Antithrombotic Therapy for Cardiac Disorders in Pregnancy


Level I

Highly complex lesions

Exclusive care in a specialist unit

Repairs with conduits, Rastelli, Fontan, MFS, Ebstein’s, pulmonary atresia, Eisenmenger syndrome, repaired TGA (arterial switch or atrial switch), CCTGA, PHT, cyanotic CHD

Level II

Lesions of moderate complexity

Shared care with regional adult cardiology unit

CoA (repaired/native), repaired AVSD, AS, PS/PR, TOF, VSD + AR, mechanical valves, HCM, DCM

Level III

Simple lesions

Care predominantly in general adult cardiology unit

Repaired PDA/VSD/TAPVD/ASD, mild PS/PR, small VSD



TGA complete transposition of great arteries, CCTGA congenitally corrected transposition of great arteries, ASD atrial septal defect, AVSD atrioventricular septal defect, AS aortic stenosis, PS pulmonary stenosis, PR pulmonary regurgitation, TOF tetralogy of Fallot, VSD ventricular septal defect, AR aorta regurgitation, PDA patent ductus arteriosus, MFS Marfan syndrome, HCM hypertrophic cardiomyopathy, DCM dilated cardiomyopathy, CoA coarctation of the aorta, TAPVD total anomalous pulmonary venous drainage





10.3 Thromboprophylactic Agents Commonly Used in Heart Disease


The reader should also refer to Chap. 2.


10.3.1 Aspirin


Aspirin is the most widely used antithrombotic agent in patients with cardiovascular disease. It is given to patients with coronary artery disease and those with low a low TE risk. It crosses the placenta but at a thromboprophylactic dose (75–150 mg once daily; low dose aspirin (LDA)) is considered safe during all trimesters of pregnancy. Higher anti-inflammatory and analgesic doses are not recommended.


10.3.2 Clopidogrel


Clopidogrel is mostly used at a dose of 75 mg od in combination with aspirin (75 mg od) as part of a dual antiplatelet regimen following coronary (or other vascular) interventions. For bare metal coronary stents, dual antiplatelet therapy is given for 1 month, with aspirin lifelong thereafter, and for drug-eluting coronary stents, dual therapy (doses as above) is recommended for a minimum of 12 months with aspirin lifelong (75 mg od). Clopidogrel crosses the placenta and, although there are no reliable safety data available for its use during pregnancy, case reports and anecdotal evidence suggest that it may be safe [6, 7].


10.3.3 Dipyridamole


Dipyridamole is an antiplatelet agent often used alone or in combination with aspirin for secondary thromboprophylaxis, most commonly in patients with cerebrovascular disease. The usual dose is 200 mg twice daily. There are no safety data for its use during pregnancy, but it has been used in combination with aspirin or warfarin, during both pregnancy and breastfeeding [8].


10.3.4 Warfarin


Warfarin (or oral coumarol derivatives) is the most commonly used oral vitamin K antagonist (VKA). It is used in patients at high risk of thromboembolism, for example, patients with prosthetic valves, a previous history of VTE (pulmonary embolism (PE) or deep venous thrombosis (DVT)), atrial fibrillation, or dilated cardiomyopathy with poor systolic function. The dose is adjusted to achieve a target international normalized ratio (INR), which is determined by the indication for treatment. Warfarin crosses the placental barrier and increases the risk of spontaneous miscarriage and perinatal death [912]. It also causes an embryopathy [1315] and fetal coagulopathy, which may lead to spontaneous fetal intracerebral hemorrhage [16, 17]. The risk of warfarin embryopathy (WE) is particularly high between 6 and 12 weeks of gestation. It is characterized by nasal hypoplasia and epiphyseal changes, and some evidence of lower intelligence in the long term [18, 19]. The reported incidence of WE is between 0 and 20 % [20] and appears to be greater if the warfarin dose is in excess of 5 mg per day [21]. In a systematic review of the literature published between 1966 and 1997 on anticoagulation in pregnant women with mechanical heart valves, Chan et al. found that the use of vitamin K antagonists throughout pregnancy was associated with congenital anomalies in 35 of 549 live births (6.4 %) [22]. A subsequent systematic review covering the years 2000–2009 reported a slightly lower risk (3.7 %) [23]. A multicenter observational, prospective study not included in the systematic reviews, using data collected by institutes collaborating in the European Network of Teratology Information Services (ENTIS) during individual risk counseling between 1988 and 2004, reported an increased frequency of structural defects in 666 pregnant women exposed to VKA during the first trimester compared to a non-exposed group of 1,094 women. However, there were only two cases of coumarin embryopathy among 356 live births (0.6 %; both phenprocoumon). The authors concluded that elective termination of a wanted pregnancy is not recommended if (inadvertent) exposure took place in early pregnancy, and that close follow-up by the obstetrician including level II (3D) ultrasound should be recommended in any case of VKA exposure during pregnancy [24].


