Prevention of thromboembolic events after radical prostatectomy in patients with hereditary thrombophilia due to a factor V Leiden mutation by multidisciplinary coagulation management

Rndi M.Pose,Sophie Knipper ,Jons Ekrutt ,Mr K?lker,b ,Pierre Tennstedt ,Hns Heinzer ,Dery Tilki,b,Florin Lnger,Mrkus Grefen

a Martini-Klinik Prostate Cancer Centre,University Hospital Hamburg-Eppendorf,Germany

b Department of Urology,University Hospital Hamburg-Eppendorf,Germany

c Department of Hematology and Oncology,University Medical Centre Hamburg-Eppendorf,Hamburg,Germany

KEYWORDS Prostate cancer;Prostatectomy;Factor V Leiden mutation;Thromboembolism;Thrombophilia

Abstract Objective: To examine the perioperative impact of factor V Leiden mutation on thromboembolic events’ risk in radical prostatectomy (RP) patients.With an incidence of about 5%,factor V Leiden mutation is the most common hereditary hypercoagulability among Caucasians and rarer in Asia.The increased risk of thromboembolic events is three-to sevenfold in heterozygous and to 80-fold in homozygous patients.Methods: Within our prospectively collected database,we analysed 33 006 prostate cancer patients treated with RP between December 2001 and December 2020.Of those,patients with factor V Leiden mutation were identified.All patients received individualised recommendation of haemostaseologists for perioperative anticoagulation.Thromboembolic complications(deep vein thrombosis and pulmonary embolism) were assessed during hospital stay,as well as according to patient reported outcomes within the first 3 months after RP.Results: Overall,85(0.3%)patients with known factor V Leiden mutation were identified.Median age was 65 (interquartile range: 61-68) years.There was at least one thrombosis in 53(62.4%)patients and 31(36.5%)patients had at least one embolic event in their medical history before RP.Within all 85 patients with factor V Leiden mutation,we experienced no thromboembolic complications within the first 3 months after surgery.Conclusion: In our cohort of patients with factor V Leiden mutation,no thromboembolic events were observed after RP with an individualised perioperative coagulation management concept.This may reassure patients with this hereditary condition who are counselled for RP.

1.Introduction

Prostate cancer is one of the most common male malignancies in the Western world.Here,radical prostatectomy(RP) represents one of the most frequently used treatment options in localised prostate cancer,usually performed as either retropubic open RP (ORP) or robot-assisted RP (RARP) [1].According to current literature,the incidence of venous thromboembolism (VTE) in RP varies depending on the risk group of patients and the respective surgical technique from 0.2% to 0.9% in RARP without pelvic lymph node dissection from 3.9% to 15.7% in ORP with extended pelvic lymph node dissection [2].The corresponding risk of bleeding is indicated as 0.4% in RARP and 0.2% in ORP [2].

With an incidence of about 5%,factor V Leiden mutation is the most common hereditary thrombophilia among Caucasians and less common among African,Southeast Asian,as well as in the indigenous population of Australasian and American [3-5].Activated protein C (APC)-resistance,caused by factor V Leiden mutation [6],was first reported in 1993 by Dahlb?ck et al.[7].In more than 90% of cases,APC resistance is due to a point mutation in the gene encoding factor V,also known as the factor V Leiden mutation or R506Q[3,4].This was first described by Bertina et al.[3].Homozygosity for factor V Leiden mutation occurs in about 1 in 5000 and the risk of VTE is increased three-to seven-fold in individuals heterozygous for factor V Leiden mutation,and up to 80-fold in homozygotes [6,8].APC inactivates factors Va and VIIIa with its cofactor protein S and thus represents an important natural anticoagulant [6].Furthermore,APC indirectly promotes fibrinolysis [6].APC-resistance due to factor V Leiden mutation is found in 20% of unselected patients with first-episode thrombosis,50% of familial thrombosis,and 60% of thrombotic patients known to have normal levels of protein S,protein C,antithrombin,and antiphospholipid antibodies [6].

All RP patients in our clinic receive early mobilisation and take chemical thrombosis prophylaxis with low-molecular-weight heparin from the evening before the planned RP until 4 weeks after the operation in accordance with the National Institute for Health and Care Excellence(NICE,UK) guidelines [9,10].In general,perioperative anticoagulation needs to be individualised,especially in oncological patients for whom pelvic surgery is planned.It is unknown if factor V Leiden mutation patients may be at higher risk of thromboembolic events when treated with RP.Therefore,we aimed at evaluating all patients with known factor V Leiden mutations with regard to surgical outcomes and symptomatic VTE,as well as bleeding complications.

