RU2618402C1 - Method for thrombotic complications prediction after pancreatoduodenectomy in case of pancreas head cancer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: tPA-AG and tPA-act content is determined in pancreatic head cancer patient plasma citrate on the 1st day after pancreatoduodenectomy, and the ratio of tPA-AG/tPA-act is calculated; at its values below 50, thrombosis is predicted in the post-hospital period of 2.5 to 6 months after release, and at values of 50 or higher, post-release period without development of thrombotic complications is predicted.

EFFECT: method allows to objectively assess individual response to pancreatoduodenectomy that will allow timely modification of the treatment regimen.

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Description

The invention relates to medicine, namely to oncology, and can be used to identify patients predisposed to the development of thrombotic complications on the 1st day after pancreatoduodenal resection.

In pancreatic head cancer, the only chance for a favorable treatment outcome is pancreatoduodenal resection or radical surgery, but this does not exclude postoperative complications. There are no single criteria for choosing a treatment method that excludes postoperative complications that begin at the molecular level, then moving on to the cellular, organ, and systemic ones. The relationship of thrombotic complications with cancer has long attracted the attention of scientists. Post-mortem studies have shown that the incidence of venous thrombosis in patients with disseminated tumor processes reaches 40-50% (see Molvar C. Inferior vena cava filtration in the management of venous thromboembolism: filtering the data. Semin Intervent Radiol. 2012 Sep; 29 (3 ): 204-217).

With oncological pathology, the state of hypercoagulation is due to the development of the tumor itself and the concomitant disorders of hemostasis. A dangerous consequence of venous thrombosis can be pulmonary embolism. M.D. Ter-Hovhannesov and A.V. Majuga (2001) considers it natural that the frequency of venous thrombosis in patients with oncopathology increases, leading to an increase in the frequency of pulmonary embolism. According to the authors, surgical treatment, which in itself carries a high risk of developing venous thrombosis and thromboembolism, in combination with an active oncological process, is characterized by a greater risk of developing these formidable complications. Even with the same volume of surgery, the risk of developing thrombosis in cancer patients is more than 3 times higher than in others (see Hillen HFP Thrombosis in cancer patients. Ann Oncol. 2000. VII (Suppl. 3): 273-276. ESMO, 2000. PMID: 11079152).

Other risk factors are such as chemotherapy and hormone therapy, prolonged immobilization of patients, the presence of a permanent venous catheter, the development of inflammation, etc. Most often, venous thrombosis is detected in patients with pancreatic cancer (see Ter-Ovanesov MD, Majuga A.V. Thrombotic complications in oncology: practical experience.Practical oncology. 2001; 5 (1): (March), 25-32; see Maraveyas A. Pancreatic cancer: A model cancer for the study of the therapeutic effects of anticoagulants. World J Gastrointest Oncol. 2009 Oct 15; 1 (1): 38-40). Triggers can be either the body’s own reaction to the development of neoplasia, or more specific factors: the release of highly active tissue thromboplastin and other fibrinolysis activators into the bloodstream, as well as a change in the content of specific procoagulants in the bloodstream (see Ter-Ovanesov MD, Majuga A.V. Thrombotic complications in oncology: practical experience.Practical oncology. 2001; 5 (1): (March), 25-32; see Burris N.A. Low-molecular-weight heparins in the treatment of cancer-associated thrombosis: a new standard of care? 3rd. Semin Oncol. 2006 Apr; 33 (2 Suppl 4): S3-16; quiz S41-42).

In routine blood tests in patients with early forms of pancreatic cancer, usually no abnormalities are detected, in the later stages they show an acceleration of ESR, moderate anemia. In a biochemical blood test, hypoproteinemia is usually determined (see Kulchiev A.A. et al. Surgical diseases. For postgraduate training, Specialty No. 0401226 "Surgery." Textbook. Vladikavkaz 2009. 558 p.). The same authors indicate that determining the level of tumor markers in the blood is much more informative for predicting complications (continued growth after surgery, metastasis). The most sensitive and specific (about 90%) for pancreatic cancer are carbonic anhydrate glycoprotein (CA-19-9) of embryonic origin and CA 494 antigen in the blood.

