions regarding optimization of procedural safety in patients with coagulation disorders.

Key Words: Bleeding; Cardiac arrhythmia; Catheter ablation; Coagulation disorders; Thrombosis

n recent decades catheter ablation (CA) has become ing CA in patients with coagulation disorders is very low. the treatment of first choice for many patients with The aim of this review was to systematically analyze pos- I symptomatic arrhythmias. Aligned with constant sible procedural risks and pitfalls depending on the underly- improvements in CA techniques, indications for the proce- ing and provide clinical guidance based on the dure are constantly expanding.1 Thus, a further increase in available literature. Because of the number of coagulation the number of CA procedures is inevitable.2 CA is regarded disorders and the lack of data regarding CA in specific dis- as safe procedure, with low complication and high success orders, we focused on the most common coagulation dis- rates that are continually improving with increased experi- orders, namely heparin-induced (HIT), ence and new technological developments. Despite prog- hemophilia, heterozygous (FV) Leiden , ress in the CA technique, the risk of complications remains (vWD), light chain amyloidosis, a part of everyday practice, with bleeding and thrombosis antiphospholipid syndrome, myelodysplastic syndrome, being the most clinically relevant complications.3 However, immune-mediated disorders and hereditary hemorrhagic the ablation procedure is associated not only with a sig- . nificant bleeding risk, related to either vascular access or cardiac perforation, but also formation caused Methods by biophysical aspects of radiofrequency energy transmis- sion, increased tissue temperature, local endothelial dam- This systematic review was conducted in accord with the age, and the presence of catheters in the and vessels. Preferred Reporting Items for Systematic Reviews and The rate of adverse events depends strongly on physician Meta-Analyses (PRISMA) guidelines. experience, the technology used, and the type of the proce- A systematic search was performed of the PubMed data- dure.4 However, patient-related risk factors also contribute. base from inception to April 2019. The search strategy In particular, that increase the tendency for bleeding focused on identifying studies and case reports that or thrombosis are particular challenges, and so specific steps described electrophysiological procedures in patients with should be undertaken in order to safely perform CA in . The reference lists of the included articles such patients. Unfortunately, the level of evidence regard- and other published reviews were also examined to identify

Received February 6, 2020; revised manuscript received March 10, 2020; accepted March 25, 2020; J-STAGE Advance Publication released online April 29, 2020 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw (B.K., P.B., M.P., P.L., M. Grabowski, M. Gawałko, G.O., J.K.); Department of , Oncology and Internal Medicine, Medical University of Warsaw, Warsaw (J.D.-S., G.B.), Poland; and Department of Electrophysiology, Helios Klinikum Koethen, Koethen (J.K.), Germany Mailing address: Jedrzej Kosiuk, MD, PhD, Department of Electrophysiology, Helios Klinkum Koethen, Hallesche Strasse 29, 06366 Koethen, Germany. E-mail: [email protected] ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Advance Publication 2 KRZOWSKI B et al. any additional studies relevant to this review. HIT HIT is an adverse drug reaction, with 2 separate types: Inclusion and Exclusion Criteria Type I, a less dangerous and self-limiting type caused by Studies were included if they described the procedures of non-immune mechanisms; and Type II, a potentially lethal, CA or electrophysiological study (EPS) in patients with although rarer, type. The autoimmune-mediated response coagulation disorders a priori, or if coagulation disorder in Type II HIT is caused by the development of IgG anti- appeared as a complication after CA. Studies and case bodies directed against a complex consisting of heparin reports were excluded if: (1) they did not precisely describe and factor 4 (PF4). In addition, are acti- the periprocedural events; (2) they presented partial data; vated through their Fcg IIa receptors.5 HIT Type II is a and (3) the manuscript was not available for review in prothrombotic condition, manifesting both venous and English or was only available in abstract form. The decision arterial thrombosis. to exclude conference abstracts was based on the limita- Clinical Relevancy in the Setting of a CA Procedure tions in assessing the study quality of conference abstracts Although HIT is estimated to occur in 0.7–5% of patients alone and difficulties in extracting the required depth of receiving unfractionated heparin (UFH),6 electrophysiolo- information from such abstracts. gists should be aware of the possibility of HIT Type II fol- lowing the index procedure and must be capable of conducting Study Selection a safe CA procedure in patients with a history of HIT. Two reviewers (B.K., J.D.