Aortic aneurysm and chronic disseminated intravascular coagulation: a retrospective study of 235 patients

Abstract

Chronic disseminated intravascular coagulation (DIC) is a rare but devastating complication of aortic aneurysm (AA). This study investigated the clinical manifestations, laboratory findings, and treatment of patients with AA-associated chronic DIC (AA-DIC) and explored the mechanisms, duration, and therapeutic response of AA-DIC. We retrospectively reviewed the medical records of 235 AA patients admitted at the Peking Union Medical College Hospital between September 2009 and January 2015. The patients were classified as those with DIC (AA-DIC) and those without DIC (non-DIC). The AA-DIC group showed a significantly higher proportion of female patients and a significantly longer AA disease course than the non-DIC group did. The AA-DIC patients presented mural thrombi, dissecting aneurysms, a family history of AA, and diabetes significantly more frequently than the non-DIC patients did. Furthermore, multiple regression analyses revealed that sex, mural thrombus, aneurysm type, diabetes, and stent surgery are possible independent risk factors for AA-DIC patients. Fifty-two (22.1%) patients presented AA-DIC. Among these patients, 43 had non-typical DIC and 9 had typical DIC; the mortality rate of the latter was 22.2%. The mean age of the patients with typical DIC was significantly higher than of that of patients with non-typical DIC. The non-typical DIC patients also presented abnormal coagulation disorders of varying degrees. Furthermore, heparin or low-molecular-weight heparin improved the clinical symptoms and laboratory parameters in patients with AA and typical DIC. Thus, chronic DIC should be considered in patients with AA.

Keywords

aortic aneurysm / disseminated intravascular coagulation / anticoagulation therapy

Introduction

Disseminated intravascular coagulation (DIC) can vary in severity. This condition is caused by consumptive coagulopathy and is characterized by bleeding tendency, a hypercoagulable state, and multiple organ failure. DIC may occur secondary to severe infections, malignant hypertension, malignant tumors, liver failure, extensive burns, abnormal pregnancy, and congenital vascular abnormalities, among other diseases. Patients with acute onset DIC present a poor prognosis, with mortality rates of 50%–60%, and chronic DIC may last several months or years. Compensatory mechanisms in chronic DIC result in mild or even occult clinical symptoms [ 1– 3] that can only be identified by sensitive laboratory tests.

Abdominal aortic aneurysm (AA) is a localized enlargement of the abdominal aorta with the diameter exceeding 3 cm or more than 50% larger than the normal diameter. For the thoracic aorta, a diameter greater than 3.5 cm is generally considered dilated, whereas a diameter greater than 4.5 cm would be considered aneurysmal. The common causes of AA include hypertension, atherosclerosis, mechanical injury, infections, and congenital anomalies [ 4, 5]. The risk of rupture associated with AA significantly increases when the aneurysm diameter is>5 cm, which is also an indication for surgery [ 6].

Chronic DIC is a rare but devastating complication of AA, and this condition was first described by Fine in 1967 [ 7]. Few case reports exist on this complication in AA patients, but the clinical manifestations, laboratory findings, and treatment of patients with AA-associated chronic DIC (AA-DIC) have not been studied in detail. The mechanisms, duration, and therapeutic response of AA-DIC are also not well understood. Therefore, in this single-center retrospective study, we aimed to examine the clinical features of DIC in Chinese patients with AA.

Methods

Patients and methods

The medical records of 235 patients who were diagnosed with AA and admitted to Peking Union Medical College Hospital (PUMCH) between September 2009 and January 2015 were retrospectively reviewed. All of the patients signed informed consent forms at the time of admission and agreed to submit their blood samples for data collection and analysis for medical research purposes. This study was approved by the ethics committee of PUMCH.

The patients were classified as those with DIC (AA-DIC; n = 52) and those without DIC (non-DIC; n = 183). The AA location, DIC classification, clinical manifestations, laboratory findings, treatment, prognosis, and follow-up findings were investigated.

Diagnostic criteria

AA-DIC was classified and diagnosed on the basis of the following symptoms proposed by Siebert and Natelson in 1976 [ 8]: (1) a chronic bleeding tendency; (2) evidence of consumptive coagulopathy; (3) recovery of abnormal laboratory values following AA repair; (4) maintenance of normal coagulation parameters for at least 3 months postoperatively; and (5) receipt of conservative treatment without other diseases in addition to meeting criteria (1) and (2) and recovering after anticoagulant therapy.

