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P U B L I S H E D B Y E L S E V I E R

STATE-OF-THE-ART REVIEW

Blood Disorders in PatientsUndergoing TranscatheterAortic Valve Replacement

A Review

Hugo De Larochellière, MD,a Rishi Puri, MBBS, PHD,b John W. Eikelboom, MBBS,c Josep Rodés-Cabau, MDa

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Blood Disorders in Patients Undergoing Transcatheter Aortic Valve

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ISSN 1936-8798/$36.00

From the aDepartment of Cardiology, Quebec Heart and Lung InstitutebDepartment of Cardiology, Cleveland Clinic, Cleveland, Ohio; and the cPo

versity and Hamilton Health Sciences, Hamilton, Ontario, Canada. Dr. Rodé

Lifesciences and Medtronic; and holds the Canadian Research Chair “Fondatio

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and 4) recognize the main predictors of von Willebrand factor abnor-

malities post-TAVR.

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y have no relationships relevant to the contents of this

7, 2018, accepted September 25, 2018.

De Larochellière et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 1 2 , N O . 1 , 2 0 1 9

Blood Disorders in TAVR J A N U A R Y 1 4 , 2 0 1 9 : 1 – 1 1

2

Blood Disorders in Patients

UndergoingTranscatheter Aortic Valve Replacement

A Review

Hugo De Larochellière, MD,a Rishi Puri, MBBS, PHD,b John W. Eikelboom, MBBS,c Josep Rodés-Cabau, MDa

ABSTRACT

Transcatheter aortic valve replacement (TAVR) is well established for treating patients with severe aortic stenosis

considered at intermediate to high surgical risk. Blood disorders such as anemia, thrombocytopenia, and acquired type 2A

von Willebrand disease are relatively frequent in TAVR candidates, and multiple studies to date have highlighted their

potential clinical association with mortality and/or bleeding complications post-TAVR. The present review provides an

overview of various blood disorders observed pre- and post-TAVR, with special focus on their incidence, etiology, clinical as-

sociation, and management. (J Am Coll Cardiol Intv 2019;12:1–11) © 2019 by the American College of Cardiology Foundation.

T ranscatheter aortic valve replacement(TAVR) is now the standard of care for pa-tients with severe symptomatic aortic valve

stenosis deemed at intermediate or higher surgicalrisk (1,2). Despite significant reductions in mortalityand morbidity post-TAVR, suboptimal TAVR-relatedoutcomes are still observed in a significant proportionof patients. In patients at high surgical risk, 1-yearmortality ranges from 17% to 24% (3,4), and aboutone-third of patients fail to experience improvedquality of life and functional capacity (5,6). Severalstudies have evaluated the incidence and potentialnegative impact of blood disorders on TAVR out-comes, and some preliminary data exist on potentialtreatment strategies. This review provides an over-view of the incidence, clinical associations, and treat-ment of blood disorders in TAVR recipients, withspecific focus on anemia, thrombocytopenia, and he-mostasis or acquired type 2A von Willebrand disease.

ANEMIA

PREVALENCE AND CAUSES PRE-TAVR. AmongTAVR candidates, the prevalence of pre-proceduralanemia ranges across studies from 45% to 64%(7–18), with severe anemia occurring in 11% to 18% ofpatients (Table 1) (7,9,13,17). This prevalence seemsmuch higher than that reported in cardiac surgerycandidates, with rates of pre-procedural anemiaranging from 16% to 36% (19–21). Unlike surgicalaortic valve replacement (SAVR), TAVR is offeredalmost exclusively to elderly patients, and anemia’sincidence is known to increase with age (22). Also, the

vast majority of TAVR candidates harbor heightenedsurgical risk due to the presence of multiple noncar-diac comorbidities. Hence, common causes of anemiasuch as nutritional deficiencies, chronic diseases (i.e.,chronic kidney disease), inflammatory diseases, andmyelodysplastic syndromes are more frequent inTAVR candidates, contributing to the greater likeli-hood of baseline anemia.

Scarce data exist, however, on the causes ofanemia among TAVR candidates. A study of 438consecutive TAVR recipients found potential treat-able causes of anemia in 90% of patients (13). Inter-estingly, more than half of these patients wereconsidered to have confirmed or possible iron defi-ciency, a reversible etiology (13) (Figure 1). Similarly, ahigh incidence (48%) of anemia secondary to irondeficiency was confirmed in another recent TAVRstudy (17).

