10.4081/btvb.2022.34
Patients with mechanical prosthetic heart valves (MHV) need vitamin K antagonist (VKA) treatment, due to the high thrombotic risk. The need to evaluate the bleeding risk of these patients is of great clinical relevance. This is an observational retrospective multicenter study among Centers affiliated to the Italian Federation of Anticoagulation Clinics on MHV patients, with the aim to evaluate the risk of major bleeding (MB) and associated risk factors. 2357 patients with MHV were included in the study, patients were followed for 24.081 pt-years; 246 patients had MB (rate 1.0 ×100 pt-yrs), 54 were intracranial hemorrhage (rate 0.22 ×100 pt-yrs). Patients with MB were significantly older, more affected by peripheral obstructive arterial disease (POAD) and atrial fibrillation (AF), and presented a history of previous MB, with respect to patients who did not bleed. Patients with MB showed a trend for lower time in therapeutic range (TTR), and a significant number of patients had a TTR in the lower quartile. Patients with MB had a higher mortality rate with respect to patients who did not bleed (p=0.001). The history of previous bleeding, the presence of POAD or of AF, and a TTR in the lowest quartile, were significantly associated with MB. MHV patients treated with VKAs followed by Anticoagulation Clinics, showed a low bleeding risk. Risk factors associated with major bleeding are older age, the presence of POAD or AF, the history of previous bleeding, and poor quality of anticoagulation. Patients who experienced MB during anticoagulation are at high risk of death.
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Bleeding, Thrombosis and Vascular Biology
Bleeding
Major bleedings in mechanical prosthetic heart valves patients on Vitamin K antagonist treatment. Data from the PLECTRUM Study
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2022-04-11
2022-05-23
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Bleed Thromb Vascul Biol
Sophie Testa
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Poli D, Antonucci E, Pengo V, et al. Risk of reoperation in bioprosthetic valve patients with indication for long-term anticoagulation. Results from the observational retrospective multicentre PLECTRUM study. Open Heart 2018;5:e000837.
Major bleedings in mechanical prosthetic heart valves patients on Vitamin K antagonist treatment. Data from the PLECTRUM Study
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                                                                                                          ORIGINAL ARTICLE

Major bleedings in mechanical prosthetic heart valves patients on Vitamin K
antagonist treatment. Data from the PLECTRUM Study
Daniela Poli,1 Emilia Antonucci,2 Gualtiero Palareti,2 Roberto Facchinetti,3 Pietro Falco,4 Giuseppina Serricchio,5
Teresa Lerede,6 Lucilla Masciocco,7 Paolo Gresele,8 Sophie Testa,9 on behalf of the Italian Federation of Anticoagulation
Clinics
1
  Center of Atherothrombotic Disease, Careggi University Hospital, Firenze; 2Arianna Anticoagulazione Foundation, Bologna;
3
  Test Lab, Ospedale Civile Maggiore Integrated University Hospital, Borgo Trento; 4Medical Pontino Specialist Outpatient Clinic,
Latina; 5Test Lab, Sant'Anna Hospital, San Fermo della Battaglia, & Lariana Local Health Unit, Como; 6Thrombosis and Hemostasis
Center, Immunohematology and Transfusion Medicine, Papa Giovanni XXIII Hospital, Bergamo; 7Department of Internal Medicine,
Lastaria Hospital, Lucera; 8Department of Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia;
9
  Haemostasis and Thrombosis Centre, Cremona Local Health Unit, Cremona, Italy



ABSTRACT
     Patients with mechanical prosthetic heart valves (MHV) need vitamin K antagonist (VKA) treatment, due to the high thrombotic




                                                                                               ly
risk. The need to evaluate the bleeding risk of these patients is of great clinical relevance. This is an observational retrospective multi-




                                                                                        on
center study among Centers affiliated to the Italian Federation of Anticoagulation Clinics on MHV patients, with the aim to evaluate
the risk of major bleeding (MB) and associated risk factors. 2357 patients with MHV were included in the study, patients were followed
                                                                           for 24.081 pt-years; 246 patients had MB (rate 1.0 ×100 pt-yrs),
                                                                           54 were intracranial hemorrhage (rate 0.22 ×100 pt-yrs). Patients