-S.) independently screened the The exact prevalence of HIT is difficult to establish, titles and abstracts of all publications identified and excluded because its incidence depends on several risk factors, such articles that were irrelevant to the topic. The reviewers then as duration of heparin therapy, heparin type (UFH > low evaluated the full text of eligible articles for suitability molecular weight heparin, bovine > porcine), type of pro- based on the strict inclusion and exclusion criteria. A third cedure (surgical > medical patients), and sex (female > male).7 reviewer (J.K.) was used to resolve discrepancies. The main clinical manifestations of HIT Type II are deep thrombosis (DVT), (PE), Results and Discussion arterial thrombosis (including limb artery thrombosis), thrombotic , , and necrotizing The data collected from 18 studies and case reports is sum- skin lesions at heparin injection sites.6,7 The typical HIT- marized in Table. The sections below discuss specific coag- associated fall in platelet count is >50% and occurs 5–10 ulopathies in detail. days after starting heparin. An earlier onset of HIT may be observed if the patient has

Table. Summary of Publications Reporting Electrophysiological Procedures in Patients With Coagulopathies

Publication type Description Conclusions HIT Case report10 Bivalirudin use during CA (VT, PVI) in 2 patients with HIT Bivalirudin is a therapeutic option for history; no complications observed anticoagulation during CA in patients with HIT history Case report11 Bivalirudin use during cryoballoon ablation (PVI) in a Bivalirudin in conjunction with apixaban is an patient with HIT history option during cryoballoon ablation in patients with HIT history Case report12 Bivalirudin use during CA (PVI) in a patient with HIT history; Bivalirudin is a therapeutic option for no complications observed anticoagulation during CA in patients with HIT history Case report13 Bivalirudin use during CA (VT) in a patient with HIT history; Bivalirudin is safe in patients with HIT and no complications observed renal failure during CA Case report17 HIT as a complication after CA procedure (SVT) Patients undergoing CA are at risk of HIT Case report18 Atypical HIT presentation in a patient 5 months after short Rare presentation of HIT can occur during CA exposure to LMWH; thrombus attached to ablation catheter during CA (PVI) with subsequent HIT confirmation Case report19 Ischemic stroke 36 h after CA (PVI) due to HIT-related Attention should be paid to DVT in patients and iatrogenic right-to-left shunt undergoing CA in order to reduce stroke risk Hemophilia Case report37 12-year-old male with mild hemophilia A Continuous recombinant Factor VIII infusion underwent successful cryoablation because provides sufficient coagulation status to of AVNRT; no complications observed undergo CA Case series38 Summary of 18 cardiac and Patients with hemophilia can safely undergo cauterization procedures in patients with cardiac procedures hemophilia; one patient underwent EPS Case report39 Successful CA using cryoballoon catheter in a patient with Standard factor replacement protocol can be mild to moderate hemophilia safely used in a patient scheduled for CA Lower-intensity intraprocedural anticoagulation and avoiding postprocedural anticoagulation may allow safely PVI

(Table continued the next page.) Advance Publication Ablations in Patients With Coagulopathies 3

Publication type Description Conclusions Heterozygous mutation Single-center cohort Analysis of thrombotic complications after CA Factor V Leiden is one of the risk factors for study58 for SVT: 1 pulmonary embolization related to Factor V PE in patients undergoing SVT CA Leiden among 7 patients with thrombotic complications per 453 procedures Case report59 PE as a complication after AV node ablation Proper prophylaxis to prevent serious major complications after CA in a patient with risk factors is highest priority Light chain amyloidosis Case-control study60 The aim of this study was to define intracardiac conduction, There was a high recurrence rate: CA appears atrial arrhythmia substrate, and to have a limited role in the control of ablation outcomes in a group of advanced CA patients arrhythmias referred for