CLINICAL ASSOCIATION. Baseline anemia correlateswith negative outcomes post-TAVR, includingincreased risk for blood transfusion, acute kidneyinjury, and long-term mortality (7–15,18,23) (Table 1).Despite normally lesser amounts of intraproceduralblood loss during TAVR (9), patients with pre-procedural anemia receive more blood transfusionscompared with those without anemia (7–13,15,18).The lower baseline hemoglobin levels result in TAVRrecipients’ reaching transfusion thresholds muchquicker, invariably with lesser amounts of blood loss,thus triggering blood transfusion. Furthermore, Araiet al. (7) found an association between pre-proceduralanemia and acute kidney injury post-TAVR. Whether

AB BR E V I A T I O N S

AND ACRONYM S

DAPT = dual antiplatelet

therapy

EPO = erythropoietin

SAVR = surgical aortic valve

replacement

TAVR = transcatheter aortic

valve replacement

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anemia is a cause of acute kidney injury or a marker ofrisk is not clearly established. Further studies arewarranted to better understand this association.

Multiple studies have demonstrated an associationbetween baseline anemia and long-term mortality inTAVR recipients (7–9,12,13,18,23). However, themechanisms explaining such an association remainlargely unknown, and more studies are needed toenhance our knowledge regarding the clinical asso-ciation of anemia in such patients. In fact, anemiamay be only a manifestation of frailty, which isknown to increase the risk for mortality in TAVR re-cipients (24). In addition to the impact on mortality,pre-procedural anemia has also been associated witha higher rate of hospitalizations (16,25), longerhospitalization times (7,18), and decreased functionalperformance post-TAVR (10,13,26).

The increased risk for mortality and lack of func-tional improvement at mid-term follow-up placebaseline anemia (and iron deficiency) as a majorfactor determining TAVR treatment futility. Thishighlights the importance of considering anemiaduring a patient’s TAVR evaluation and reinforces theneed for future registries to better define the clinicaloutcomes in such patients.

PRE-TAVR TREATMENT. Despite ample evidenceshowing its negative clinical association(7–16,18,23,25,26), baseline anemia is commonlyoverlooked in TAVR recipients. In a real-world prac-tice study, it was shown that only a minority of pa-tients (13%) with anemia related to iron deficiencywere receiving iron supplementation prior to theTAVR procedure (13).

Blood transfusions have been associated withincreased morbidity and mortality following cardiacinterventions (8,9,19). Reducing the rate and numberof blood transfusions has become a priority in cardiacsurgery, especially in elderly patients and those withpre-operative anemia (27). Also, a meta-analysisshowed a significant reduction of blood transfusionswith pre-operative erythropoietin (EPO) administra-tion in cardiac surgery (28). To date, 2 studies haveattempted to implement treatment strategies toreduce blood transfusions in anemic patients pre-TAVR. EPICURE (Erythropoietin þ Iron Therapy forAnemic Patients Undergoing Aortic Valve Replace-ment), a randomized double-blind trial of 100 pa-tients, failed to demonstrate favorable outcomes(including a reduction in blood transfusions) in pa-tients receiving EPO and intravenous iron before theprocedure (29). The high comorbidity burden, therelatively short interval between EPO infusion andthe TAVR procedure, and a significant increase in the

use of the transfemoral approach (with alower rate of major or life-threatening com-plications compared with transapical andtransaortic approaches) may explain thediscordant results of this study comparedwith published surgical research.

Another study (observational) assessed theimpact of a blood conservation approach totreat anemia pre-TAVR and to further reduceblood transfusions (17). A total of 60 patients

were referred to the blood conservation clinic with amedian time pre-TAVR of 34 days. The various ap-proaches used to treat baseline anemia were oral iron,intravenous iron, and EPO. The blood conservationapproach succeeded in increasing the average he-moglobin by 1 g/dl and in reducing the blood trans-fusion rate from 33% to 15% (p < 0.001) (oddsratio: 0.28; 95% confidence interval: 0.11 to 0.69;p ¼ 0.006) (17).

