Risk factors for hypercoagulability after laparoscopic hepatic haemangioma resection

Abstract

Background:

Laparoscopic hepatectomy with a small incision, light abdominal wall trauma and rapid postoperative recovery has been widely used in the surgical treatment of benign liver diseases. However, the occurrence of complications, such as deep-vein thrombosis, associated with laparoscopic techniques has raised concerns. This study aimed to investigate the factors influencing the development of a hypercoagulable state in patients following laparoscopic hepatic haemangioma resection.

Materials and Methods:

Between 2017 and 2019, 78 patients to be treated by laparoscopic hepatic haemangioma resection were selected prospectively for the study. The differences in relevant clinical factors between patients with and without blood hypercoagulability at 24 h after surgery were compared, and the factors influencing the development of blood hypercoagulability after surgery were analysed.

Results:

The study included 78 patients, split into the hypercoagulable group (n = 27) and nonhypercoagulable group (n = 51). Compared with patients who did not develop blood hypercoagulability, patients who did had significantly higher preoperative levels of fibrinogen (Fib), D-dimer (D-Di), fibrinogen degradation products (FDP), platelet count (PLT), low-density lipoprotein cholesterol (LDL-C) and history of hyperlipidaemia whereas high-density lipoprotein cholesterol (HDL-C) levels were significantly lower (P < 0.05.) in hypercoagulable group. Univariate and multifactorial logistic regression analyses showed that a history of hyperlipidaemia, Fib ≥3.83 g/L, D-Di ≥9.12 μg/ml, FDP ≥14.64 μg/ml, PLT ≥292 × 10⁹/L, HDL-C ≥1.25 mmol/L and LDL-C ≥2.03 mmol/L was the most common independent risk factors for the development of a hypercoagulable state of blood in patients after laparoscopic hepatic haemangioma resection (P < 0.05).

Conclusion:

For patients undergoing laparoscopic hepatic haemangioma resection, attention should be paid to the development of a hypercoagulable state in those with the risk factors described in this study.

INTRODUCTION

Hepatic cavernous haemangioma (HCH) is the most common benign tumour of the liver, accounting for 73% of all benign liver tumours.[1,2] With a prevalence of 0.4%–7.3% in adults and an autopsy incidence of 3%–20%, HCH occurs more commonly in adult females.[3,4] Small hepatic haemangiomas are mostly asymptomatic, do not require treatment and are often observed through follow-up imaging. However, large or rapidly growing hepatic haemangiomas can cause symptoms such as abdominal pain, feeling of fullness, nausea, vomiting and dyspepsia. Rarely, serious manifestations such as cholestasis, ascites, biliary haemorrhage and Kasabach–Merritt syndrome occur,[5] and in these cases, surgical removal of the hepatic haemangiomas is an effective measure.

Laparoscopic hepatic haemangioma resection has been widely used as a surgical treatment because of its advantages of minimal trauma and rapid recovery;[6] however, it also has its own disadvantages. Increased plasma fibrinogen levels; significant increases in fibrin (Fib) and fibrinogen degradation products (FDP) due to increased pro-aggregation and procoagulation factors in the patient’s blood and impaired antiaggregation, anticoagulation and fibrinolytic mechanisms; venous stasis; hypoproteinaemia; hyperlipidaemia; haemoconcentration; increased blood viscosity and use of hormones and diuretics,[7,8] ultimately lead to increased levels but reduced activity of protein C and protein S, resulting in a hypercoagulable state. Paolillo V and Madhusudhan et al.[9,10] have reported that large haemangiomas can cause compression of the bile ducts, portal veins or inferior vena cava, causing the formation of a hypercoagulable state of blood and leading to the development of pulmonary embolism, especially very large haemangiomas can cause the formation of deep vein thrombosis (DVT) in the lower extremities. However, there are no prospective, randomised, controlled trials to assess the risk of post-operative hypercoagulation in patients undergoing hepatectomy for other benign hepatic tumours. However, there are some retrospective studies have established the incidence of blood hypercoagulation and venous thromboembolism (VTE) after hepatectomy.[11-14] It is reported that factors such as age, history of hyperlipidaemia, high preoperative systolic blood pressure, high preoperative low-density lipoprotein cholesterol (LDL-C) levels, CO₂ pneumoperitoneum and surgical position and approach.[15,16] In addition, DVT and subcutaneous emphysema increase the risk of inducing post-operative blood hypercoagulability. In addition, DVT and subcutaneous emphysema increase the risk of inducing post-operative blood hypercoagulability.

