Clinical trial NCT04517461: Coagulation and Vitamin K in Head and Neck Microvascular Free Flap Surgery
Official title: Coagulation and Vitamin K in Head and Neck Microvascular Free Flap Surgery
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Head and Neck Cancer
Intraoperative Complications
Coagulation Disorder, Blood
Vitamin K Deficiency
Thrombosis
Anticoagulants and Bleeding Disorders
Head and Neck Procedural Complication
Lead sponsor: Region Skane
Sponsor class: OTHER
First posted: 2020-08-18
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: All patients that present at, or are referred to, the Department of Otorhinolaryngology - Head and Neck Surgery at Skåne University Hospital in Lund with conditions requiring head and neck surgery including resection and reconstruction with a microvascular free flap. This includes patients from the entire southern health care region, "Södra sjukvårdsregionen".

Brief summary: For patients with large head and neck tumors the recommended treatment, in many cases, is a combination of extensive surgery and postoperative radiotherapy. The surgical procedure involves resection of the tumor and reconstruction with a so called microvascular free flap, i.e. tissue transferred from for instance the arm or leg to the resection site. Complications of this complex procedure include, but are not limited to, bleeding and blood cloths (thrombosis) in the transferred tissue (free flap), which can cause very serious complications including need for further surgery and loss of the flap.

Routine blood tests can measure parts of the system that regulates bleeding and the forming of blood clots, the so called coagulation system, but these tests don't cover the whole system. There are however more advanced instruments, such as ROTEM, rotational thromboelastometry, which provide a more global view of the hemostatic potential of whole blood. ROTEM is one of few more advanced assays that can be analyzed in emergency situations in major hospitals. Other more advanced coagulation assays are thrombin generation and measurements of specific coagulation factors, several of which are vitamin K dependent. Vitamin K is essential in the coagulation system and also involved in many other physiological processes. Deficiency of this vitamin is common, but not well studied in patients undergoing head an neck free flap surgery.

The investigators plan to study ROTEM and other above mentioned coagulation parameters in patients undergoing major head and neck surgery including microvascular free flap reconstruction to assess if these parameters can help predict patients at risk for bleeding or flap thrombosis. Further on this could hopefully enable prevention of complications and improve treatment of coagulation complications that still occur.

Detailed description: Microvascular reconstructive free flap surgery is an important part of the recommended treatment for extensive head and neck tumors. However, the procedure includes risks of perioperative coagulation related complications, such as bleeding, but also thrombosis in the flap blood vessels. In about 10% of cases this requires reoperation, but, in spite of intense efforts, about 5% of all patients suffer from flap failure, i.e. necrosis of the free flap. This results in significant suffering for the patients who must undergo further surgery and oftentimes considerable prolonged hospital stay etc. This in turn leads to increased health care costs. There are several indications that tendency towards thrombosis can increase the risk of flap failure.

Previous studies have indicated that increased levels of fibrinogen and inherited thrombophilia, such as APC resistance, are associated with thrombotic free flap complications, but more conventional coagulation parameters, such as PK/INR and aPTT have not shown the same connection. Low fibrinogen levels have also been associated with bleeding complications.

Most patients undergoing the above mentioned surgery receive anticoagulant therapy. However, there is no international consensus on any specific pharmacological regime. Many different prophylactic therapies are used, including low molecular weight heparin, dextran and acetylsalicylic acid. Still coagulation-related complications are difficult to prevent.

Defective coagulation apparently seems to be associated with bleeding and thrombotic perioperative complications. It would therefore be desirable to increase the knowledge about factors influencing the development of these complications, and the patients at risk for them. ROTEM, rotational thromboelastometry, is a viscoelastic essay that provides a more global view of the hemostatic potential in whole blood, and it is also one of few more advanced assays that can be analyzed around the clock in many Swedish hospitals.

The aim of this project is to study perioperative coagulation and vitamin K status, and thereby further on hopefully be able to prevent, and improve the treatment of, bleeding and thrombosis related complications in patients undergoing head and neck microvascular free flap surgery.

Eligibility criteria: Inclusion Criteria:

* Patients undergoing head and neck surgery including resection and reconstruction with a microvascular free flap at Skåne University Hospital in Lund, Sweden, who accept participation in the study.

Exclusion Criteria:

* Age under 18 years.
* Inability to understand information or make an informed choice about participation.
* Hospitalization \> 24 h prior to primary surgery.