The treatment of pre-TAVR anemia may be helpfulto reduce blood transfusions. However, only scarcedata exist in TAVR recipients, and to date, no ran-domized clinical trial has shown the clinical benefit ofany specific intervention in such patients. Thus, theusual management of anemia in elderly patientsshould be recommended in patients undergoingTAVR with no further specific measures. We proposean integrated approach for managing anemia in TAVRcandidates inspired by Goodnough and Schrier (30)(Figure 2). Further trials are needed to evaluate spe-cific measures to correct anemia and reduce bloodtransfusions in TAVR candidates.

POST-TAVR HEMOGLOBIN DROP: INCIDENCE AND

CAUSES. Multiple studies have highlighted a signifi-cant drop in hemoglobin level following TAVR(7,8,13,18,31) (Figure 3). Arai et al. (7) reported that 53%of patients had hemoglobin decreases >2 g/dl post-TAVR, with reductions >4 g/dl in 11% (7). Althoughthis compares favorably with the hemoglobin dropobserved during cardiac surgery (including SAVR) (32),it is much higher compared with the drop of about 1 g/dl in the first 24 h following other interventional car-diology procedures, such as percutaneous coronaryintervention (33). The reasons underscoring thesehemoglobin decrements post-TAVR are likely multi-factorial. Bleeding related to access-site complicationsis by far the most important cause of blood loss duringTAVR (1,34). The use of large-bore catheters in elderlyand high-risk patients initially translated into highrates (w10%) of major vascular complicationsfollowing TAVR (1,34). However, newer generationdevices and increasing operator and center experiencein vascular access hemostasis translated into

TABLE 1 Incidence and Clinical Association of Anemia in Transcatheter Aortic Valve Replacement Recipients

First Author (Ref. #)Age(yrs)

STS-PROM/LogisticEuroSCORE I (%)

AnemiaPrevalence

SevereAnemia

Blood Transfusions($1 U: Anemia vs. Control)

Acute Kidney Injury(Anemia vs. Control)

Long-Term Mortality(1-Year Mortality:

Anemia vs. Control)

Arai et al. (7)(n ¼ 3,472)

82.6 —/21.6 — 17% 26% vs. 15%(p < 0.01)

Severe vs.no/mild anemia

OR: 1.82; 95% CI:1.50–2.21; p < 0.01

24% vs. 15% (p < 0.01)Severe vs. no/mild anemiaHR: 1.44; 95% CI:

1.28–1.63; p < 0.01

Nuis et al. (8)(n ¼ 1,696)

81 —/19 57% — 23% vs. 10%(p < 0.001)

No statisticallysignificant difference

31% vs. 21% (p < 0.001)HR: 1.42; 95% CI:

1.12–1.81; p ¼ 0.004*HR: 2.78; 95% CI: 1.60–4.82;

p < 0.001

Seiffert et al. (10)(n ¼ 1,201)

82 5.6/16.9 59% — OR: 6.74; 95% CI:4.83–9.55; p < 0.001

OR: 0.85; 95% CI:0.73–0.98; p ¼ 0.025

Baseline Hb

HR: 1.13; 95% CI: 0.79–1.61;p ¼ 0.504

3-yr mortality

Nuis et al. (9)(n ¼ 995)

82 —/17 57% 18% 2.5 U vs. 1.1 U (p < 0.001)Severe vs. no anemia

Not statistically significantin multivariate analysis

HR: 1.49; 95% CI: 1.01–2.20;p ¼ 0.043

>30-day mortality formoderate baseline anemia

HR: 1.75; 95% CI: 1.18–2.60;p ¼ 0.005

>30-day mortality for severebaseline anemia

Seiffert et al. (11)(n ¼ 597)

81.7 5.7/18.3 59.3% — OR: 0.39; 95% CI:0.33–0.49; p < 0.01

Baseline Hb

— —

Debonnaire et al. (23)(n ¼ 551)

82 —/18.3 — — — — HR: 2.03; 95% CI: 1.11–3.73;p ¼ 0.022

1-yr mortality for Hb <10g/dl

Rheude et al. (12)(n ¼ 549)

81 —/13 45.4% — 25% vs. 4% (p < 0.001)$2 U transfused

6% vs. 1%(p ¼ 0.005)

14% vs. 3% (p < 0.001)HR: 2.81; 95% CI: 1.69–4.67;

p < 0.001Mortality and rehospitalization

De Larochellière et al.(13) (n ¼ 438)