EPS; no complications observed Case series61 26 CA on patients with cardiac amyloidosis; no complications CA brings about symptom relief in patients observed with cardiac amyloidosis, but mortality from the underlying disease remains high Case report62 Patient scheduled for AF ablation; Electroanatomical mapping can help establish intraprocedural ECG recordings with clinical presentation cardiac amyloidosis diagnosis indicated infiltrative cardiomyopathy Despite non-diagnostic cMRI, endomyocardial biopsy revealed cardiac amyloidosis; no complications observed Myelodysplastic syndrome Case series63 14 patients underwent epicardial high-intensity focused No conclusions in terms of ablation in patients ultrasound treatment for AF; there were no deaths directly with MDS related to the procedure, but the only patient with MDS died due to septic complications Idiopathic thrombocytopenic Case report64 Left ventricle perforation during CA for VT in a patient with Patients with accompanying diseases require ITP multidisciplinary approach to avoid dangerous complications Hereditary hemorrhagic telangiectasia Case report65 Atypical atrial flutter CA in a patient with HHT; No conclusions in terms of ablation in patients no complications observed with HHT AF, atrial fibrillation; AV, atrioventricular; AVNRT, atrioventricular nodal re-entry tachycardia; CA, catheter ablation; cMRI, cardiac magnetic reso- nance imaging; DVT, ; ECG, electrocardiogram; EPS, electrophysiological study; HHT, hereditary hemorrhagic telangiec- tasia; HIT, heparin-induced thrombocytopenia; ITP, idiopathic ; LMWH, low molecular weight heparin; MDS, myelo- dysplastic syndrome; PE, pulmonary embolism; PVI, pulmonary vein isolation; SVT, supraventricular tachycardia; VT, ventricular tachycardia.

been treated with heparin in the previous 30–100 days and in irrigated tip catheters and sheaths needs to be switched circulating antibodies remain in the body.8 Even though to bivalirudin. Furthermore, it is of clinical importance the exact mechanism underlying the development of HIT that bivalirudin has no reversal agent and should be mon- remains unclear, there are a few hypotheses, including the itored by activated clotting time (ACT) or activated partial release of procoagulants from activated platelets, the genera- thromboplastin time (aPTT). tion of platelet microparticles, or endothelial cell activation.9 Another off-label protocol describes initiation of antico- Periprocedural Preparations for Patients With a Known agulation using an i.v. bolus of argatroban (350 μg/kg) History of HIT There are no guidelines or recommenda- administered over 3–5 min, followed by continuous i.v. tions regarding anticoagulation in patients with HIT Type infusion at 25 μg · kg−1 · min−1 to achieve a therapeutic ACT II during CA. However, in analogy to the recommenda- of 300–450 s. The ACT should be checked 5–10 min after tions for coronary intervention,6 bivalirudin can be suc- administration of the bolus dose, and the rate of infusion cessfully used for left sided CA procedures (Figure 1). This should be adjusted accordingly (10–40 μg · kg−1 · min−1).14 strategy has been confirmed by case reports of patients HIT Secondary to CA HIT manifesting during or directly undergoing CA due to ventricular tachycardia and atrial after CA ablation may be a serious clinical problem need- fibrillation (AF) in patients with normal renal function,10–12 ing careful evaluation. It is crucial to quickly distinguish and in patients with renal dysfunction in whom the bivali- between HIT Type I and HIT Type II. HIT Type I occurs rudin dose was adjusted.13 One procedure has been per- 2–4 days after heparin administration and is associated formed in a patient receiving apixaban.11 In all cases, drug with a slight decrease in platelet count (the platelet count administration was stopped at the end of the procedure is usually >100,000/mm3), no clinical symptoms, and nor- and no adverse effects were registered. malization of the platelet count despite heparin continua- Periprocedural therapy should begin with a 0.75-mg/kg, tion. In case of potentially life-threatening HIT Type II, a i.v., bolus of bivalirudin, which is followed by infusion at quick diagnosis by assessing the HIT score is crucial to a rate of 1.75 mL · kg−1 · h−1 that is stopped at the end of the take appropriate action and prevent a dangerous course of procedure with no need to monitor coagulation status. It events. If the score HIT score is ≤3, HIT can be excluded should be also noted that heparin in irrigation fluids used and there is no need for laboratory testing. Otherwise, Advance Publication 4 KRZOWSKI B et al.