2.Patients and methods

2.1.Study population

Within our prospectively collected database,we analysed a total of 33 006 patients treated with RP in our European Tertiary Care Centre between December 2001 and December 2020.Overall,we identified 85 patients with factor V Leiden mutation in the known medical history who underwent RP.The patients presented to us for RP with an externally confirmed factor V Leiden mutation diagnosis and we did not retest the diagnosis.Written external diagnoses were available for 51(60.0%)of the patients.In the case of 34 patients,these were unspecified diagnoses from doctors’ letters or anamnestic statements.All patients received individualised perioperative pharmacological thromboprophylaxis according to the recommendations by a consulting haematologist.The recommendations ranged from normal pharmacological thromboprophylaxis with low-molecular-weight heparin according to the NICE guidelines[9]for 4 weeks to an extended administration to 5 or 6 weeks for some of the patients.Moreover,in some cases,there was a staggered administration of low-molecular-weight heparin in,for example,prophylactic followed by intermediate,half-therapeutic doses up to an individual coagulation concept in fully anticoagulated patients,as recently described in patients with oral anticoagulation in standard medication [10,11].

Especially,bleeding and(symptomatic)thromboembolic complications (deep vein thrombosis and pulmonary embolism) were assessed during hospital stay,as well as according to patient reported outcomes within the first 3 months after RP.Standardised questionnaires were used for outcome measurements containing explicit questions about thromboembolic events and additional information was obtained from rehabilitation files and other physician’s reports as previously described [12,13].

All RPs (either ORP or RARP) were performed by highly trained surgeons for both surgical approaches.Routinely,during the inpatient stay,an ultrasound examination including an examination of the iliac vessels is performed on all patients in our clinic every 2 days and before discharge.Postoperative laboratory checks are also carried out routinely[10,11].Data assessment was performed using our prospective institutional database(FileMaker Pro 10;FileMaker,Inc.,Santa Clara,CA,USA).All patients agreed on data collection by informed consents.The study was approved by our internal review board(number 2019-PS-38).

2.2.Statistical analyses

The aim of this study was the assessment of peri-and postoperative outcomes,such as the length of surgery,intraoperative blood loss,blood transfusion rate,perioperative complication,length of hospital stay,in hospital complication,and postoperative morbidity.

Descriptive statistics included frequencies and proportions for categorical variables.Means,medians,and ranges were reported for continuously coded variables.For all statistical analyses R software environment for statistical computing (R Foundation for Statistical Computing,Vienna,Austria,version 4.0.3) was used.

3.Results

Basic descriptive patient characteristics are shown in Table 1.According to the respective thromboembolic history,the patients received an individualised perioperative coagulation management concept after consultation with the haematologists.Preoperative information on zygosity,VTE history,pre-existing anticoagulation,use of antiplatelet drugs,relevant co-morbidities,and individualised coagulation management performed are tabulated in Table 2.

Table 1 Basic patient characteristics of the 85 factor V Leiden mutation patients who underwent radical prostatectomy.

Table 2 Factor V Leiden mutation patients (n=85) who underwent radical prostatectomy: distribution of the underlying factor V mutation,pre-existing oral anticoagulation,use of TA,previous thromboembolic diseases,previous diseases of importance to the physiology of coagulation,coagulation management concept determined by a haematologist in consultation.

Overall,85 (0.3%) patients with known factor V Leiden mutation were identified.At least one thrombosis had 53(62.4%)patients and 31(36.5%)patients had at least one embolic event in their medical history (Table 2).The median age was 65 years (interquartile range [IQR]: 61-68 years).The median body mass index was 25.4 (IQR:23.8-28.8) kg/m2;the median intraoperative blood loss was 500(IQR:300-800)mL;the median operation time was 185.2 (IQR: 153.5-210.0) min;and the median hospitalisation time was 8 (IQR: 7-8) days.Pelvic lymph node dissection was performed in 74 (87.1%) patients and 12(IQR: 5-19) lymph nodes were dissected in median(Table 1).The median activated partial thromboplastin time before RP was 29.6(IQR:27.0-31.6)s and thus within the normal range (26.0-36.0 s).The median baseline haemoglobin value was 14.4 g/dL (Table 1).Before discharge,the median haemoglobin value was 11.7 g/dL.Only one(1.2%) patient required intraoperative transfusions.In this patient,the transfusion indication was an intraoperative arterial injury,which ultimately had to be treated by conversion from RARP to ORP with the involvement of the vascular surgery colleagues.Moreover,one (1.2%) patient had documented prolonged haematuria.There were no further complications,such as re-operation or continuous bladder irrigation noted.No patient received a transfusion postoperatively during hospitalisation time.None of the 85 patients with factor V Leiden mutation experienced a thromboembolic complication within hospital stay and the first 3 months after surgery.