79 7.2/— 64% 11.9% 39.7% vs. 20.0%(p < 0.001)

3.4 � 2.9 U vs.2.4 � 1.8 U (p < 0.001)

— 30.8% vs. 15.9% (p ¼ 0.005)Hb <10g/dl

Hellhammer et al.(14) (n ¼ 376)

81 —/19.7 63.6% — — 25.1% vs. 10.9% (p ¼ 0.001) —

Binder et al. (15)(n ¼ 373)

81.5 7.4/— 56.3% — OR: 0.79; 95% CI:0.71–0.87; p ¼ 0.001According to low Hb

— —

De Backer et al. (16) 79.5 —/12.4 49% — — — —

Shuvy et al. (17) 82.6 9.7/— 62% 11% — — —

Van Mieghem et al.(18) (n ¼ 118)

82 6/12.3 49% — 86% vs. 33% (p < 0.001)3.3 � 3.1 vs. 1.5 � 2.3

(p < 0.001)

14% vs. 22%(p ¼ 0.34)

44% vs. 15%(p ¼ 0.006)

HR: 2.10; 95% CI: 1.06–4.18;p ¼ 0.034

*Hb <10 g/dl.

CI ¼ confidence interval; EuroSCORE ¼ European System for Cardiac Operative Risk Evaluation; Hb ¼ hemoglobin; HR ¼ hazard ratio; OR ¼ odds ratio; STS-PROM ¼ Society of Thoracic Surgeons PredictedRisk of Mortality.

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significant reductions in vascular complications inrecent times; yet the rate of major vascular complica-tions remains about 5% (35,36). Also, the use of non-transfemoral access routes, particularly transapicaland transaortic approaches, in patients with inappro-priate iliofemoral arterial access has been associatedwith a major increase in bleeding complications (37).In addition to overt bleeding secondary to vascularcomplications, a significant proportion of patientsundergoing TAVR exhibit notable drops in hemoglobinlevels despite having no obvious source of bleeding or

having bleeding not directly related to the procedure(typically genitourinary or gastrointestinal) (38).Finally, an inflammatory state and hemodilutionresulting from the return of interstitial fluids afteracute stress may also contribute to falling hemoglobinlevels post-TAVR (39).

POST-TAVR HEMOGLOBIN DROP: CLINICAL

ASSOCIATION. Multiple studies have demonstratedthe negative clinical association of major or life-threatening bleeding post-TAVR, with a significant

FIGURE 1 Causes of Anemia

Causes of anemia overall and according to sex in a cohort of 114 consecutive patients who

underwent transcatheter aortic valve replacement. Reprinted with permission from

De Larochellière et al. (13).

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increase in the risk for early and late mortality (34).However, fewer data exist on hemoglobin levels athospital discharge or within the months following aTAVR procedure. Of note, we showed that >90% ofTAVR recipients had some degree of anemia uponhospital discharge, and about two-thirds of themcontinued to remain anemic at 6 months (13).Nombela-Franco et al. (25) identified lower hemo-globin levels at hospital discharge as an independentrisk factor for early (<30 days) rehospitalization post-TAVR (25). Also, lower hemoglobin levels at 6 monthspost-TAVR have been associated with poorerfunctional status and decreased exercise capacity(13,40). Thus, treating post-procedural anemia wouldpotentially benefit a large number of TAVR recipientsin terms of optimizing functional performance andquality of life.

THROMBOCYTOPENIA IN TAVR

THROMBOCYTOPENIA POST-TAVR: INCIDENCE AND

POTENTIAL CAUSES. According to the commondefinition of thrombocytopenia (platelet count#150 � 109/l), approximately 40% of patients presentwith some degree of thrombocytopenia pre-TAVR(41), and the incidence of thrombocytopenia post-TAVR ranges from 69% to 87% (41–43). Moderate tosevere post-procedural thrombocytopenia (plateletcount #100 � 109/l) occurs in 25% to 60% of patientsacross studies (41,42,44–46), whereas severe throm-bocytopenia (platelet count #50 � 109/l) is observedin 2% to 6% (44,45,47). The average decrease inplatelet count following TAVR is about 40%, rangingfrom 34% to 45% (43,44,47) (Table 2). The vast ma-jority of studies showed a nadir of platelet count 48 hpost-procedure, with a frequent return to baselineplatelet count after 7 days (42,46,48) (Figure 4).Persistent thrombocytopenia after TAVR occurs in35% of patients, mainly in those with pre-proceduralthrombocytopenia (41).