Figure 1. Recommendations for procedures in patients with known or suspected heparin-induced thrombocytopenia (HIT). PF4, platelet factor 4.

heparin should be switched to a different It is of note that due to a decrease in C decline, (argatroban, fondaparinux, danaparoid bivalirudin, lepi- vitamin K antagonists (VKAs) are not recommended at rudin) depending on the clinical situation,6,15 and further the beginning of the therapy and can only be introduced laboratory testing of anti-PF4/heparin antibodies is when the platelet count has recovered.20 Conversely, novel needed.16 It is also worth keeping in mind that there is a oral (NOACs) do not decrease very high prevalence of heparin/PF4 antibodies in cardiac levels and are therefore potentially an alternative treatment patients, but very few have of these patients have HIT; option.21 It is also worth noting that argatroban affects the therefore, this test should not be performed in a patient INR, which complicates the monitoring of the effect of without clinical symptoms of HIT.17 warfarin after platelet count recovery. An overlap of 5 In case of suspected HIT, clinical observations should be days between a non-heparin anticoagulant and a VKA is made, focusing on thromboembolic complications such as regarded as the minimum and safe period.6,15 It is also neurological symptoms, swollen limbs, and shortness of recommended that VKAs are initially administered at low breath. Standard postprocedural echocardiography is doses.6 Because of its limited indications, argatroban is advisable in every patient with a history of HIT to rule out infrequently used by clinicians, and a lack of experience adverse events such as PE or pericardial effusion. In case may result in inaccurate dose adjustment.22 of the need for anticoagulation after the procedure, a switch from bivalirudin to an alternative anticoagulant is Hemophilia recommended. Argatroban is currently the only US Food Hemophilia is an X-linked congenital bleeding disorder and Drug Administration (FDA)-approved drug for HIT that generally affects males. Although the mutation is treatment, but current guidelines recommended the use of usually inherited, approximately one-third of all cases are bivalirudin for surgeries and percutaneous coronary inter- caused by spontaneous . ventions (PCIs).6 Hemophilia A, which accounts for 80–85% of hemophilia, Recently, Vaidya et al reported a case of the formation is caused by Factor VIII (FVIII) deficiency, whereas hemo- of a strand resembling a thrombus attached to the philia B is caused by a decrease in Factor IX (FIX). Both ablation catheter despite a target ACT of 300 s and an types are the result of respective clotting factor gene muta- international normalized ratio (INR) of 2.6.18 Although tions. The bleeding tendency in hemophilia is directly cor- such early manifestation is unusual, the HIT diagnosis was related with the level of blood clotting factor. confirmed by laboratory testing.18 Another postprocedural Coincidence With Arrhythmias Data describing the HIT Type II presentation has been descried after AF abla- specific prevalence of arrhythmias in patients with hemo- tion: 36 h after the procedure, symptomatic cerebral embo- philia is very limited. In the US, Humphries et al reported lization originating from a DVT was diagnosed despite trend towards a lower occurence of ventricular arrhythmias standard anticoagulation.19 Rice reported a case of docu- in patients with hemophilia A compared to control group mented complete thrombotic vein occlusion and subsequent (0% vs. 4.5%; P=0.071).23 However, there was no difference PE occurring 2 weeks after CA due to supraventricular in AF prevalence between patients with hemophilia and tachycardia (SVT).17 After determination of the platelet control group (5.4% vs. 6.3%, respectively; P=1.0).23 In a count and laboratory testing for specific antibodies, HIT European trial, overall AF prevalence in patients with Type II was diagnosed. A direct inhibitor was hemophilia reached 0.84%.24 Similar to trends seen in the administrated as initial therapy with a subsequent change general population, the prevalence of AF increased with to warfarin.17 age (0.42% in patients aged 40–60 years, 3.4% in patients Advance Publication Ablations in Patients With Coagulopathies 5

Figure 2. Periprocedural process in a patient with hemophilia. aPCC, activated prothrombin complex concentrate; FVIII, Factor VIII; FIX, Factor IX; rFVIIa, activated recombinant FVII.