                                                                                   e
                                                                           with MB were significantly older, more affected by peripheral
   Correspondence: Daniela Poli, Centro Trombosi, Viale Morgagni
   85, 50134 Firenze, Italy.
                                                                              us
                                                                           obstructive arterial disease (POAD) and atrial fibrillation (AF),
                                                                           and presented a history of previous MB, with respect to patients
                                                                           who did not bleed. Patients with MB showed a trend for lower
   Tel.: +39.055.7945453.
                                                                              al
   E-mail: polida@aou-careggi.toscana.it                                   time in therapeutic range (TTR), and a significant number of pa-
                                                                           tients had a TTR in the lower quartile. Patients with MB had a
                                                           ci

   Key words: Mechanical heart valves; Anticoagulation; Vitamin K          higher mortality rate with respect to patients who did not bleed
                                                         er


   antagonists; Bleeding.                                                  (p=0.001). The history of previous bleeding, the presence of
                                                                           POAD or of AF, and a TTR in the lowest quartile, were signifi-
   Contributions: DP conceived conceptual design of the study, per-
                                                        m



   formed data interpretation, wrote and revised manuscript; DP and        cantly associated with MB. MHV patients treated with VKAs
   EA performed experimental analysis, and interpretation; RF, PF,         followed by Anticoagulation Clinics, showed a low bleeding
                                            om




   GS,TL, LM, performed data acquisition; GP, PG, ST performed             risk. Risk factors associated with major bleeding are older age,
   data interpretation and revised manuscript. All authors reviewed        the presence of POAD or AF, the history of previous bleeding,
   the manuscript.                                                         and poor quality of anticoagulation. Patients who experienced
                                      -c




                                                                           MB during anticoagulation are at high risk of death.
    Conflict of interest: The authors declare no potential conflict of in-
                             on




    terest.

    Funding: Arianna Anticoagulation Foundation that supported the
                                                                               INTRODUCTION
                       N




    START Register. The Foundation had no role in study design, col-
    lection, analysis and interpretation of data, in writing the report,
                                                                                   Patients with mechanical heart valves (MHV) require
    and in the decision to submit the paper for publication.
                                                                               long-term oral anticoagulant therapy with vitamin K an-
    Received for publication: 11 April 2022.                                   tagonists (VKAs) for the high risk of valve thrombosis
    Accepted for publication: 6 July 2022.                                     and systemic embolism.1,2 The number of implantations
    Publisher’s note: All claims expressed in this article are solely those    of MHV is dramatically reduced in the recent years in
    of the authors and do not necessarily represent those of their affili-     western countries, where widespread antibiotic treatment
    ated organizations, or those of the publisher, the editors and the re-     has reduced the incidence of rheumatic heart disease
    viewers. Any product that may be evaluated in this article or claim        among young people. In these countries, the need for car-
    that may be made by its manufacturer is not guaranteed or endorsed
    by the publisher.                                                          diosurgery is mainly due to degenerative valve disease oc-
                                                                               curring in elderly patients, in whom the use of biological
    ©
     Copyright: the Author(s), 2022                                            valves is preferred.3-6 Instead, the need for heart valve
    Licensee PAGEPress, Italy
    Bleeding, Thrombosis and Vascular Biology 2022; 1:34
                                                                               prosthesis implantation is still a serious problem in low-
    doi:10.4081/btvb.2022.34                                                   income countries.7 Notwithstanding the reduction of
                                                                               MHV implantation in western countries, patients who
    This work is licensed under a Creative Commons Attribution-
                                                                               carry a MHV need long-life anticoagulation and therefore
    NonCommercial 4.0 International License (CC BY-NC 4.0).
                                                                               a not negligible number of MHV patients are still on an-

                                                Bleeding, Thrombosis and Vascular Biology 2022; 1:34
44                                                        D. Poli et al.