A range of mechanisms has been proposed toexplain platelet drops post-TAVR. Jilaihawi et al. (46)demonstrated a similar rate of thrombocytopeniaamong patients undergoing TAVR and SAVR (46).However, because TAVR is a much less invasive pro-cedure, the causes of thrombocytopenia followingSAVR cannot be entirely extrapolated to TAVR pa-tients. Thrombocytopenia post-TAVR may be relatedto the thromboinflammatory state created by theprocedure coupled with a reduced capacity forplatelet renewal in older patients (49,50). Some havesuggested that platelet activation may occur on thesurface of the prosthetic heart valve during an in-flammatory state (43,50). However, despite some

studies demonstrating a rise in inflammatory bio-markers post-TAVR, the association between inflam-mation and thrombocytopenia post-TAVR requiresfurther investigation (43,49,50). Vascular complica-tions, bleeding, and multiple blood transfusions mayalso play a significant role in early thrombocytopeniafollowing TAVR (44). Finally, heparin-inducedthrombocytopenia may contribute to the occurrenceof thrombocytopenia post-TAVR, but its incidence isvery low (0.5%) (51).

THROMBOCYTOPENIA POST-TAVR: CLINICAL

ASSOCIATION. Dvir et al. (44) first described an as-sociation between thrombocytopenia and mortalitypost-TAVR. In their study, the 1-year mortality ratewas 16% for those with no or mild thrombocytopeniaup to 20% to 67% for moderate and severe thrombo-cytopenia, respectively (p < 0.001) (44). Severethrombocytopenia was subsequently identified as anindependent risk factor for long-term mortality(hazard ratio: 3.44; 95% confidence interval: 1.02 to11.60; p ¼ 0.046) (44). Similarly, Jilaihawi et al. (46)outlined the negative impact of persistent moderateto severe thrombocytopenia upon 1-year mortalitypost-TAVR (hazard ratio: 3.65; 95% confidence inter-val: 1.63 to 8.16; p ¼ 0.002). Other studies have showna tendency toward an increased risk for mortalityamong patients exhibiting thrombocytopenia post-TAVR (45–47) (Table 2).

Post-procedural thrombocytopenia has also beenassociated with an increased rate of bleeding com-plications and transfusion rates among TAVRrecipients. Dvir et al. (44) reported 30-day life-threatening bleeding rates of 3%, 15.7%, and 37.5%

FIGURE 2 Stepwise Approach to Treating Baseline Anemia in Patients Undergoing Transcatheter Aortic Valve Replacement

Treatment flowchart modified from Goodnough et al. (30). eGFR ¼ estimated glomerular filtration rate; ESA ¼ erythropoietic-stimulating

agent; Hb ¼ hemoglobin; IV ¼ intravenous; TSAT ¼ transferrin saturation.

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for no or mild, moderate, and severe thrombocyto-penia, respectively (p < 0.001). Sedaghat et al. (45)observed a significant increase in major bleeding(from 2.8% to 16.4%) in patients with $50% decreasesin platelet counts post-procedure (Table 2).

The mechanisms linking post-TAVR thrombocyto-penia and mortality are not well understood; theincreased rate of bleeding complications has beensuggested as one of the underlying mechanisms. Also,thrombocytopenia post-TAVR may be a marker ofsevere impairment in general homeostasis; ratherthan being directly implicated in the causal pathwayto death, platelet count could be viewed as a “finalcommon pathway” of several death correlates, akin toserum albumin levels when assessing frailty (52).Current data would suggest systematic platelet

counts post-TAVR as a valid prognostic marker.However, data remain scarce and limited to studieswith small sample sizes. Confirmation of these data inlarger cohorts of contemporary patients is warranted.