Due to the factors such as hyperlipidaemia in patients before laparoscopic hepatic haemangioma resection, high intraoperative bleeding and post-operative liver insufficiency, it is easy to cause the formation of hypercoagulable state of blood in patients after hepatectomy, mainly including the formation of DVT and pulmonary embolism (PE).[12,17] It seriously affects the prognosis and survival quality of patients and is also not conducive to the optimal allocation of social medical resources. Therefore, it is important to understand the patient’s own condition, surgery-related and other morbidity factors for comprehensive judgement before surgery and formulate reasonable thromboprophylaxis measures after surgery to improve the patient’s post-operative hypercoagulable state, to reduce the incidence of VTE. At present, there is a lack of important molecular markers that predict the development of a hypercoagulable state in patients after hepatic haemangioma resection, and there are few studies on factors that influence the development of this state in patients after laparoscopic hepatic haemangioma resection. This study will focus on these markers and factors and provide evidence for the prevention and treatment of a hypercoagulable state.

MATERIALS AND METHODS

Study design and registration

This retrospective single-centre randomised controlled trial was designed and conducted in the Department of Hepatobiliary Surgery, the Affiliated Hospital of Southwest Medical University, China, and the study protocol was approved by the China Clinical Trials Registry Ethics Committee (Number: ChiCTR2100054265) and supported by the Ethics Committee of the Affiliated Hospital of Southwest Medical University (Number: KY2021279), and the clinical investigators have good training experience in clinical practice and all play a special role in this study individually.

Patient screening and eligibility

We retrospectively selected 78 patients who came to our hospital for laparoscopic hepatic haemangioma resection from August 2017 to December 2019. According to the presence or absence of a hypercoagulable state 24 h after surgery, patients were divided into the hypercoagulable group (n = 27) and nonhypercoagulable group (n = 51). There were 12 male and 15 female cases in the hypercoagulable group, and these patients ranged in age from 35 to 75 years old (mean ± Standard deviation [SD] = 48.93 ± 8.98). There were 13 males and 38 females in the nonhypercoagulable group, and these patients ranged in age from 37 to 68 years old (mean ± SD = 50.75 ± 8.25) [Figure 1].

Figure 1.

Flowchart of patient section in the laparoscopic hepatic haemangioma resection trial. PLT: Platelet count, Fib: Fibrinogen, D-Di: D-dimer, HDL-C: High-density lipoprotein cholesterol, LDL-C: Low-density lipoprotein cholesterol

Inclusion criteria

(i) The patients had to meet the indications for laparoscopic hepatic haemangioma resection; (ii) could not suffer from other serious organ diseases; (iii) must have signed informed consent for the study and for laparoscopic hepatic haemangioma resection; (iv) had to have provided complete patient details.

Exclusion criteria

(i) Hepatic malignancy; (ii) patients combined haematologic disorders and coagulation abnormalities; (iii) missing or incomplete follow-up data; (iv) anticoagulant drug administration within the week before surgery. Clinical assessment of DVT risk was performed according to the Wells score system.[18] Patients with a Wells score of >2 warrant ultrasound examination of their legs to verify DVT.