10.3.5 Unfractionated Heparin


Unfractionated heparin (UFH) is an anti-thrombotic agent that can be given intravenously (IV) or subcutaneously (SC). At a dose of 5,000 IU SC two to three times daily, it can be used for thromboembolism prophylaxis. Therapeutic UFH may be used for patients with mechanical heart valves, pulmonary embolism, and acute coronary syndromes. Dosing is largely empirical, with different centers often using different dosing regimens. Most regimens require a bolus intravenous dose followed by a maintenance dose of 1,000–1,500 IU/h by continuous IV infusion, with a target activated partial thromboplastin time (APTT) ratio between 1.5 and 2.5 compared with the arithmetic mean of the normal range [25, 26] (or the laboratory reference range). It is well documented that achievement of a target APTT ratio within the first 24 h is difficult, because results vary considerably, even when measured every 4 h [27]. UFH does not cross the placenta and therefore has no fetal side effects. Maternal side effects include heparin-induced thrombocytopenia (HIT) in 1–3 % of patients [2830] and osteoporosis. The latter is rare with short-term use and at low dose, however in a small prospective study to evaluate subclinical heparin-induced osteoporosis in pregnancy, a 10 % or greater decrease in bone density from baseline was reported in around 36 % of 14 women and none of the controls, with no dose-response relationship demonstrated. Furthermore, Dahlman [32] reported a symptomatic vertebral fracture rate of 2.2 % at therapeutic dose, in 4 of 184 women for whom the dosage of heparin ranged from 15,000 to 30,000 (mean 24,500) IU per 24 h, and the duration of treatment ranged from 7 to 27 (mean 17) weeks [31, 32].


10.3.6 Low Molecular Weight Heparin (LMWH)


Low molecular weight heparin (LMWH) has replaced UFH as the anticoagulant of choice for the majority of prothrombotic conditions during pregnancy [33]. Its use in patients with mechanical valves in pregnancy, however, remains contentious, with reports of high rates of thromboembolic complications in this group [34, 35]. It is administered SC and does not cross the placenta; there are therefore no adverse fetal effects. It has a better side-effect profile than UFH, with substantially less HIT <0.1 % [26, 28, 36] and osteoporosis (<0.1 %) [37, 38], has a longer half-life than UFH (3–6 h after SC injection), and has a more predictable anticoagulant effect. LMWH is eliminated by the kidneys. In the presence of renal insufficiency, the half-life is prolonged and dose adjustment is needed [39]. Prophylactic dose LMWH (LMWH-P) is generally administered once daily (the dose varies between different preparations), whereas high prophylactic (LMWH-HP) and therapeutic doses (LMWH-T) have twice daily (12 hourly) dosing regimens (see Tables 10.2 and 10.3). For the treatment and prevention of DVT and PE, routine anti-Xa monitoring is not recommended except in specific situations including at the extremes of body weight (<50 or >90 kg) or if there is renal insufficiency [26]. If used in patients with mechanical heart valves, however, anti-Xa must be measured every 1–2 weeks (peak levels at 3–5 h post-dose depending on the preparation) with regular dose adjustment to maintain anti-Xa levels between 1.0 and 1.2 IU/mL [40].