Primary outcomes:
measure: Perioperative changes in ROTEM MCF EXTEM
timeFrame: Day 0 to day 6
Secondary outcomes:
measure: Perioperative changes in ROTEM Clotting time
timeFrame: Day 0 to day 6
measure: Perioperative changes in ROTEM Clot Formation Time
timeFrame: Day 0 to day 6
measure: Perioperative changes in ROTEM alpha angle
timeFrame: Day 0 to day 6
measure: Perioperative changes in ROTEM Lysis Index 60
timeFrame: Day 0 to day 6
measure: Perioperative changes in ROTEM Maximum Clot Firmness
timeFrame: Day 0 to day 6
measure: Perioperative changes in prothrombin time
timeFrame: Day 0 to day 6
measure: Perioperative changes in activated partial thromboplastin time
timeFrame: Day 0 to day 6
measure: Perioperative changes in thrombocyte levels
timeFrame: Day 0 to day 6
measure: Perioperative changes in thrombin generation; lag time
timeFrame: Day 0 to day 6
measure: Perioperative changes in thrombin generation; peak thrombin
timeFrame: Day 0 to day 6
measure: Perioperative changes in thrombin generation; area under the curve
timeFrame: Day 0 to day 6
measure: Perioperative changes in specific coagulation factors; protein C (kIU/L)
timeFrame: Day 0 to day 6
measure: Perioperative changes in specific coagulation factors; protein S
timeFrame: Day 0 to day 6
measure: Perioperative changes in specific coagulation factors; fibrinogen
timeFrame: Day 0 to day 6
measure: Perioperative changes in specific coagulation factors; antithrombin
timeFrame: Day 0 to day 6
measure: Perioperative changes in fibrinolytic activation
timeFrame: Day 0 to day 6
measure: Perioperative changes in the vitamin K-dependent protein Gas6
timeFrame: Day 0 to day 6
measure: Perioperative changes in the vitamin K-dependent protein dp-uc-MGP
timeFrame: Day 0 to day 6
measure: Perioperative changes in the vitamin K-dependent protein Axl-receptor
timeFrame: Day 0 to day 6
measure: Perioperative changes in the vitamin K-dependent protein PIVKA-II
timeFrame: Day 0 to day 6
measure: Coagulation related complications
timeFrame: Day 0 until end of hospital stay or a at the latest day 30 days after the primary operation.
measure: Perioperative changes in ROTEM FIBTEM Maximum Clot Firmness
timeFrame: Day 0 to day 6
measure: Perioperative changes in ROTEM INTEM Clotting Time
timeFrame: Day 0 to day 6
Other outcomes:
Locations:
city: Lund
country: Sweden
facility: Region Skåne
state: Skåne
Study officials:
affiliation: Skane University Hospital
name: Caroline U Nilsson, MD, PhD
role: STUDY_CHAIR
References:
citation: Cervenka B, Bewley AF. Free flap monitoring: a review of the recent literature. Curr Opin Otolaryngol Head Neck Surg. 2015 Oct;23(5):393-8. doi: 10.1097/MOO.0000000000000189.
citation: Copelli C, Tewfik K, Cassano L, Pederneschi N, Catanzaro S, Manfuso A, Cocchi R. Management of free flap failure in head and neck surgery. Acta Otorhinolaryngol Ital. 2017 Oct;37(5):387-392. doi: 10.14639/0392-100X-1376.
citation: Kolbenschlag J, Daigeler A, Lauer S, Wittenberg G, Fischer S, Kapalschinski N, Lehnhardt M, Goertz O. Can rotational thromboelastometry predict thrombotic complications in reconstructive microsurgery? Microsurgery. 2014 May;34(4):253-60. doi: 10.1002/micr.22199. Epub 2013 Oct 21.
citation: Lison S, Weiss G, Spannagl M, Heindl B. Postoperative changes in procoagulant factors after major surgery. Blood Coagul Fibrinolysis. 2011 Apr;22(3):190-6. doi: 10.1097/MBC.0b013e328343f7be.
citation: Handschel J, Burghardt S, Naujoks C, Kubler NR, Giers G. Parameters predicting complications in flap surgery. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013 May;115(5):589-94. doi: 10.1016/j.oooo.2012.09.007. Epub 2012 Dec 12.
citation: Kolbenschlag J, Diehm Y, Daigeler A, Kampa D, Fischer S, Kapalschinski N, Goertz O, Lehnhardt M. Insufficient fibrinogen response following free flap surgery is associated with bleeding complications. GMS Interdiscip Plast Reconstr Surg DGPW. 2016 Nov 22;5:Doc22. doi: 10.3205/iprs000101. eCollection 2016.
citation: Zhou W, Zhang WB, Yu Y, Wang Y, Mao C, Guo CB, Yu GY, Peng X. Are antithrombotic agents necessary for head and neck microvascular surgery? Int J Oral Maxillofac Surg. 2019 Jul;48(7):869-874. doi: 10.1016/j.ijom.2018.10.022. Epub 2018 Nov 26.