Routine coagulation tests are recommended for hypercoagulopathy

Routine coagulation tests include (i) assessment of the exogenous coagulation system based on measurement of PT or the International Standardized Ratio (INR); (ii) assessment of the endogenous coagulation system based on measurement of activated partial thromboplastin time (APTT); (iii) assessment of the common coagulation pathways based on measurement of thrombin time (TT) and fibrinogen levels; (iv) assessment of the fibrinolytic system based on assays of D-dimers (D-Di) and FDPs and (v) estimation of the platelet count (PLT). Previous studies have recommended that patients whose PT >18s, INR >1.5, APTT >60s or TT >15s can be diagnosed as nonhypercoagulation, without the influence of anticoagulant drugs or abnormal blood specimens.[19-21]

Measuring methods

The clinician recorded each patient’s age, sex, body mass index (BMI), smoking and alcohol habits, history of hypertension, diabetes and hyperlipidaemia. Measurements of pre-operative systolic and diastolic blood pressure were recorded in detail on the basis of medical record information and clinical examination. Drawing 2–10 mL of preoperative fasting venous blood, the RT7200Q automatic haematology analyser from Shenzhen Radu Company and the AU2700 automatic biochemical analyser from Olympus Company, Japan, were used to detect each biochemical index, including molecular markers fib, PLT, D-Di, high-density lipoprotein cholesterol (HDL-C) and LDL-C levels. Of these, D-Di was detected by double-antibody sandwich enzyme-linked immunosorbent assay; Fib and FDP were detected by immunoturbidimetric method; BMI was calculated using the formula BMI = body mass (kg)/height (m²). History of smoking and alcohol consumption were based on Centre for Disease Control Behavioural Risk Factor Surveillance System.

Statistical analysis

Values were expressed as the mean ± SD, using the independent sample t-test. The countable data were analysed using the χ² test or Fisher’s exact test. P < 0.05 was considered as the difference with statistical significance. One-way and multiway factors were analysed using unconditional logistic regression. Statistical analyses were conducted using the SPSS version 26.0 for Windows (SPSS, Chicago, IL, USA).

RESULTS

Comparison of clinical characteristics between the two groups of patients

Among 78 patients undergoing laparoscopic hepatic haemangioma resection, blood hypercoagulability occurred in 27 cases (34.62%) and did not occur in 51 cases (65.38%). The differences between the two groups were statistically significant (P < 0.05) in terms of historical hyperlipidaemia, Fib, D-Di, FDP, PLT, LDL-C and HDL-C. However, in sex; age; BMI; history of smoking, alcohol consumption, diabetes and hypertension; preoperative systolic and diastolic blood pressures; procedure time; intraoperative bleeding; haemangioma diameter and number of haemangiomas, the differences between the two groups were not statistically significant (P > 0.05). As illustrated in Table 1, the hypercoagulation group had significantly higher Fib, PLT, D-Di, LDL-C and history of hyperlipidaemia than the nonhypercoagulation group but had significantly lower HDL-C than the nonhypercoagulation group. In this study, two patients in the hypercoagulation group developed VTE, which was detected by colour Doppler ultrasound or multilayer spiral computed tomography, both of which were lower extremity DVT, while no venous thrombosis was detected in the nonhypercoagulation group. No PE was found in either group [Table 1].

Table 1.