>60 years).24 Taking into consideration the better care and tions. The principal rule of hemophilia treatment is to increased life expectancy of patients with hemophilia,25 the prevent and treat bleeding, which is achieved by the admin- number of patients with hemophilia who will need to istration of specific blood clotting factor concentrate.27 undergo CA is estimated to increase. There are several steps that should be followed when Special Interventional Aspects Hermans et al recom- preparing for CA in patients with hemophilia (Figure 2). mended that patients with hemophilia should undergo any However, the timing is of greatest importance. It is advis- invasive procedure, including CA, in a comprehensive hemo- able to schedule CA early in the week and early in the day philia treatment center, or at least in consultation with one.26 for optimal support from the laboratory and blood bank Despite the growing prevalence of CA in patients with to maintain adequate clotting factor coverage during CA hemophilia, the level of evidence is too low to provide guide- and healing.27 lines regarding CA in these patients. However, there are rec- If clotting factors are not available, fresh frozen plasma ommendations for coronary interventions in patients with (FFP) is an alternative, even though it is not recommended hemophilia that may be used for CA to some extent: the as first-line treatment. A 1-mL aliquot of FFP contains 1 postulated peak factor levels should be at least 80% at the unit of factor activity; however, it is difficult to achieve time of the procedure and adequate correction with clotting FVIII levels higher than 30% and FIX levels greater than factor concentrates is required until 48 h after the procedure.27 25%. Heparin can be administered according to standard Nonetheless, high factor levels may result in the develop- cardiologic treatment protocols if the clotting factor level ment of occlusive thrombi. Therefore some authors suggest is >80% during and >30% 48 h after the procedure.27,32 a target peak level for early PCI of ≥30%,28 whereas for Antifibrinolotic agents are not recommended and there minor the recommended desired level is 40–80%.27 is only very limited data regarding emacizumab,33 which is Because blood clotting inhibitors are present in 20–30% a bispecific antibody bridging activated Factor IX and of patients with severe hemophilia A and are rarely observed to restore the function of activated FVIII.34 in patients with hemophilia B,29 reliable monitoring of clot- In addition, inhibitors to the blood clotting factors admin- ting factor levels and inhibitor testing is required. Inhibitor istered should be examined before the CA procedure to presence is suspected in case of prolonged aPTT, which is not ensure that factor administration will provide the expected fully corrected by adding pooled normal plasma to patients’ effect. In patients with inhibitor, especially with anamnestic plasma.27 The Nijmegen modification of the FVIII inhibitor levels of inhibitor above 5 Bethesda units/mL, the use of offers the highest available specificity and sensitivity, bypassing agents (activated prothrombin complex concen- and its use is therefore recommended to find an inhibitor.30 trates and activated recombinant FVII) is recommended.35 Preprocedural Preparations Patients with hemophilia Assuming that CA can be delayed, 9- to 33-month immune scheduled for CA require an individual, multispecialist tolerance induction therapy should be considered in order approach in order to safely undergo the procedure.31 More- to enable standard factor infusion.36 over, anticoagulation therapy should be reconsidered with Moreover, femoral catheterization is preferred over neck special attention focusing on the risk of bleeding complica- venous access because of bleeding complications connected Advance Publication 6 KRZOWSKI B et al. with the latter.37 is recommended for all patients with Type 1 vWD, as well Previously Published Reports Although in every described as for most patients with Type 2 vWD.48 can case of CA in a patient with hemophilia a different replace- be used either