Unfortunately, these methods are not applicable for predicting complications such as thrombosis after pancreatoduodenal resection in pancreatic cancer. It is necessary to take into account the state of the blood coagulation system, the balance of which with the fibrinolytic system can be disturbed for various reasons (the effect of the underlying disease, concomitant diseases, prolonged drug exposure, immobility of bedridden patients, etc.).

Given the relationship of cancer and coagulation disorders, it is necessary to find criteria for predicting the development of complications such as thrombosis, if possible in the early stages, for the correction of therapeutic regimens. This is especially important in connection with the traumatic effect of surgical treatment, which directly affects endogenous adaptive protective systems, in particular, coagulation and anticoagulation systems.

A known method for the early diagnosis of postoperative complications is acute pancreatitis after operations on the abdominal organs (see Vansovich V.E. Prevention and early diagnosis of acute pancreatitis after operations on the organs of the abdominal cavity. J. Clinical Surgery, 1990, No. 11). The diagnosis was made on the basis of the clinical picture and a number of traditional clinical tests (determination of amylase, lipase, protein, sugar, bilirubin, urea, alkaline phosphatase, etc.).

However, the present study was conducted in the analysis of the clinical material of patients with advanced postoperative complication - pancreatitis and its results were used to diagnose an existing complication. The author did not present the results of using the identified criteria for an early forecast of the development of this complication. Not included in the risk group and patients who are predisposed to the development of this complication. Other complications were not predicted by the authors.

A known method for determining biochemical markers of early diagnosis of postoperative pancreatitis as complications after surgery in blood serum and urine in cancer patients (see Gunina L.M. et al. Biochemical criteria for early diagnosis of postoperative pancreatitis in cancer patients. J. Clinical Surgery, 1991 No. 50). 68 out of 88 patients with oncological diseases of the abdominal cavity had an operative trauma or pancreatic resection. Biochemical parameters in blood and urine were determined (amylase activity, blood alanine aminotransferase, bilirubin, total protein, medium molecular weight peptides (PSMM) and kinin system components with inhibitors). A slight increase in serum amylase activity was detected in 82.6% of patients with postoperative pancreatitis on days 1, 3-5, 7-8 after surgery. Hyperamilazuria at the same time was noted in only 33% of all cases of acute postoperative pancreatitis. The activity of kallikrein was increased, and the content of prekallikrein was reduced, the activity of inhibitors was reduced. The authors consider the indicator "peptides of average molecular weight" to be the most informative indicator for early diagnosis of this complication.

However, as noted by the authors themselves, the increase in enzyme activity, as a rule, was insignificant, especially against the background of ongoing intraoperative drug prophylaxis. The informativeness of the “PSMM” indicator for the early postoperative prognosis of acute pancreatitis was revealed.

This method was not used for the diagnosis and prognosis of other types of complications after surgery on the abdominal organs, in particular for the prognosis of postoperative thrombosis after pancreatoduodenal resection.

In the dissertation M.A. Bernshtein (see Bernshtein MA Diagnosis and treatment of functional disorders of the digestive system after pancreatoduodenal resection. Diss. ... Candidate of Medical Sciences, St. Petersburg, 2010, 125 pp.) The diagnostic significance of determining the pancreatic elastase-1 enzyme was evaluated as an indicator of exocrine pancreatic function. The author systematized the concept of the morphofunctional state of the liver, pancreas, and upper gastrointestinal tract after pancreatoduodenal resection. Based on extensive clinical material, the author has studied the feasibility of using and the diagnostic value of determining the level of pancreatic elastase-1 for assessing exocrine pancreatic function after pancreatoduodenal resection. In addition to assessing the functions of the resected pancreas, other digestive organs were evaluated depending on the type of pancreatoduodenal resection, which will help in their medical correction.