ticoagulant treatment. Moreover, an increasing number of             reduction of 2 g/dL or more and/or need for transfusion
patients coming from low-income countries are now liv-               of two or more blood units. Follow-up started at enroll-
ing in the west, due to the widespread immigration. After            ment and was stopped at patient’s death, at the occurrence
the premature stopping of the RE-ALING trial, where                  of the first adverse event or when a patient was no longer
dabigatran was compared with warfarin in patients with               monitored by the participating Center.
prosthetic heart valves, due to the excess of bleeding and               The quality of anticoagulation control was calculated
thrombotic events in the group of patients treated with              as Time in Therapeutic Range (TTR) by using the linear
dabigatran, VKAs are nowadays the unique treatment                   interpolation method by Rosendaal et al.13 TTR was ana-
available for these patients.8 Therefore, the need to eval-          lyzed considering the INRs recorded in the last year of
uate the bleeding risk of long-term anticoagulation is of            follow-up, and the intended anticoagulation ranges re-
great clinical relevance. For this reason, we performed the          ferred to the last year of follow-up for the examined pa-
observational, retrospective, multicenter PLECTRUM                   tients.
study, whose results have been previously published.9                    The present study was approved by the local Institu-
    In this sub-study we aimed to evaluate the risk of               tional Committees on Human Experimentation.
bleeding in anticoagulated MHV patients and the associ-
ated risk factors.                                                   Statistical analysis




                                                                                              ly
                                                                         Baseline characteristics were summarized with de-




                                                                                      on
MATERIALS AND METHODS                                                scriptive statistics. Categorical variables were reported as
                                                                     counts and percentages and continuous variables were ex-
    The FCSA-START Valve Study (PLECTRUM) is an




                                                                                 e
                                                                     pressed as median and interquartile range (IQR). Inci-
observational retrospective multicenter study performed              dence rates of adverse events were calculated as the
within the Italian Survey on anTicoagulated pAtients Reg-
isTer (START Register),10 and conducted among 33 Cen-
                                                                           us
                                                                     number of events per 100 patient-years of observation,
                                                                     and rate ratios were given with their 95% confidence in-
                                                                   al
ters affiliated to the Italian Federation of Anticoagulation         tervals (CI). For this calculation, observation started at the
Clinics (FCSA). Centers were asked to select from their              beginning of the follow-up and ended when patients ex-
                                                      ci

databases patients in whom a mechanical heart valve pros-            perienced either death, a major outcome or stopped regu-
                                                    er


thesis or a bio-prosthesis was implanted after 1990 and              lar monitoring at the participating Center. Analyses were
who were followed for the management of anticoagula-                 performed with the Fisher exact test (for categorical data),
                                                   m



tion; 3029 patients were enrolled in the study, of whom              the unpaired t test (for normally distributed data), and the
2357 patients received MHV implantation. Methods have                Mann-Whitney test (for non-normally distributed data).
                                          om




been previously described.9 Briefly, participating Centers           All variables found to be significant at univariable analy-
followed patients for the management of anticoagulation              sis were subsequently entered into a multivariable analy-
after hospital discharge. All Centers adhere to FCSA and
                                     -c




                                                                     sis. Risk was expressed as odds ratio (OR) with 95% CI.
participate in the specifically designed laboratory external         A 2-sided value of p<0.05 was chosen for statistical sig-
                             on




quality control program, which is run 3 times per year and           nificance. Kaplan-Meier survival curves for bleeding
uses lyophilized plasma samples obtained from anticoag-              events were also provided.
ulated patients.11 At enrollment, patients’ demographic in-
                         N




                                                                         We used the SPSS version 25 software (SPSS Inc,
formation and clinical data were collected. The center               Chicago, IL, USA) and the Stata version 14 software
provides regular INR measurements, prescribes the daily              (Stata Corp, College Station, TX) for Windows for data
VKA dosages and schedules the date for the subsequent                processing.
visits. According to the routine practice of the participat-
ing centers, follow-up visits were scheduled every 2 to 4
weeks for INR monitoring. Patients who missed check-                 RESULTS
ups for >2 months were contacted (personally or through
their family or general practitioner), and the reason for in-            A total of 2357 patients with MHV were included in
terrupting treatment monitoring was recorded. The occur-             the PLECTRUM study, for a total of 24,081 patient/years
rence of bleeding or thrombotic complications during                 of observation. Clinical characteristics of this cohort are
follow-up is recorded. Major Bleeding (MB) was defined               reported in Table 1. Among these patients, 246 MBs were
accordingly with the definition reported by Palareti et al.,         recorded during the observation period, with a rate of
in use in Italian centers during the study period:12 fatal           1.0×100 patient-years (pt-yrs). As detailed in Table 2, 54
(death due to hemorrhage); intracranial (documented by               of these events were intracranial hemorrhage (ICH) (rate
imaging), ocular (with blindness), articular, or retroperi-          0.22×100 pt-yrs). Among patients who experienced MB,
toneal; if surgery or angiographic intervention was re-              40 died during follow-up: 12 patients for MB, 18 for heart
quired to stop bleeding; and if bleeding led to hemoglobin           failure, 1 for stroke, 2 for cancer, 2 for respiratory failure