intravenously, subcutaneously (the formula- ment protocol has been used, all protocols had a common tion is not universally licensed), or intranasally. The typical target of peak factor level ≥80%.37–39 DeWitt et al reported i.v. dose is 0.3 µg/kg dissolved in 50–100 mL of 0.9% NaCl a case of a patient undergoing CA because of atrioven- and infused intravenously over 30–60 min.49 Because of the tricular nodal re-entry tachycardia.37 during risk of tachyphylaxis, desmopressin should not be given the procedure was achieved using continuous recombinant for more than 3–5 days. Antifibrinolytic therapy (i.e., FVIII infusion, which was later continued after the proce- or epsilon-aminocaproic acid) should be dure with an FVIII dosage target to maintain >100% considered as adjunctive treatment.49 FVIII activity after CA.27,40 During the CA, standard hep- Preprocedural Preparations and Special Interventional arinization was performed.37 Aspects Available data show decreased cardiovascular An alternative strategy has been presented by MacKinlay risk in patients with vWD,50 as well as a lower risk of devel- et al, who describe experience gained during 12 cardiovas- oping both venous and arterial thrombosis.51 Therefore, cular procedures, of which 1 was an electrophysiological only very few cases of patients undergoing PCI have been study.38 In that heterogeneous case series, satisfactory fac- reported,52 and there are no recommendations or even case tor level was achieved by bolus administration or continu- reports regarding electrophysiological procedures in patients ous infusion, with a common factor target peak level of with vWD. In this context, general recommendations for 100%. No bleeding complications were observed.38 patients undergoing invasive procedures should be applied However, patients undergoing AF ablation may require when approaching CA in patients with vWD. In the case more aggressive heparinization. For example, Lin et al of patients who do not respond to desmopressin therapy, reported a case in which maintained ACT was targeted in concentrate containing vWF should be administered. It the lower range, between 250 and 300s, to lower bleeding has been postulated that, when preparing patient for minor risk and FVIII was replaced by bolus infusion.39 No surgery, peak levels of FVIII:C and VWF:RCo are ≥80– adverse events were observed.39 100 and ≥50 IU/dL.49 In addition, the estimated minimum Patient Care After the Procedure Subsequent anticoagu- level of FVIII:C and VWF:RCo should be >50 IU/dL on lation is a challenging issue in patients with hemophilia the day of surgery and >30 IU/dL for 3–5 days after the collectively, because bleeding is the most likely complica- procedure. However, it is suggested that levels >250 IU/dL tion.41 Current recommendations are that warfarin antico- are avoided.49 Considering intraprocedural pharmacother- agulation therapy should be considered if the clotting apy, thromboprophylaxis is not given routinely to patients factor level is >20%.24,42 There are no data regarding the with vWD undergoing surgery; nevertheless, heparin should use of NOACs in patients with hemophilia; nonetheless, it not be ruled out during left-sided procedures. Finally, patients seems reasonable to reflect on lower NOAC doses and with with vWD should be precisely assessed and the risk : ben- an available reversal agent. In patients with factor level efit ratio should be analyzed in terms of anticoagulation <20% and high a CHA2DS2VASC score, the use of low- after the procedure. dose aspirin has been suggested,42 even though aspirin is not recommended for stroke prevention in patients with Heterozygous FV Leiden Mutation AF and without hemophilia.41 Heterozygous FV Leiden mutation, named after the city of Leiden in the Netherlands where this syndrome was first vWD described,53 is one of the most common congenital causes Among all inherited bleeding disorders, vWD is considered of increased thromboembolic risk. It is triggered by a sin- to be the most common; according to epidemiological gle point mutation that results in the loss of 1 of 3 activated studies, vWD affects