However, this study did not investigate factors by which it is possible to predict the development of postoperative thrombosis during pancreatoduodenal resection.

In a detailed review of M.D. Ter-Hovhannesova and A.V. Majugi (see Ter-Ovanesov MD, Majuga A.V. Thrombotic complications in oncology: practical experience. Practical oncology. 2001; 5 (1): (March), 25-32), which we selected as a prototype, a detailed analysis of the factors leading to postoperative thrombosis is given. The authors believe that postoperative patients should be monitored and upcoming changes in coagulation and anticoagulation indices should be detected.

This makes a lot of sense, but you have to spend considerable time on such examinations. In addition, the process is somewhat cumbersome, because it is associated with difficulties in recording patients with a remote location, and often blood changes are recorded too late. Finally, the authors did not attempt to predict the development of postoperative thrombosis immediately after surgery, in 1-2 days.

The literature data emphasize the presence of high reactivity of the cardiovascular system in response to hyperfermentemia, which, ultimately, allows you to diagnose acute postoperative pancreatitis and some other complications in the early stages after surgery by a comprehensive examination of the patient. However, none of the criteria used allows predicting the development of postoperative thrombosis 1-2 days after pancreatoduodenal resection. In the available literature, we also did not find information about the early prognosis of postoperative thrombosis.

The balance of biochemistry “coagulation / fibrinolysis” depends on many factors and is crucial in maintaining blood rheology in cancer, in particular for pancreatic cancer. The content and activity of tPA, a tissue plasminogen activator or thromboplastin, which is synthesized in the vascular endothelium, blood and liver cells, has a great influence on the balance of these systems. Normally, tPA is contained in the blood in the form of an inactive proenzyme (tPA-AG, antigenic form), the amount of active thromboplastin (tPA-act) tends to zero. In injuries, including operating ones, the amount of tPA-act increases somewhat and depends on the degree of activation of the enzyme, in which way the activation of coagulation will go - intensify or slow down.

The technical result of the invention is the prediction of the development of thrombotic complications after pancreatoduodenal resection in pancreatic head cancer due to the identification on the 1st day after pancreatoduodenal resection of the patient's individual predisposition to the development of thrombotic complications in the post-hospital period.

The goal is achieved by the fact that on the 1st day after pancreatoduodenal resection in a citrated blood plasma, the tPA-AG and tPA-act content is determined, their ratio tPA-AG / tPA-act ratio is calculated and, with its value below 50, thrombosis development is predicted in the period from 2.5 to 6 months after discharge, and with its value of 50 and above, the course of the period after discharge is predicted without the development of thrombotic complications.

The invention "A method for predicting the development of thrombotic complications after pancreatoduodenal resection in pancreatic head cancer" is new, since it is not known from the level of medical advances in predicting the development of thrombosis in the post-hospital period.

The novelty of the invention lies in the fact that on the 1st day after pancreatoduodenal resection in the patient’s blood, tPA-AH and tPA-act are determined, the ratio of their ratio “tPA-AG / tPA-act” is calculated, and if the value is below 50, the presence of an individual predisposition is detected to postoperative thrombotic complications, and at a value of 50 and above, the course of the postoperative period without thrombotic complications is predicted.

In open sources of information from Russia, the CIS countries and abroad, no indications of a similar method for predicting the development of thrombotic complications in the post-hospital period have been found.

The invention is industrially applicable, as it can be reproduced and repeated many times in any clinical laboratory of medical institutions of the healthcare system.

The method is as follows.

On the 1st day after surgery, the patient is sampled in a test tube with 3.8% sodium citrate in a ratio of 9: 1 to obtain a citrated blood plasma. Citrate blood is centrifuged, citrate plasma is obtained and used to determine t-PA on the same day. The determination is carried out by ELISA using the "t-PA Combi Actibind ELISA Kit", designed to quantify the concentration of antigen and activity of human tissue plasminogen activator (t-PA) in plasma samples (citrate or EDTA) by enzyme-linked immunosorbent assay (tPA Cat. No. : TS 16000].