                                     Bleeding, Thrombosis and Vascular Biology 2022; 1:34
                    Major bleedings in mechanical prosthetic heart valves patients on Vitamin K antagonist treatment                    45



and 3 for sudden death; in 2 patients in whom MB was
excluded, the cause of death was not reported.                           DISCUSSION
    Co-morbidities and risk factors for bleeding in patients                 The principal finding of this observational study is the
who experienced MB and who did not, are reported in                      low rate of bleeding in patients with MHV on long-term
Table 3. Patients with MB were significantly older, more                 anticoagulation with VKA followed by Anticoagulation
frequently affected by peripheral obstructive arterial dis-
ease (POAD) and atrial fibrillation (AF), and more often
presented a history of previous MB with respect to pa-
tients who did not bleed (Figure 1A). Moreover, among
patients with MB a trend for lower time in therapeutic
range (TTR) was present, and a higher number of patients,
even if not statistically significant had a TTR in the lower
quartile (Figure 1B). Patients with MB showed a higher
mortality rate with respect to patients who did not bleed
(rate 1.35×100 pt-yrs and 0.6×100 pt-yrs, respectively;
Relative Risk 2.1, 95% CI 1.4-3.0; p=0.000).




                                                                                           ly
    We performed a univariate and multivariate analysis




                                                                                   on
for risk factors associated with MB (Table 4), and found
that history of previous bleeding, presence of POAD or
AF, and TTR in the lowest quartile were significantly as-




                                                                             e
sociated with MB.
                                                                         us
Table 1. Characteristics of the whole cohort.
                                                                      al
                                                       Number (%)
                                                     ci

All patients                                               2357
                                                   er


Males, n (%)                                            1301 (55.2)
Median age at implantation (years) (IQR)              59.0 (49.7-65.7)
                                                  m




Site of prosthesis valve, n (%)
                                       om




 Aortic                                                 1408 (59.7)
 Mitral                                                  682 (28.8)
 Mitral-aortic                                           267 (11.5)
Vitamin K antagonist, n (%)
                                  -c




 Warfarin                                               1929 (81.8)
 Acenocoumarol                                           428 (18.2)
                            on




Follow-up
 Median follow-up (years) (IQR)                        9.7 (5.0-14.1)
                    N




 Total follow-up (pt-yrs)                                 24,081
Adverse events during follow-up, (rate ×100 pt-yrs)
 Major bleeding                                          246 (1.0)
 Stroke/TIA/peripheral embolism                          164 (0.7)
IQR, interquartile range.



Table 2. Type of major bleedings.
                                                       Number (%)
Total bleedings                                             246
Fatal                                                     12 (4.9)
Gastrointestinal bleeding                                78 (31.7)
Intracranial hemorrhage                                  54 (22.0)
Muscular hematoma                                        36 (14.6)
Hb drop >2 g/dL and/or transfusion ≥2 RBC units          29 (11.8)       Figure 1. Cumulative survival of major bleeding A) in relation
Other Bleeding                                           49 (19.9)
                                                                         to the history of bleeding event, B) in relation to lower quartile
                                                                         of INR (TTR <47%).
Hb, hemoglobin; RBC, red blood cell.


                                           Bleeding, Thrombosis and Vascular Biology 2022; 1:34
46                                                              D. Poli et al.




Clinics. Among patients who experienced MB, one fifth                         a rate of major bleeding of 1.9 per 100 patient-years (95%
had intracerebral bleedings, and the overall mortality rate                   CI, 1.7 to 2.0), with a rate of intracerebral bleeding of 0.5
of MBs was 4.9%, so confirming the low rate of serious                        per 100 patient-years. The wide-ranged target INR-levels
bleeding complications. Cannegiter et al. in 1994 found                       with older generation MHV may have contributed to these