Table 10.2
Indications and recommended regimens for anticoagulation and low dose aspirin in pregnancy








































































Cardiac lesion

Thromboprophylactic agent during pregnancy

Dose

Mitral stenosis (mild)/SR

LDA

75 mg od

Mitral stenosis (>mild)/SR

LMWH

P/HP/T

LV dilatation EF <40 %

LMWH

P/HP/T

LV dilatation EF >50 %

LDA

75 mg od

Persistent AF

LMWH

HP/T

Paroxysmal AF

LMWH

HP/T

LVNC EF >50 %

Aspirin

75 mg od

LVNC EF <40 %

LMWH

P/HP

Severe LA dilatation (> ×cm2)

LMWH

P/HP

Fontan (any)

LMWH

HP/T

Unrepaired ASD/PFO

LDA

75 mg od

Unrepaired ASD/PFO with a history of stroke

LMWH

HP/T

>Mild Ebstein’s

LMWH

P/HP

ARVC RVEF <40 %

LMWH

P/HP

Prosthetic heart valves

LMWH ± LDA

HI


LMWH low molecular weight heparin, P prophylactic dose, HP high prophylactic dose, T therapeutic (“treatment” dose), HI high intensity, LDA low dose aspirin, EF ejection fraction, SR sinus rhythm, AF atrial fibrillation, LA left atrium, LVNC left ventricular non-compaction, ASD atrial septal defect, PFO persistent foramen ovale, ARVC Arrhythmogenic Right Ventricular Cardiomyopathy, RVEF right ventricular ejection fraction



Table 10.3
Weight-adjusted dosing regimens for LMWH






















































Weight (kg)

Enoxaparin

Dalteparin

Tinzaparin (75 U/kg od)

P dose
     

<50

20 mg od

2,500 U od

3,500 U od

50–90

40 mg od

5,000 U od

4,500 U od

91–130

60 mg od

7,500 U od

7,000 U od

131–170

80 mg od

10,000 U od

9,000 U od

>170

0.6 mg/kg od

75 U/kg od

75 U/kg od

HP dose

40 mg bd

5,000 U bd

4,500 U bd

T dose

1 mg/kg bd antenatally

1.5 mg/kg od postnatally

100 U/kg bd or 200 U/kg od postnatally

175 U/kg od (ante- and postnatally)


If the creatinine clearance (Cockcroft and Gault) is <30 mL/min (<20 mL/min for tinzaparin), the LMWH dose should be reduced accordingly

Doses above as per RCOG guidelines for prevention of VTE in pregnancy [33] and the Heart Disease and Pregnancy – study group statement (http://​www.​rcog.​org.​uk/​womens-health/​clinical-guidance/​heart-disease-and-pregnancy-study-group-statement)


10.4 Maternal Heart Disease Associated with Increased Thromboembolic Risk


For simplicity heart disease will be categorized as acquired, inherited, or congenital. The focus will be on those conditions associated with increased thromboembolic risk, rather than an exhaustive list of all cardiac disorders. Indications and recommended regimens for anticoagulation and low dose aspirin in pregnancy are summarized in Table 10.2.


10.4.1 Acquired Heart Disease



10.4.1.1 Valvular Heart Disease



Native Obstructive Valvular Disease

There are two main valve lesions associated with increased thromboembolic risk, both in the pregnant and nonpregnant state, namely, mitral stenosis (usually rheumatic [RHD]) and tricuspid stenosis (rare and due to RHD or abnormality of valve leaflets or its apparatus). Mitral stenosis (MS) is more common, but it is now rare in the developed world (0.02 % prevalence [41]), whereas in some parts of the developing world, the incidence is much higher (0.2–0.5 % in rural India and parts of Arabia) [42, 43]. There has been a resurgence of RHD in some areas of the UK where there are large immigrant communities, and some UK centers report that around 10–15 % of maternal heart disease is rheumatic in origin [44].

Rheumatic mitral valve disease may cause valvular stenosis (MS) or regurgitation (MR). As a consequence of these valve lesions, the left atrium dilates which leads to a high incidence of atrial arrhythmias (flutter [AFL] and/or fibrillation [AF]). Most women with more than mild mitral or tricuspid stenosis will be anticoagulated with warfarin or another VKA (target INR 2.5 (range 2.0–3.0)) even if in sinus rhythm, due to the presence of sluggish intra-atrial blood flow and the risk of atrial arrhythmia. Too often the first presentation of mitral stenosis is cerebral thromboembolism associated with new onset of AF. If there is persistent AF or a prior history of paroxysmal atrial fibrillation or flutter (PAF/PAFL), this is also an indication for anticoagulation with warfarin, irrespective of the degree of valve obstruction. If there is only mild stenosis (MVA >1.6 cm2) and mild left atrial (LA) dilatation (<3.9 cm or 20 cm2) and no prior history of arrhythmia, aspirin alone is used for thromboprophylaxis. During pregnancy, patients previously on warfarin are converted to LMWH-T, while those previously taking aspirin are commenced on prophylactic dose LMWH.