THROMBOCYTOPENIA POST-TAVR: INSIGHTS ON

ANTITHROMBOTIC THERAPY. According to currentU.S. and European guidelines, dual antiplatelet ther-apy (DAPT) is recommended for 3 to 6 months post-TAVR, despite no evidence-based data supportingsuch a recommendation (53,54). A recent patient-level meta-analysis including 3 small randomizedtrials comparing DAPT with single-antiplatelet ther-apy post-TAVR showed an increased risk for major/life threatening bleeding complications with DAPT,with no benefit on ischemic complications including

FIGURE 3 Changes in Hemoglobin Levels Following Transcatheter Aortic Valve Replacement

Changes in hemoglobin level over time, overall (A) and according to the presence of anemia at baseline (B). Reprinted with permission from

De Larochellière et al. (13).

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FIGURE 4 Course

Replacement

Platelet counts were

except for the seven

(p ¼ 0.40). Reprinte

TABLE 2 Acquired Thrombocytopenia Following Transcatheter Aortic Valve Replacement

First Author(Ref. #)

Age(yrs)

STS-PROM/Logistic

EuroSCORE (%)ValveTypes

AccessRoute

SignificantThrombocytopenia(<100 � 109/l) Long-Term Mortality Major Bleeding

Dvir et al. (44)(n ¼ 488)

84.7 11.2/30.2 SAPIEN: 96%CoreValve:

4%

TF: 69%TA/direct aortic:

31%

36% OR: 3.44; 95% CI: 1.02–11.6;p ¼ 0.046

1-yr mortality for severethrombocytopenia

10% vs. 8.8% vs. 15.8% (p ¼ 0.64)3% vs. 15.7% vs. 37.5% (p < 0.001)30-day major and life-threatening

bleeding according to no/mild,moderate, and severethrombocytopenia

Sedaghat et al.(45)(n ¼ 307)

81 8.6/25.4 CoreValve:77%

SAPIEN: 15%Accurate: 2%Centera: 1.3%EvolutR: 1%

TF: 100% 25.4% 30.9% vs. 19.3% (p ¼ 0.08)DPC $50% and DPC <50%,

respectively

16.4% vs. 2.8% (p < 0.001)30-day major bleeding for DPC

$50% and DPC <50%,respectively

Jilaihawi et al.(46)(n ¼ 246)

85 11/27 SAPIEN: 79%SAPIEN XT:

21%

TF: 81.3%TA: 18.7%

39% HR: 1.47; 95% CI: 0.98–2.22;p ¼ 0.065

*Major thrombocytopenia

OR: 0.89; 95% CI:0.51–1.60; p ¼ 0.69

McCabe et al.(42)(n ¼ 112)

82 9.2/— SAPIENSAPIEN XT

TF: 78.6%TA/direct aortic:

31.4%

34% — 6% vs. 0% vs. 5% (p ¼ 0.33)In-hospital bleeding

complication for no, mild,and moderate/severethrombocytopenia

Flaherty et al.(41)(n ¼ 90)

81 8.7/— SAPIENSAPIEN XT

TF: 66% 63% — OR: 1.04; 95% CI: 0.97–1.12; p ¼ 0.29In-hospital major bleeding associated

with major thrombocytopenia

DPC ¼ decreased platelet count; TA ¼ transaortic; TF ¼ transfemoral; other abbreviations as in Table 1.

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stroke (55). The ongoing POPular-TAVI (AntiplateletTherapy for Patients Undergoing Transcatheter AorticValve Implantation) randomized trial (NCT02247128)should provide a more solid evidence base regardingthe optimal antiplatelet regimen post-TAVR. Mean-while, available data showing harm and no beneficialeffects of DAPT post-TAVR, along with the high

of Platelet Counts Following Transcatheter Aortic Valve

significantly different from baseline for all time points (p < 0.05),

th post–transcatheter aortic valve replacement (TAVR) day

d with permission from Sedaghat et al. (45).

prevalence of blood disorders (i.e., anemia andthrombocytopenia), call into question the currentDAPT recommendation in TAVR recipients.