approximately 1% of the general protein C (APC) cleavage sites, leading to a 10-fold slower population, although far fewer patients present with bleed- rate response and resistance to APC. Due to the increased ing tendencies or require treatment.43 thrombin generation, a hypercoagulable state is present.53 Both a quantitative lack and a qualitative defect of vWF Clinical Implications The most common manifestation can be the underlying cause of the disease. In addition to of FV Leiden is DVT and PE, but thrombosis also occurs being involved in primary adhesion, vWF carries and sta- in unusual locations.54 Interestingly, increased mortality or bilizes FVIII in secondary hemostasis; therefore, FVIII reduction in normal life expectancy has not been observed.55 deficiency can also be seen. The most common and least Although in many individuals the mutation is asymptom- symptomatic vWD is Type 1, which is characterized by atic, 10% of heterozygotes will suffer venous thromboem- quantitative deficiency of vWF and accounts for approxi- bolism (VTE) over their lifetime.55 Clinical expression of mately 85% of vWD cases.44 Dysfunctional vWF is the FV Leiden becomes much more relevant when it is com- reason for coagulation disability in Type 2 vWD. The most bined with other inherited or acquired thromboembolic symptomatic, Type 3 vWD, accounts for <5% of cases and risk factors, such as hormone replacement therapy, hyper- is caused by the absence of circulating vWF.45 homocysteinemia, minor injury, air travel, obesity, oral Diagnosis is based on a combination of personal bleeding contraceptives, or malignancy.54 Because the incidence of history and laboratory testing, including, initially, determi- DVT after AF ablation is reported to be 0.33%, compared nation of total vWF protein levels via vWF antigen, vWF with 2.38% in non-AF ablation,56 CA must be considered activity via (vWF:RCo), and FVIII as one of the risk factors having supra-additive thrombo- coagulant activity (FVIII:C).46 For patients with Type 1 embolic effect. vWD, it is generally agreed that a diagnosis is made when Preprocedural Preparations and Special Interventional vWF activity is <0.30 IU/mL in a patient with mucocuta- Aspects Standard screening for FV Leiden is not recom- neous bleeding.47 mended. Nonetheless, in the case that FV Leiden is known Treatment varies according to vWD type. Desmopressin to be present or symptoms have occurred in the past, the Advance Publication Ablations in Patients With Coagulopathies 7 patient should be accurately assessed for other risk factors. trophysiol 2015; 26: 378 – 384. Every additional risk factor for VTE tilts the scale towards 4. Holmqvist F, Kesek M, Englund A, Blomstrom-Lundqvist C, Karlsson LO, Kenneback G, et al. A decade of catheter ablation i.v. heparin use, even in the case of right-sided ablations. of cardiac arrhythmias in Sweden: Ablation practices and out- The European Heart Rhythm Association recommends comes. Eur Heart J 2019; 40: 820 – 830. the use of i.v. heparin during AF and atrial flutter ablation, 5. Qian Y, Pan J, Zhou X, Weiser P, Lu H, Zhang L. Molecular as well as its consideration in other right-sided ablations.57 mechanism underlines heparin-induced thrombocytopenia and Taking into consideration multiplied VTE risk in the pres- thrombosis. Prog Mol Biol Transl Sci 2010; 93: 395 – 421. 6. Watson H, Davidson S, Keeling D; Haemostasis and Thrombosis ence of a combination FV Leiden and other risk factors, Task Force of the British Committee for Standards in Haematology. one can consider the use of heparin in all CA, with ACT Guidelines on the diagnosis and management of heparin-induced target level >300 s in AF ablation. Because of a lack of thrombocytopenia: Second edition. Br J Haematol 2012; 159: evidence, no specific recommendations regarding ACT can 528 – 540. 7. Lovecchio F. Heparin-induced thrombocytopenia. Clin Toxicol be made when considering right-sided procedures. There- (Phila) 2014; 52: 579 – 583. fore, the decision regarding the anticoagulation scheme 8. Greinacher A, Kohlmann T, Strobel U, Sheppard JA, Warkentin should be made based on team experience. TE. The temporal profile of the anti-PF4/heparin immune response. Previously Published Reports It is unknown whether Blood 2009; 113: 4970 – 4976. 