Other acquired obstructive valve lesions such as aortic stenosis (AS) are not associated with an increased risk of thrombus formation per se, as there is a high velocity of blood flow across the valve. Thromboembolism risk assessment in AS should, however, take into account the degree of valvar calcification/thickening and left ventricular size and function. In the presence of a heavily calcified valve or significant LV dilatation (LV end-diastolic diameter >6.2 cm or >3.8 cm/m2) [45] and or dysfunction (EF <40 %), there may be an increased thromboembolic risk, and treatment with aspirin or LMWH should be considered during pregnancy.


Regurgitant Valve Lesions

The most common regurgitant valve lesions are mitral (MR) and aortic regurgitation (AR).

The common causes of MR are valve leaflet prolapse, myxomatous degeneration, annular dilatation, or following infective endocarditis. Irrespective of etiology, when important MR is present, it causes left atrial dilatation, and there is a risk of atrial arrhythmias, which is an indication for thromboprophylaxis (see Table 10.2).

AR frequently occurs in the context of aortic root dilatation secondary to aortopathy and connective tissue disease such as Marfan syndrome or bicuspid aortic valve (BAV), but endocarditis is also a common cause. Thromboprophylaxis is rarely indicated in those with aortopathy because the assessment of risk versus benefits of treatment must take into account the increased risk of aortic dissection in this patient group.


Ischemic Heart Disease (IHD)

The number of women with IHD in pregnancy is increasing due to advancing maternal age and increasing risk factors for IHD in younger people. It is therefore not surprising that pregnant women with acute coronary syndromes including myocardial infarction, coronary dissection, and long-term sequelae of IHD now account for the largest number of maternal cardiac deaths in the UK, a trend likely to continue [46]. Women with a prior history of IHD and prior coronary intervention are treated with dual antiplatelet therapy (aspirin and clopidogrel) for 4 weeks if a bare metal stent is deployed [47, 48] and 12 months for a drug-eluting stent [49, 50]. Aspirin 75 mg od is safe in pregnancy, but there is only anecdotal evidence for the safety of clopidogrel in pregnancy. However, when assessing the risks versus benefits of stopping clopidogrel, it must be borne in mind that stent thrombosis may be a fatal event and continuation of therapy is usually indicated.


Prosthetic Heart Valves

Prosthetic valves may be tissue/bioprosthetic (homografts/xenografts/pericardial) or mechanical (metal). Mechanical valves are highly thrombogenic and require anticoagulation with warfarin to prevent valve thrombosis [51]; bioprosthetic valves, on the other hand, do not require formal anticoagulation with warfarin.

The European Society of Cardiology (ESC) offers guidance on target INR levels for different types of metallic prostheses and patient-related factors influencing thromboembolic risk in the nonpregnant state, as follows [52]:

(a)

Prostheses

Low thromboembolic risk prostheses include Carbomedics (aortic position), Medtronic Hall, St. Jude Medical and ON-X. Medium thromboembolic risk prostheses are other bileaflet valves; and high thromboembolic risk prostheses are Lillehei-Kaster, Omniscience, Starr-Edwards valves, Bjork Shiley and other tilting-disc valves.

 

(b)

Patient-Related Factors

Mitral, tricuspid, or pulmonary valve replacement; previous history of thromboembolism; atrial fibrillation; left atrial diameter >50 mm; left atrial spontaneous echo contrast; mitral stenosis of any degree; LVEF <35 %; and hypercoagulable states such as pregnancy. If more than one patient-related risk factor is present, the INR target is increased to a higher value.

 

(c)

Recommended INR Levels



  • Low-risk prosthesis and no patient risk factor: INR target 2.5 (range 2.0–3.0); ≥1 risk factor: target INR 3.0 (range 2.5–3.5)


  • Medium-risk prosthesis and no patient risk factor: INR target 3.5 (range 3.0–4.0); ≥1 risk factor: target INR 4.0 (range 3.0–4.0)


  • High-risk prosthesis and no patient risk factor: INR target 3.5 (range 3.0–4.0); >1 risk factor: target INR 4.0 (range 3.5–4.5).