The principle of the method. The method is based on the use of antibodies that do not affect the functional activity of tPA and are immobilized in the wells of the microplate. They are used to bind tPA contained in plasma to the surface of the wells. After the first incubation, unbound plasma components are removed by washing, then a substrate solution for determining activity containing Glu plasminogen, CNBr fragments of fibrinolysis and a chromogenic plasmin substrate is added to the wells. As a result of the reaction between the plasmin and the chromogenic substrate of the plasmin, a colored product is formed. The intensity of the developed staining, proportional to the amount of tPA-act in the test sample, is measured photometrically. After measurement, the solution for determining the activity is removed by washing, and tPA-AG remains bound to antibodies adsorbed in the wells of the microplate; therefore, a conjugate of monoclonal antibodies to tPA recognizing both forms of tPA is added to the wells. At the end of the incubation with antibodies and washing, horseradish peroxidase (POC) is added to the wells, resulting in a colored product. Staining intensity is proportional to the concentration of tPA in the test sample. Solutions for performing the method are standardized by the manufacturer and with adequate sample preparation, reproducibility of 90-95% is ensured.

The analysis requires conventional ELISA equipment.

As examples, we provide extracts from the medical history.

1. Patient M., date of birth 01/05/1958. Department of Abdominal Oncology No. 1: extract from the medical record of an inpatient.

Date of receipt: 05/23/2014.

Complaints at admission: On the presence of cholangiostomy in the right hypochondrium, inconvenience, poor appetite, weakness, weight loss.

Objective (local) status: lymph nodes, accessible palpations are not enlarged, Shchetkin's symptom is negative, abdomen is soft, painless on palpation.

CT scan dated May 19, 2014. Pancreatic head cancer 4.4 × 3.5 cm with germination in the duodenum. The Wirsung duct is expanded to 0.7 cm. The cyst of the right lobe of the liver is up to 1.8 cm, the state after CCC. The structure is diffuse-heterogeneous, retroperitoneal lymph nodes are not enlarged.

Verification of the process (histological analysis) is a moderately differentiated ductal adenocarcinoma with infiltrative growth, stromal fibrosis, marked necrosis.

Ultrasound: 05/06/2014, Hepatosplenomegaly. Diffuse changes in the liver parenchyma. Chronic cholecystitis. Neoplasm in the head of the pancreas. Choledochoectasia, expansion of the main pancreatic duct. Condition after percutaneous transhepatic cholangiostomy. Hyperplasia of the retroperitoneal lymph nodes in the epigastrium.

FDS: May 16, 2014. ulceration in the postbulbar part of the duodenum, covered with necrotic masses. Gastritis RN-6.0

ECG: from 05/05/14, Left ventricular hypertrophy.

05/25/2014 - operation under TVA + mechanical ventilation - pancreato-duodenal resection (PDR).

Final diagnosis Pancreatic cancer T ₃ N ₁ M ₀ , st III, cl. column 2 (s-25).

At 1 day after the PDR: tPA-AG = 10.21 ng / ml of blood plasma; tPA-act = 0.472 units / ml of blood plasma. Coefficient (K) tPA-AG / tPA-act = 21.6.

They suggested a risk of increased thrombosis in the circulation.

Anticoagulant therapy was prescribed for the period of inpatient treatment.

For control on day 7, citrate plasma was re-taken, results: tPA-AG = 8.261 ng / ml of blood plasma; tPA-act = 0.327 units / ml of blood plasma. K = 25.3

It is concluded that it is necessary to continue anticoagulant therapy in the hospital and after discharge at the place of residence.

06/20/2014. discharged without complications, in satisfactory condition. At the control inspection did not appear. Death in August 2014. Complication: thrombosis of the lower extremities.

2. Patient S., date of birth 01/05/1939. Department of Abdominal Oncology No. 1 RNII: extract from the medical record of a hospital patient.

Date of admission to the hospital 09/26/2014.