9. Greinacher A. Clinical practice: Heparin-induced thrombocyto- patients with FV Leiden are more likely to suffer from post- penia. N Engl J Med 2015; 373: 252 – 261. procedural complications. Recently, a single center study 10. Baetz BE, Gerstenfeld EP, Kolansky DM, Spinler SA. Bivalirudin analyzing thrombotic complications after CA for supraven- use during radiofrequency catheter ablation procedures in two tricular arrhythmias reported 1 case of massive pulmonary patients with a history of heparin-induced thrombocytopenia. embolization related to FV Leiden among 7 patients with Pharmacotherapy 2010; 30: 952. 58 11. Ellis ER. Successful use of bivalirudin in place of heparin infusion thrombotic complications from a total of 400 patients. for pulmonary vein isolation using a cryoballoon catheter in a Similarly, Pesut et al reported a case of a patient suffering patient with heparin allergy. HeartRhythm Case Rep 2017; 3: 10 – 12. from symptomatic pulmonary thromboembolism following 12. Bellmann B, Nagel P, Muntean BG. Successful intraprocedural atrioventricular node ablation. The only prothrombotic anticoagulation with bivalirudin during pulmonary vein isolation in a patient with known heparin-induced thrombocytopenia type conditions established in that patient were FV Leiden and II. J Arrhythm 2016; 32: 154 – 155. methylenetetrahydrofolate reductase (MTHFR) C677T 13. Ho G, Tran HA, Urey MA, Adler ED, Pretorius VG, Hsu JC. mutations, both heterozygous.59 Successful ventricular tachycardia ablation in a patient with a In both cases, no heparin was administrated during biventricular ventricular assist device and heparin-induced throm- bocytopenia using bivalirudin. HeartRhythm Case Rep 2018; 4: right-sided ablation. 367 – 370. 14. Grouzi E. Update on argatroban for the prophylaxis and treat- Review Limitations ment of heparin-induced thrombocytopenia type II. J Blood Med In this review we precisely describe the most popular coag- 2014; 5: 131 – 141. 15. Linkins LA, Dans AL, Moores LK, Bona R, Davidson BL, ulopathies, but also draw attention to available evidence. Schulman S, et al. Treatment and prevention of heparin-induced Despite our highest efforts in studying the literature, most thrombocytopenia: Antithrombotic Therapy and Prevention of of the articles cited regarding CA in coagulation disorders Thrombosis, 9th ed: American College of Chest Physicians evi- are case reports, which have low scientific power. dence-based clinical practice guidelines. Chest 2012; 141(Suppl): e495S – e530S. To the best of our knowledge, no recommendation, case 16. Warkentin TE. Heparin-induced thrombocytopenia: Pathogenesis reports, or expert opinions have been published regarding and management. Br J Haematol 2003; 121: 535 – 555. the long list of rare coagulopathies. 17. Rice L. Heparin-induced thrombocytopenia in the cardiac patient: 10 points to help the physician. Methodist Debakey Cardiovasc J 2011; 7: 6 – 9. Conclusions 18. Vaidya R, Pruthi R, Thompson C. An unusual presentation of heparin-induced thrombocytopenia in the setting of catheter- In conclusion, careful evaluation of coagulation status and directed ablation of atrial fibrillation. Blood Coagul Fibrinolysis individual risk, in close collaboration with a hematologist, 2014; 25: 188 – 190. is advisable. There is a large spectrum of possible modifica- 19. Itabashi R, Yazawa Y, Kawata K, Shigehatake Y, Yang S, Otomo K, et al. Paradoxical brain emboli related to heparin-induced tions regarding periprocedural coagulation status, which thrombocytopenia after catheter ablation. J Stroke Cerebrovasc makes most CA procedures feasible, even if associated Dis 2015; 24: e219 – e221. with an increased risk of adverse events. 20. Srinivasan AF, Rice L, Bartholomew JR, Rangaswamy C, La Perna L, Thompson JE, et al. Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced throm- Acknowledgments / Conflicts of Interest bocytopenia. 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