HEMOSTASIS AND ACQUIRED

VON WILLEBRAND DISEASE

Aortic stenosis is associated with acquired type 2Avon Willebrand disease. The shear stress triggered bythe valve stenosis induces the cleavage of the vonWillebrand factor by the protease ADAMTS13 (56).The resulting fragments of von Willebrand factorcleavage are inactive, reducing the hemostasiscascade and increasing bleeding complications (56).First described in 1958, Heyde’s syndrome refers tothe association between aortic valve stenosis andgastrointestinal bleeding from angiodysplasia (56).Among patients undergoing TAVR, Godino et al. (57)reported a 1.7% rate of Heyde’s syndrome and 7.5%of patients with histories of gastrointestinal bleedingfrom another source or unknown origin. In anotherstudy, Spangenberg et al. (58) identified the presenceof abnormal von Willebrand multimers in 42% ofTAVR candidates, with 18% and 3.2% of patients withbleeding episodes and proven Heyde’s syndrome,respectively (58). Two additional studies demon-strated a similar prevalence of Heyde’s syndrome inpatients undergoing TAVR (59,60). Although an in-crease in gastrointestinal bleeding was reported in

CENTRAL ILLUSTRATION Clinical Association of Blood Disorders in Transcatheter Aortic ValveReplacement Candidates

De Larochellière, H. et al. J Am Coll Cardiol Intv. 2019;12(1):1–11.

TAVR ¼ transcatheter aortic valve replacement.

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 1 2 , N O . 1 , 2 0 1 9 De Larochellière et al.J A N U A R Y 1 4 , 2 0 1 9 : 1 – 1 1 Blood Disorders in TAVR

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patients with severe aortic stenosis undergoingTAVR, the incidence of bleeding complications inthese patients has never been compared with that ofpatients with other cardiovascular diseases. Weshould therefore remain cautious in interpreting thisassociation.

In patients undergoing TAVR, high–molecularweight multimers increase proportionally to thedrop in mean pressure gradient and return to anormal value in the vast majority of patients (58,60).Residual paravalvular leaks post-TAVR, however,negatively influence the normalization of von Wille-brand factors (58). Godino et al. (57) demonstratedthat pre-procedural bleeding disorders resolved in allpatients post-TAVR out to 2 years of follow-up.Hence, TAVR could have a positive impact on hemo-stasis and von Willebrand type 2A disease. Moreover,all patients exhibiting bleeding complications during

the TAVR procedure were diagnosed of subclinicalvon Willebrand dysfunction (60). These data suggestthat von Willebrand factor monitoring could be usefulto predict procedural bleeding, but further studies arewarranted.

Two ongoing trials are evaluating hemostatic pa-rameters and von Willebrand factor multimer activityin TAVR recipients in order to determine the best post-procedural antithrombotic regimen (NCT02812953and NCT03248232). In addition to platelet dysfunc-tion, the impact of coagulation factors on post-TAVRbleeding should also be evaluated in further trials.

CONCLUSIONS

TAVR is a well-established therapy for managingpatients with severe aortic stenosis. The over-whelming majority of emphasis among the TAVR

De Larochellière et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 1 2 , N O . 1 , 2 0 1 9

Blood Disorders in TAVR J A N U A R Y 1 4 , 2 0 1 9 : 1 – 1 1

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community thus far has focused on improving trans-catheter valve technology, design iterations, andprocedural-technical aspects. The present reviewhighlights the clinical relevance of common hemato-logic disorders in TAVR candidates (CentralIllustration). In addition to relatively high rates ofanemia and thrombocytopenia pre- and post-TAVR,these conditions have been associated with pooreroutcomes, including increased mortality risk at mid-term follow-up. It also seems that a large proportionof anemic patients undergoing TAVR remain un-treated, despite unraveling a reversible cause ofanemia in more than half of these patients. Thesefindings should alert the TAVR community to takeinto account the presence (and severity) of blooddisorders when evaluating TAVR patients, as well asto implement the appropriate measures for managing

these pathologies. A stepwise and personalizedapproach to treat baseline anemia is suggested ac-cording to the actual published research. Futurestudies are needed to increase our knowledge ofblood disorders in TAVR candidates and to evaluatethe clinical benefits of specific measures aimed ataddressing blood disorders (in particular anemiaand iron deficiency) in these patients. Finally,hemostatic markers such as von Willebrand factormerit further evaluation in order to predict proce-dural bleeding and to determine the best antith-rombotic regimen.

ADDRESS FOR CORRESPONDENCE: Dr. Josep Rodés-Cabau, Quebec Heart and Lung Institute, Laval Uni-versity, 2725 Chemin Ste-Foy, Quebec City, QC G1V4G5, Canada. E-mail: josep.rodes@criucpq.ulaval.ca.

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KEY WORDS anemia, aortic stenosis,hemostasis, thrombocytopenia

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