Table 3. Characteristics of patients with and without major bleedings.
                                                           Major bleeding                   No major bleeding                    p value
                                                            N. 246 (%)                         N. 2111 (%)
Age years (IQR)                                            60.7 (52.3-67.0)                   58.8 (49.6-65.6)                       0.03
Females                                                      117 (47.6)                           941 (44.5)                          0.5
Hypertension                                                 168 (68.3)                           1284 (60.8)                         0.2
Diabetes mellitus                                             37 (15.0)                           260 (12.3)                          0.6
Coronary artery disease                                       36 (14.6)                           254 (12.0)                          0.6
Peripheral obstructive arterial disease                       25 (10.2)                            86 (4.1)                          0.000




                                                                                                         ly
Heart failure                                                  13 (5.3)                            152 (7.2)                          0.2




                                                                                                  on
Atrial fibrillation                                          115 (46.7)                           793 (37.6)                         0.006
Previous ischemic stroke/TIA                                  25 (10.2)                            152 (7.2)                          0.3
Previous major bleed                                          42 (17.1)                            44 (2.1)                          0.000




                                                                                          e
Aspirin treatment                                             31 (12.6)                            206 (9.8)                          0.3
Target INR ≥3.0
Mitralic or mitro-aortic valve
                                                             168 (69.1)
                                                              99 (40.2)
                                                                                   us             1518 (71.8)
                                                                                                  850 (40.3)
                                                                                                                                      0.3
                                                                                                                                      1.0
Renal failure (eGFR <30mL/min)                                 1 (0.4)                             25 (1.2)                           0.3
                                                                             al
eGFR <60 mL/min                                               44 (17.9)                           352 (16.7)                          0.6
                                                            ci

TTR in the lowest quartile                                    77 (31.3)                           490 (23.2)                         0.01
TTR median (IQR)                                             56 (44-73)                            61 (8-74)                         0.07
                                                          er


Anemia (Hb <10 g/dL)                                           15 (6.1)                            105 (5.0)                          0.4
                                                         m



Platelet count <100,000/mL                                     5 (2.0)                             21 (1.0)                           0.2
Hb, hemoglobin; IQR, interquartile range.
                                                om




Table 4. Univariate and multivariate analysis of risk factors associated with major bleeding.
                                            -c




                                                                  Univariate analysis                                 Multivariate analysis,
                                   on




                                                            OR (95%CI)                p value                               p value
Females                                                     1.1 (0.8-1.4)                  0.5
                             N




Age >59 years                                               1.4 (1.0-1.8)                  0.02                                0.2
Hypertension                                                1.2 (0.9-1.7)                  0.2
Diabetes mellitus                                           1.1 (0.8-1.6)                  0.6
Coronary artery disease                                     1.1 (0.7-1.6)                  0.6
Peripheral obstructive arterial disease                     2.5 (1.6-4.0)                 0.000                               0.001
Heart failure                                               0.7 (0.4-1.2)                  0.2
Atrial fibrillation                                         1.5 (1.1-1.9)                 0.004                               0.04
Previous ischemic stroke/TIA                                1.3 (0.8-2.1)                  0.3
Previous major bleeding                                     8.7 (5.6-13.6)                0.000                               0.000
Renal failure (eGFR <30 mL/min)*                            0.3 (0.5-2.5)                  0.3
eGFR <60 mL/min                                             1.1 (0.8-1.7)                  0.6
Mitral valve                                                1.0 (0.8-1.3)                  0.9
INR range 2.5-3.5                                           1.2 (0.6-2.3)                  0.6
TTR <47%                                                    1.5 (1.1-2.0)                 0.009                               0.05
Aspirin treatment                                           1.2 (0.8-1.8)                  0.3
Anemia (hemoglobin <10 g/dL)                                1.3 (0.7-2.3)                  0.4
Platelet count <100.000/mL                                  2.0 (0.7-5.4)                  0.2
*Calculated with Cockroft-Gault formula.