 

The American Heart Association/American College of Cardiology (AHA/ACC) guidelines, on the other hand, recommend a target INR of 3.0, regardless of valve type and patient risk, with additional LDA if this is felt to be necessary [51].

The British Committee for Standards in Haematology (BCSH) guidelines recommend that the target INR should be raised from 2.5 to 3.0 and 3.0 to 3.5 in the low risk and medium risk groups, respectively, taking into account any additional patient risk factors for thrombosis, namely: mitral, tricuspid or pulmonary position; previous arterial thromboembolism; atrial fibrillation; left atrium diameter >50 mm; mitral stenosis of any degree; left ventricular ejection fraction <35 %; left atrial dense spontaneous echo contrast [53].

The main challenge regarding the use of anticoagulation for mechanical valves during pregnancy is that there is no ideal anticoagulant that is both safe and effective for both mother and fetus. Warfarin therapy throughout pregnancy results in the lowest observed rate of thromboembolism (3.9 %). However, VKA use is associated with fetal and neurodevelopmental problems [19, 22]. In these women, the rate of thromboembolism with UFH is high at 25 % if used throughout pregnancy and 9 % if used for the first trimester [54]. Therapeutic dose LMWH is an attractive alternative to warfarin and UFH however, in the HIP-CAT study, which compared enoxaparin with sequential UFH and warfarin in pregnant women with mechanical valves, 2/7 women receiving therapeutic dose enoxaparin 1 mg/kg 12-hourly developed fatal valve thrombosis [54]. James et al. found an overall thromboembolism rate of 22 % and a maternal mortality of 4 % [35]. Another study [34] found an overall incidence of valve thrombosis of 8.6 % (7/81) and an overall thromboembolism rate of 12.4 % (10/81). Notably, 9 of these 10 patients received a fixed dose of LMWH, and in 2 of these a low fixed dose was used. Among 51 pregnancies where anti-Xa levels were monitored, only one patient was reported to have had thromboembolism. Subsequent studies [12, 40] reported that compliance with therapeutic dose enoxaparin and aspirin is associated with a low risk of valve thrombosis: 5 thromboembolism events in 34 pregnancies treated with enoxaparin and one event in 12 pregnancies treated with LMWH (8 with dalteparin and 4 with enoxaparin) respectively, with non-compliance or subtherapeutic anti-Xa levels contributory in each case of thromboembolism. However, other authors reported fatal valve thrombosis despite therapeutic anti-Xa levels in 1 of 23 pregnancies and other adverse cardiac events in 22 % (5/23) [55]. Women must therefore be counseled of the pros and cons, regarding the choice of anticoagulant and anticoagulant regimen, in order to make an informed decision about which treatment regimen to use during pregnancy. Goland et al. reported that adjusted dose LMWH for women with mechanical heart valves is commonly associated with subtherapeutic trough levels, and suggest measurement of trough as well as peak anti-Xa levels to assure an adequate level of anticoagulation [56].

There is no consensus between cardiac societies on the optimal regimen, and current guidelines (ACCP, AHA/ACC and the ESC [28, 51, 52]) offer different advice. In practice most cardiologists consider three possible treatment regimens:

1.

Warfarin throughout pregnancy, if the dose is <5 mg od, until week 36, then conversion to UFH or LMWH in preparation for delivery.

 

2.

Stop warfarin before week 6 and convert to adjusted therapeutic dose UFH or LMWH for weeks 6–12. Then resume warfarin until week 36 when UFH or LMWH is restarted in preparation for delivery.

 

3.

Stop warfarin before week 6 and convert to adjusted high intensity LMWH, and continue LMWH for duration of pregnancy until the time of delivery [40, 55].