Complaints on admission to pain in the right hypochondrium, weight loss, general weakness.

Previous treatment: 05/05/2014 surgery - percutaneous, transhepatic cholangiostomy.

On September 17, 2014, an operation was performed - under local anesthesia, stenting of the bile ducts under ultrasound and X-ray control. 09/18/2014, plasmapheresis was performed.

Blood group B (III) third Rh (-) negative.

RW, HIV infection and viral hepatitis are negative, dated 09.16.2014.

ECG from 10/01/2014 when compared with an ECG from 09/15/2014, conclusion: sinus normosystole is noted; some improvement in recovery processes in the myocardium of the posterior parts of both ventricles. There are no rhythm disturbances, the rest of the data is the same.

FLO from 09.15.2014, conclusion: heart and lungs without pathology.

FDS dated 09/30/2014, conclusion: Cancer of the large duodenal papilla, with a possible spread to the surrounding fiber (sprouting from the outside?). Condition after stenting of the bile ducts and percutaneous transhepatic cholangiostomy. Atrophic gastroduodenitis with symptoms of intestinal metaplasia. Duodeno-gastric reflux. Xanthomas of the stomach. RN-5.5 Nr - (-).

СРКТ of the organs of the chest, abdominal cavity and pelvis from 08/01/2014, conclusion: lungs without foci. Pancreas - a cystic heterogeneous formation is determined in the projection of the head: tumor 42 × 41 mm without germination in the surrounding tissue. Common pancreatic duct up to 2.7 mm. Gall bladder - stones up to 24.4 mm, retroperitoneal lymph nodes are not enlarged. The mucosa of the duodenum 12 is infiltrated, compacted to 14 mm.

Ultrasound of the abdominal organs 08/01/2014, conclusion: tumor pancreas, obstructive jaundice, calculous cholecystitis, splenomegaly.

Consultation of a chemotherapist RNII from 10.21.2014, conclusion: considering T ₃ N ₀ M ₀ , patient's age, polychemotherapy is not included in adjuvant treatment. Recommended: observation. After 1 month, perform abdominal cavity, abdominal, and pelvic organ CTGS to resolve the issue of further tactics (at the place of residence).

Consultation of a general practitioner of RNII from 09.15.2014, conclusion: coronary heart disease, angina, F.K.2. Tax Code I degree.

Verification of the process (histological analysis): 75137-40 / 14 G2 adenocarcinoma with invasion of the duodenal wall.

The performed treatment: under the conditions of OJSC No. 1 of the RNII 02.10.2014, an operation was performed - laparotomy, pancreatoduodenal resection with expanded lymphadenectomy, cholecystectomy, epicystostomy.

Final diagnosis: pancreatic head cancer, St IIA, T ₃ N ₀ M ₀ , condition after stenting of the bile ducts, class. column 2.

Concomitant diagnosis: CHD, angina pectoris, F.K. 2. Tax Code I degree. Cicatricial stricture of the neck of the bladder.

On the 1st day after the PDR: tPA-AG = 2.846 ng / ml of blood plasma; tPA-act = 0.051 units / ml of blood plasma. Coefficient (K) tPA-AG / tPA-act = 55.8.

They suggested that there was no risk of thrombosis in the circulation.

For control on day 7, citrate plasma was re-taken, results: tPA-Ar = 2.252 ng / ml of blood plasma; tPA-act = 0.033 units / ml of blood plasma. Coefficient (K) tPA-AG / tPA-act = 68.2.

It is concluded that there is no need for anticoagulant therapy.

In the postoperative period, detoxification, cardiotropic, antibacterial therapy was carried out, a course of adjuvant chemotherapy was carried out - gemcitabine 1000 mg intravenously, drip.

10.24.2014 statement: in satisfactory condition.

Recommended: follow-up examination after one month.

Inspections: 12/02/14; 02/09/15; 04/07/15; 06/08/15.

Last appearance for examination: 07/14/15 - the patient feels well, no signs of thrombosis were detected.