Patient characteristics at baseline

Factors	High coagulation group (n=27)	Non-high coagulation group (n=51)	t/χ2	P
Sex, n (%)
Male	12 (44.4)	13 (25.5)	2.910	0.088
Female	15 (55.6)	38 (74.5)
Age (years, mean±SD)	48.93±8.98	50.75±8.25	−0.890	0.370
BMI (kg/m2, mean±SD)	23.57±3.98	22.21±2.63	1.800	0.075
History of smoking, n (%)	10 (37.0)	11 (21.6)	2.147	0.143
History of drinking alcohol, n (%)	13 (48.1)	14 (27.5)	3.341	0.068
History of hypertension, n (%)	4 (14.8)	6 (11.8)	0.001	0.978
History of diabetes, n (%)	2 (7.4)	3 (5.9)	0.001	1.000
History of high blood cholesterol, n (%)	13 (48.1)	10 (19.6)	6.916	0.009
Pre-operative systolic blood pressure (mmHg, mean±SD)	124.37±20.00	124.76±15.78	−0.091	0.928
Pre-operative diastolic blood pressure (mmHg, mean±SD)	79.74±14.53	81.96±10.34	−7.810	0.437
Fib (g/L, mean±SD)	5.25±1.95	3.51±1.41	4.530	<0.001
D-Di (µg/ml, mean±SD)	7.65±5.66	4.46±3.47	3.100	0.003
FDP (µg/ml, mean±SD)	19.93±11.26	13.56±13.75	2.070	0.042
PLT (×109/L, mean±SD)	257.70±102.10	197.61±62.78	3.220	0.002
HDL-C (mmol/L, mean±SD)	1.11±0.27	1.31±0.43	−2.192	0.031
LDL-C (mmol/L, mean±SD)	2.99±0.65	2.52±0.89	2.440	0.017
Operation time (min, mean±SD)	199.81±55.20	202.55±67.86	−1.800	0.858
Intraoperative bleeding (ml, mean±SD)	546.30±519.97	761.96±769.97	−1.300	0.196
Haemangioma diameter (cm), n (%)
≥10	5 (18.5)	12 (23.5)	0.260	0.610
<10	22 (81.5)	39 (76.5)
Number of haemangiomas, n (%)
Single	25 (92.6)	42 (82.4)	0.800	0.371
Multiple	2 (7.4)	9 (17.6)

Data presented as mean±SD or as n of patients (%). 1 mmHg=0.133 kPa. SD: Standard deviation, BMI: Body mass index, Fib: Fibrinogen, D-Di: D-dimer, FDP: Fibrinogen degradation products, PLT: Platelet, LDL-C: Low-density lipoprotein cholesterol, HDL-C: High-density lipoprotein cholesterol

Univariate logistic regression analysis

The results of univariate logistic regression analysis showed that a history of hyperlipidaemia, Fib ≥3.83 g/L, D-Di ≥9.12 μg/ml, FDP ≥14.64 μg/ml, PLT ≥292 × 10⁹/L, HDL-C ≥1.25 mmol/L and LDL-C ≥2.03 mmol/L was associated with the development of a hypercoagulable state in patients after laparoscopic hepatic haemangioma resection (P < 0.05), [Table 2].

Table 2.

Univariate logistic regression analysis of factors affecting the development of a hypercoagulable state

Factors	OR	95% CI	P
Age≥38.00 years	1.027	0.969–1.087	0.368
BMI≥24.78 kg/m2	0.875	0.752–1.017	0.082
History of smoking	0.468	0.167–1.306	0.147
History of drinking alcohol	0.364	0.138–0.984	0.268
History of hypertension	0.767	0.196–2.991	0.702
History of diabetes	0.781	0.122–4.985	0.794
History of high blood cholesterol	0.263	0.094–0.731	0.011
Pre-operative systolic blood pressure≥104.00 mmHg	1.001	0.974–1.029	0.927
Pre-operative diastolic blood pressure≥70.00 mmHg	1.016	0.976–1.058	0.432
Fib≥3.83 g/L	0.542	0.389–0.754	< 0.001
D-Di≥9.12 mg/ml	0.854	0.760–0.958	0.007
FDP≥14.64 mg/ml	0.962	0.922–1.003	0.043
PLT≥292.00×109/L	0.990	0.983–0.997	0.006
HDL-C≥1.25 mmol/L	4.168	1.099–15.795	0.036
LDL-C≥2.03 mmol/L	0.482	0.260–0.896	0.021
Operation time≥195.00 min	1.001	0.993–1.008	0.855
Intraoperative bleeding≥650.00 ml	1.001	0.997–1.001	0.204
Haemangioma diameter≥10.00 cm	1.353	0.422–4.348	0.611
Number of haemangiomas	2.679	0.535–13.403	0.230

BMI: Body mass index, Fib: Fibrinogen, D-Di: D-dimer, FDP: Fibrinogen degradation products, PLT: Platelet, LDL-C: Low-density lipoprotein cholesterol, HDL-C: High-density lipoprotein cholesterol, OR: Odds ratio, CI: Confidence interval

Multifactorial logistic regression analysis

The results of multifactorial logistic regression analysis also showed that the same markers were associated with the development of a hypercoagulable state of blood in patients after laparoscopic hepatic haemangioma resection (P < 0.05), [Table 3].