4.Discussion

In principle,the major urological procedure RP is associated with a significantly increased risk of bleeding and a moderately increased risk of thrombosis compared to other abdominal and/or urological operative procedures [14,15].In general,90% of postoperative bleeding occurs during the first 4 postoperative days after RP[16].In contrast,the risk of VTE is almost constant during the first 4 postoperative weeks [16].In 2018,Pompe et al.[13]reported a complication rate of less than 0.5% in terms of thromboembolism and stroke in RP patients as well as a transfusion rate of 3.6% in our already published cohort.The current European Association of Urology thromboprophylaxis guidelines designate factor V Leiden mutation as a patient-related risk factor for thromboembolic events [16].Especially in cases with known coagulation disorders,it is important to keep the perioperative risk of patients as low as possible in the context of elective surgery.Firstly,the VTE risk for the individual patient should be as low as possible.Secondly,the risk of bleeding,which could be increased by (therapeutic) anticoagulation,should be as low as possible.

As such a disorder,the pro-thrombotic factor V Leiden mutation was shown to be an independent additional risk factor for VTE in cancer patients (two-to seven-fold increased risk) in the current literature and should therefore be considered in individual thrombosis risk assessment[17,18].However,it is unknown if factor V Leiden mutation patients may be at higher risk of thromboembolic events when treated with RP.Therefore,we aimed at evaluating all patients with known factor V Leiden mutation in terms of surgical outcomes and complications.

Our analyses demonstrated several noteworthy findings.We observed no increased perioperative VTE complication rate.Actually,none of our patients described here showed VTE within 3 months.Especially,since these patients have already had at least one thrombosis in 62.4% and at least one embolism in 36.5% in their medical history (Table 2),this should be emphasised in view of the increased risk of VTE in these special patients.Compared to our recently described cohort [13],the patients presented here did not differ regarding preoperatively assessed parameters (age,prostate-specific antigen,or body mass index).Median intraoperative blood loss and duration of surgery are also in line with the values of our described overall cohort.However,the factor V Leiden mutation cohort showed a slightly longer median hospitalisation time in comparison to our recently described cohort(8 daysvs.6 days).Furthermore,we did not see an increased risk of bleeding under the individualised coagulation management approach,as we did not observe any relevant postoperative bleeding in the described cohort.

Of note,all factor V Leiden mutation patients received an individualised coagulation management concept(Table 2).Accordingly,we have recently shown that RP is safely feasible in patients at increased intrinsic risk of thrombosis,such as those under oral anticoagulation,without increased risk of perioperative thromboembolism[10,11].However,this requires an individualised perioperative coagulation concept[10],which is ideally managed by haematologists.We presented each patient individually for consultation and had an individual concept drawn up(Table 2)to keep both the risk of VTE and bleeding as low as possible.

Several limitations of our study need to be mentioned.First and foremost are the limitations inherent to retrospective analyses including a significant risk of bias and the lack of a control group,i.e.with different anticoagulation management or other coagulation disorders.Second,our cohort included only 85 patients with known factor V Leiden mutation.Additionally,further unknown coagulation disorders may have been present in the overall cohort,especially since the incidence of factor V Leiden mutation in the general population already has reached 5%.However,to the best of our knowledge,we are the first to describe patients with factor V Leiden mutation regarding management before and after RP.Further studies are needed in order to confirm our findings.

5.Conclusion

In our cohort of patients with factor V Leiden mutation,no thromboembolic events were observed after RP with individualised anticoagulation.This may reassure patients with this hereditary condition who are counselled for RP.

Author contributions

Protocol/project development: Randi M.Pose,Sophie Knipper,Hans Heinzer,Markus Graefen.

Data collection or management: Randi M.Pose,Pierre Tennstedt,Derya Tilki,Markus Graefen.

Data analysis: Randi M.Pose,Sophie Knipper.

Manuscript writing/editing:Randi M.Pose,Sophie Knipper,Jonas Ekrutt,Mara K?lker,Hans Heinzer,Florian Langer,Markus Graefen.

Conflicts of interest

The authors declare no conflict of interest.