We examined 62 patients with pancreatic head cancer who were undergoing treatment at the Department of Abdominal Oncology of the Federal State Budgetary Institution "RNII" of the Ministry of Health of Russia. All patients underwent pancreatoduodenal resection.

To assess the state of the blood coagulation system, in connection with pancreatic head cancer and exposure to pancreatoduodenal resection, tPA was determined on the 1st day and a control study was performed on the 7th day, the coefficient tPA-AG / tPA-act was calculated, the obtained numbers were compared with the norm. The norm was considered the tPA-AG and tPA-act value, as well as the coefficient of their ratio tPA-AG / tPA-act in the blood plasma of healthy donors (table below), obtained from the Rostov-on-Don blood transfusion station. Donor gender and age differences have not been established.

In the blood plasma of 8 patients, 1-2 days after pancreatoduodenal resection according to the SI system:

tPA-AG from 7.256 ng / ml to 11.76 ng / ml, on average 8.617 ± 0.4 ng / ml;

tPA-act from 0.210 units / ml to 0.632 units / ml, on average 0.347 ± 0.02 units / ml;

coefficient tPA-AG / tPA-act from 21.5 to 42.3 - an average of 24.8.

The tPA-AH values in the blood plasma of these 8 patients on the 1st day after pancreatoduodenal resection exceeded the norm from 1.5 times to 2.4 times. The tPA-act values of 8 patients from the “Thrombosis” group were above the norm from 26.3 to 43.4 times, the tPA-AG / tPA-act coefficient was below the norm from 13.2 to 25.9 times.

On the 7th day, the results changed, but no significant differences from the 1st day were found (data in the table).

In the blood plasma of the remaining 54 patients, the results of the tPA study on the 1st day showed:

tPA-AG from 1.169 ng / ml to 6.696 ng / ml, on average 2.428 ± 0.1 ng / ml;

tPA-act from 0.015 units / ml to 0.33 units / ml, on average 0.026 ± 0.002 units / ml;

tPA-AG / tPA-act from 55.8 to 104.7, an average of 93.7 ± 4.9.

A retrospective analysis allowed us to conclude that the observed changes in the total activity of trypsin-like proteinases in 54 patients without the development of postoperative thrombosis (group “Without thrombosis”) had values of the coefficient tPA-AG / tPA-act above 50.

A control study of blood plasma on day 7 confirmed the results. In 8 patients, with subsequently developing thromboses and united in the “Thrombosis” group, on the contrary, tPA-AG / tPA-act values below 50 were observed at 1-2 days after pancreatoduodenal resection, on the 7th day the data were confirmed. We tried to predict the development of thrombosis after pancreatoduodenal resection according to 1 day, since an early prognosis will allow us to take the necessary preventive measures in time for the correction of therapeutic regimens immediately after surgery. The results were reproducible by 87.1% for the group “Thrombosis” and by 93.5% for the group “Without thrombosis”.

For convenience, the data are summarized in the table:

Studies of blood plasma on the 7th day were undertaken solely to monitor the condition of the blood coagulation system of the patient and verify the results.

The technical and economic efficiency of the method lies in its high specificity, the possibility of an objective assessment of an individual reaction to pancreatoduodenal resection, analysis on the day of blood collection, which will allow timely change of treatment regimen.

The specificity of the method for predicting the course of the post-hospital period without the development of thrombosis is 93.5%, for predicting the development of thrombosis in the post-hospital period is 87.1%.

Claims (1)

A method for predicting the development of thrombotic complications after pancreatoduodenal resection in pancreatic head cancer, including a blood test, characterized in that on the 1st day after pancreatoduodenal resection in the citrated blood plasma, the content of tPA-AH and tPA-act are determined, and the ratio of their ratio tPA- is calculated AT / tPA-act and with its value below 50 predict the development of thrombosis in the period from 2.5 to 6 months after discharge, and with its value of 50 and higher predict the course of the period after discharge without development of thrombotic x complications.