                                            Bleeding, Thrombosis and Vascular Biology 2022; 1:34
                 Major bleedings in mechanical prosthetic heart valves patients on Vitamin K antagonist treatment                 47



findings. More recently, several studies have demon-                bleeding.27 Moreover, patients of our cohort who experi-
strated that the risk of bleeding outweighs the risk of             enced MB also showed a trend (not statistically signifi-
thromboembolism when standard target INR are main-                  cant) to a higher incidence of several cardiovascular risk
tained,14,15 while it is more balanced when lower INR tar-          factors, such as hypertension, diabetes mellitus, coronary
get are indicated. A recent Sweden study reported a                 artery disease, ischemic cerebrovascular disease. These
bleeding risk of 2.6 per 100 patient-years in patients with         associations could explain, at least in part, the higher mor-
aortic MHV and 3.9 per 100 patient-years in patients with           tality recorded in these patients.
mitral MHV, despite the optimal anticoagulation levels                   In our cohort, among patients with MB, one fifth had
obtained (TTR >70%).16 However, previous data reported              intracerebral bleedings with a rate of 1/500 patient-years,
from the same group, showed elevated median TTR with                and the overall mortality rate of MB was 4.9%. These data
intense anticoagulant treatment among Swedish patients.17           regarding severe events are in contrast with the wide-
As a matter of fact, in this study the Authors reported a           spread trend to avoid the use of MHV due to the fear of
high median INR and high percentage of time spent above             long-term anticoagulation, in favor of the use of biological
the therapeutic range, both these conditions could be as-           valves, that could lead to an elevated risk of re- interven-
sociated with the high bleeding risk found in the study.            tion in particular among patients aged < 65 years.3,5,28 Pa-
    The risk factors significantly associated with bleeding         tients with biological heart valves frequently develop




                                                                                      ly
were the presence of POAD, of AF, a suboptimal antico-              atrial fibrillation, therefore they require long-term antico-




                                                                               on
agulation control expressed by a TTR in the lowest quar-            agulation. It is interesting to note that, among patients
tile, and a history of previous bleeding. In particular,            with biological heart valves enrolled in the PLECTRUM
history of previous bleeding and POAD are the factors               study, we found a bleeding risk similar to that of MHV




                                                                         e
showing the highest ORs for the occurrence of MB. The               patients.28
history of previous bleeding is a well-known risk factor
for bleeding and it is included in most of the published
                                                                  usStudy limitations
bleeding scores.19-21 Therefore, patients who suffered pre-
                                                           al
                                                                        We are aware of the limitations of our study. Firstly,
vious bleeding should be carefully studied to identify and
                                                                    this is an observational retrospective cohort study, and
                                              ci

correct clinical conditions associated with the risk of
                                                                    therefore we could not adjust for clinical information that
bleeding. This observation reinforces the indication to
                                            er


                                                                    were not recorded. Secondly, the observational nature of
make any effort to identify and correct modifiable bleed-
                                                                    the study could have enhanced the risk of underreporting
                                           m



ing risk factors, such as uncontrolled hypertension.22
                                                                    adverse events. However, patients included in the study
Moreover, particular attention should be paid to patients
                                  om




                                                                    were followed by the Anticoagulation Clinics for many
who experienced gastro-intestinal bleeding, who need pe-
                                                                    years, suggesting a stable patient-doctor relation and care-
riodic hemoglobin levels control and occult blood testing,
                                                                    ful adverse event reporting. Moreover, participating Cen-
in addition to a careful use of proton-pump inhibitors.23,24
                             -c




                                                                    ters routinely carry out periodic checks with patients who
    The high bleeding risk of patients with POAD was
                                                                    miss the planned controls.
                     on




previously reported in the ISCOAT study.12 This was con-
firmed later in the WAVE (Warfarin Antiplatelet Vascular
Evaluation) trial among patients randomized to oral anti-
                 N




                                                                    CONCLUSIONS
coagulation and antiplatelet therapy versus antiplatelet
therapy alone, where there was an increase in bleeding                  In conclusion, patients with MHV on long-term oral
endpoints including life-threatening and intracranial               anticoagulation with VKAs followed by Anticoagulation
bleeding.25 The AHA/ACC Guideline on the Management                 Clinics, showed a low bleeding risk. Risk factors associ-
of Patients With Lower Extremity Peripheral Artery Dis-             ated with major bleeding are the presence of POAD, of
ease recommend that anticoagulation should not be used              AF, the history of previous bleeding, and a poor quality
in patients with POAD 26. Enhanced bleeding risk was                of anticoagulation. Patients who experienced MB during
also associated with a suboptimal quality of anticoagula-           anticoagulation are at high risk for death.
tion, in particular in patients with a TTR in the lowest
quartile, whereas only a trend for lower median TTR was
found in bleeding patients. This finding is not surprising          REFERENCES
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