Table 3.

Multivariate logistic regression analysis of factors affecting the development of a hypercoagulable state

Factors	OR	95% CI	P
History of high blood cholesterol	0.356	0.094–1.351	0.009
Fib≥3.83 g/L	0.624	0.422–0.924	<0.001
D-Di≥9.12 mg/ml	0.937	0.725–1.210	0.003
FDP≥14.64 mg/ml	0.978	0.904–1.058	0.042
PLT≥292.00×109/L	0.991	0.980–1.001	0.002
HDL-C≥1.25 mmol/l	5.503	0.722–35.357	0.031
LDL-C≥2.03 mmol/l	0.417	0.164–1.062	0.017

Fib: Fibrinogen, D-Di: D-dimer, FDP: Fibrinogen degradation products, PLT: Platelet, LDL-C: Low-density lipoprotein cholesterol, HDL-C: High-density lipoprotein cholesterol, OR: Odds ratio, CI: Confidence interval

DISCUSSION

Laparoscopic hepatic haemangioma resection is a common procedure in hepatobiliary surgery. Traditional open hepatic haemangioma resection is poorly targeted, slow to heal, traumatic and prone to complications,[22,23] leading to postoperative incision infection and poor recovery for patients. Laparoscopic hepatic haemangioma resection with its advantages of a small incision, less trauma, less pain for patients and shorter average hospital stay has rapidly become popular and accepted among surgeons since its introduction.[24,25] However, laparoscopic hepatic haemangioma resection also has its disadvantages, such as DVT, subcutaneous emphysema and more likely to induce the formation of a hypercoagulable state of blood after surgery.[26]

The incidence of post-operative hypercoagulability has been reported to be as high as 35%, with it being of the greatest concern in patients with combined hypertension, diabetes mellitus and hyperlipidaemia.[27] At present, there is a lack of important molecular markers to predict the development of a hypercoagulable state, and there are few studies on the factors affecting the development of such a state in patients after laparoscopic hepatic haemangioma resection.

The results of this study showed that a history of hyperlipidaemia, Fib ≥3.83 g/L, D-Di ≥9.12 μg/mL, FDP ≥14.64 μg/mL, PLT ≥292 × 10⁹/L, HDL-C ≥1.25 mmol/L and LDL-C ≥2.03 mmol/L was risk factors for the development of a hypercoagulable state in patients after laparoscopic hepatic haemangioma resection. By examining the relationship between laparoscopic cholecystectomy and risk factors for venous thrombosis. Ulrych et al.[28] found that patients with benign disease who underwent laparoscopic cholecystectomy and hernia surgery had elevated levels of coagulation markers, such as PLT, Fib, prothrombin fragment F1 + 2 and D-Di on postoperative days 7–10 compared to pre-operative days, with statistically significant differences and that patients’ blood was more likely to be in a hypercoagulable state on postoperative days 7–10. Amin et al.[29] looked at the effects of pneumoperitoneum and surgery on the coagulation system of patients in a prospective study and found that patients’ blood was in a hypercoagulable state for 8 h after laparoscopy, demonstrating that it may be at risk for thrombosis. Rottenstreich et al.[30] analysed the dynamic changes in coagulation after laparoscopic gastrectomy. All samples for complete blood count, C-reactive protein, coagulation factors, fibrinogen and thrombin generation were measured, and the study found that laparoscopic gastrectomy was associated with the development of a hypercoagulable state.