 

If UFH or LMWH is used at any stage of pregnancy, the APTT (UFH) or anti-Xa (LMWH) must be monitored. For UFH administered by continuous intravenous infusion, the APTT ratio is measured within 4 h of starting treatment and thereafter every 6 h or after every dose adjustment, aiming for an APTT ratio which is 1.5–2.5 times that of normal controls [57] (or the laboratory reference therapeutic range). If LMWH is used, the anti-Xa is measured every 1–2 weeks. The ACCP guidelines (2012) advise that if LMWH is used, doses are adjusted to achieve ‘the manufacturer’s peak anti-Xa LMWH 4 h post-SC injection’ (that is, approximately 1.0 IU/mL). As detailed above, therapeutic dose LMWH can be associated with thromboembolic events. We reported that high intensity adjusted LMWH, aiming for a peak level (4 h post-dose) of 1.0–1.2 IU/mL is associated with absence of thromboembolism unless levels of LMWH are subtherapeutic [40] (for suggested LMWH doses, see Table 10.3; in patients with prosthetic heart valves, considerable increases in LMWH doses may be needed during pregnancy, with a mean increase of >50 % reported by Quinn et al. [40]). LDA may be added to anticoagulation in women who are at particularly high risk of thrombosis, for example, those with atrial fibrillation.

In our practice, patients have a planned delivery at around 37–38 weeks gestation. A written delivery plan is formulated by the multidisciplinary team, which includes peripartum anticoagulation management and anesthetic options. For a vaginal delivery, patients are admitted for induction of labor (IOL), taking the last dose of LMWH (dalteparin 100 units/kg or equivalent) on the morning (or the evening in primigravidae) of the day prior to the day of IOL. In women also receiving LDA, this is stopped 1 week prior to elective delivery. The timeline for completion of delivery is 36 h and if unsuccessful a Cesarean section (CS) should be performed.

For elective CS, no LMWH should be administered for 24 h prior to admission, with the last dose half standard therapeutic dose (e.g. dalteparin 100 units/kg), allowing use of regional anaesthesia. Postdelivery, the management of LMWH is along the lines detailed in Chap. 4, aiming to start warfarin on day 4 postdelivery.

Tissue valves generally do not require anticoagulation, unless there is concomitant atrial arrhythmia, poor ventricular function, or significant chamber dilatation. Depending on thromboembolic risk assessment, LDA may also be given.


Acquired Dilated Cardiomyopathies (ADCM)

There are many causes of acquired DCM. In the younger age group, the most common causes are viral myocarditis, toxins, drugs, and pregnancy-associated cardiomyopathy that will be discussed in more detail below. Irrespective of the etiology, if there is only mild residual impairment of LV function, a subsequent pregnancy may precipitate a decline in function, and regular echo surveillance is advisable (monthly in our service). In the presence of severe LV or RV dilatation, there is blood stasis within the chamber, in addition to reduced endothelial antithrombotic properties and increased platelet adhesion [5860]. There is no clear consensus as to whether patients with DCM and low LV ejection fraction (<40 %) should receive thromboprophylaxis in the absence of other prothrombotic risk factors, but many are treated with warfarin, especially if there is spontaneous echo contrast on transthoracic echocardiography (TTE) [61, 62]. During pregnancy, those with DCM and poor function (EF <40 %) will be given LMWH, although the majority with this degree of LV impairment will have been advised against pregnancy as they rep-resent a high-risk group with important maternal morbidity and mortality [63]. For those with DCM and an EF >40 %, LMWH or aspirin 75 mg od should be considered.


Peripartum Cardiomyopathy (PPCM)

PPCM is defined as an idiopathic cardiomyopathy presenting with heart failure secondary to LV systolic dysfunction towards the end of pregnancy or in the months following delivery where no other cause is found. Patients may present acutely in pulmonary edema or may develop progressive signs and symptoms of congestive cardiac failure. There is important morbidity and mortality from thromboembolic complications [64], and women with a new diagnosis of PPCM should be treated with LMWH during pregnancy and converted to warfarin postpartum. Around 50 % have recovery of LV function over a timeframe of approximately 6 months and during this time they remain should warfarinized [65]. If LV function recovers, warfarin can be stopped. For subsequent pregnancies, a recurrence risk of up to 50 % is quoted, especially if there is persistent LV dysfunction following the index pregnancy [66]. If there is persistent LV dysfunction with EF <50 %, pregnancy is inadvisable, but some patients will accept risk and become pregnant and they should be considered for treatment with LMWH. If LV function is normal, aspirin should be considered.

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Oct 31, 2016 | Posted by in HEMATOLOGY | Comments Off on Antithrombotic Therapy for Cardiac Disorders in Pregnancy

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