In this study, the preoperative history of hyperlipidaemia, Fib, D-Di, FDP, PLT, LDL-C and HDL-C levels was the key influencing factors in the development of a hypercoagulable state. Some studies have shown that hyperlipidaemia can reduce fibrinolytic function and increase coagulation activity in the patient. The reason for this is that free fatty acids in hyperlipidaemic patients can provide activated contact surfaces,[31,32] increase the charge density on the surface of large particle lipoproteins and promote the activation of plasma coagulation factor VII, which ultimately aggravates blood coagulation.[33,34] The preoperative LDL-C level influences blood hypercoagulability because oxidised LDL can affect the synthesis of nitric oxide and the activity of thrombin-regulated proteins and impair the endothelial function of blood vessels.[35,36] The oxidised LDL can also form foam cells and combine with mucopolysaccharide to form insoluble precipitates, which can contribute to the development of a thrombus and a hypercoagulable state.

D-Di is a specific degradation product of fibrin monomer cross-linked by activated factor XIII and then hydrolysed by fibrinolytic enzymes, which is a valuable indicator of blood hypercoagulation and thrombotic diseases.[37,38] It is one of the markers that respond to a hypercoagulable state and secondary hyperfibrinolysis in vivo, as its elevation reflects enhanced secondary fibrinolytic activity and excessive thrombin production.[39,40] Myocardial infarction, venous thrombosis or PE, diffuse intravascular coagulation can all lead to increased D-Di.[41] Elevated D-Di after laparoscopic hepatic haemangioma resection reminds hyperfibrinolytic hydrolysis. Plasma Fib is an acute time-phase reactive protein that can rise rapidly several fold in inflammatory and stressful conditions.[42] As the most abundant coagulation protein in the blood, changes in the level of Fib are closely related to coagulation and are mainly involved in blood clotting. FDP is the amount of X (x), Y (y), D (d) and E (e) fragments generated by fibrinolytic enzymes in the circulation and which reflects the activation of the fibrinolytic system.[43] FDP is significantly increased in primary hyperfibrinolysis, and in secondary hyperfibrinolysis due to hypercoagulability, venous embolism and PE, FDP is also increased. Therefore, FDP is a sensitive indicator of hyperfibrinolysis. The liver is unable to clear fibrinolytic activators after partial hepatectomy, resulting in hyperfibrinolysis and a dramatic increase in FDP in the blood. In addition, the venous stasis that may be caused by pneumoperitoneum and inverse flexion position damages the endothelium, which activates the blood coagulation and fibrinolytic system and prevents the clearance and dilution of activated coagulation factors. The liver may be more thermally damaged during laparoscopic hepatic haemangioma resection because of the frequent use of the electrocoagulation hook for separation,[44] and the reduction of visceral blood flow caused by pneumoperitoneum gives a greater postoperative stress response, which shows a direct correlation with hypercoagulability.[45] Numerous animal experiments and clinical data suggest that platelets play a key role in hepatocyte regeneration and activated platelets promote hepatocyte regeneration through signal transduction pathways such as STAT3, AKT and ERK1/2.[46] Besides this, platelet-derived 5-hydroxytryptamine may be involved in the initiation of liver regeneration, and in a mouse model of liver regeneration, it was confirmed that partial hepatectomy can lead to thrombocytopenia.

CONCLUSION

The presence or absence of a history of hyperlipidaemia and preoperative levels of Fib, D-Di, FDP, PLT, LDL-C and HDL-C are closely related to the development of a hypercoagulable state in patients after laparoscopic hepatic haemangioma resection. In the process of laparoscopic hepatic haemangioma, clinicians should be concerned whether patients have a history of hyperlipidaemia before surgery and should pay special attention to patients with high preoperative levels of the molecular markers described in this study.

Financial support and sponsorship

This work was financially supported by National Natural Science Foundation of China, Grant/Awarding Number: 82170587; Hubei Chen Xiaoping Science and Technology Development Foundation, Grant/Awarding Number: CXPJJH11900001-2019339.

Conflicts of interest

There are no conflicts of interest.