Patients with DIC were classified in accordance with the 2001 International Society of Thrombosis and Hemostasis (ISTH) scoring system [ 9], which includes the following scores for each component: (1) platelet count (>100= 0;<100= 1;<50= 2); (2) increase in fibrin degradation products (none= 0; moderate= 2; significant= 3); (3) prolonged prothrombin time (<3 s= 0;>3 s but<6 s= l;>6 s= 2); and (4) fibrinogen concentration (>1.0 g/L= 0;<1.0 g/L= 1). The cumulative score of the components is then interpreted as follows:≥5 points, compatible with typical DIC (overt DIC); or<5 points, suggestive of non-typical DIC (non-overt DIC or occult DIC).

Statistical analysis

SPSS version 11.0 (SPSS Inc., Chicago, IL, USA) was used for data processing and analysis. Continuous variables and categorical variables were compared using t-test and Fisher’s exact test of independent samples, correspondingly. A P-value of<0.05 was considered statistically significant. The independent risk factors of AA-DIC patients were examined by multiple regression analyses.

Results

Baseline demographic data

DIC was diagnosed in 52 (22.1%) of the 235 AA patients. The baseline characteristics of the groups (AA-DIC and non-DIC) are listed in Table 1. The AA-DIC group showed a significantly higher proportion of female patients (P = 0.003) and a significantly longer disease course (P = 0.047) than the non-DIC group did. Among the 52 DIC patients, 9 presented typical DIC, whereas 43 presented non-typical DIC. AA with chronic DIC was diagnosed as the initial manifestation in 6 patients.

Clinical characteristics of AA patients with or without DIC

As shown in Table 2, abdominal AA was the most common type of AA in both groups（Fig.1）. Mural thrombi were more frequently present in the AA-DIC group than in the non-DIC group (P = 0.001). Additionally, patients with dissecting aneurysms were found to be more vulnerable to DIC (P = 0.001).

As shown in Table 3, diabetes and family history of AA were significantly more common in the AA-DIC group than in the non-DIC group (P = 0.020 and P = 0.023, respectively). The groups did not present any other significant differences (including atherosclerosis, hypertension, hyperlipidemia, and smoking). Among the 235 AA patients, 84 (35.7%) underwent surgery as follows: AA revascularization in 20 patients and stent implantation in 64 patients. Following surgery, 8 patients developed DIC after revascularization, and 23 patients developed DIC after stent implantation, with 1 patient presenting typical DIC in each group. Among them, 7 patients received anti-coagulation therapy, and none underwent reoperation.

As shown in Table 4, a multiple regression analysis of the risk factors was performed (P<0.2) for the AA-DIC group, which demonstrated that sex, mural thrombosis, aneurysm type, diabetes, and stent surgery might be relative independent risk factors for AA patients who had developed DIC.

Among the 52 patients with AA-DIC, 37 had received blood transfusions as follows: fresh frozen plasma for 31 patients, platelets for 10 patients, and fibrinogen for 11 patients. Seventeen patients (including 9 typical DIC patients) received heparin or low-molecular-weight heparin (LMWH) therapy, after which the clinical symptoms or laboratory indices (e.g., skin and mucosal ecchymosis, fibrin degradation products, prothrombin time, and fibrinogen concentration) significantly improved within 1 week.

Clinical characteristics of patients with AA-DIC

Malignant tumors of the lung, gastrointestinal tract, prostate, or hematopoietic system were not evident in any of the 52 AA-DIC patients. Among the 43 AA patients with non-typical DIC, 22 (51.2%) scored 1 point on the ISTH scoring system, 7 (16.3%) scored 2 points, 8 (18.6%) scored 3 points, and 6 (14.0%) scored 4 points. None of these patients presented clinical bleeding diathesis. The most common manifestations in the AA patients with non-typical DIC were increased D-dimer (31 patients, 72.1%) and fibrin degradation products (19 patients, 44.2%); decreased fibrinogen concentration (14 patients, 32.6%) and platelet count (9 patients, 20.9%); and prolonged prothrombin time (8 patients, 18.6%).

The clinical characteristics of 9 AA patients with typical DIC and 43 AA patients with non-typical DIC are compared in Table 5. All 9 AA patients with typical chronic DIC aged>75 years old (average age= 81 years), which is significantly higher than the age of the patients in the non-typical DIC group (P = 0.031). Two patients died, yielding a mortality rate of 22.2%. All 9 patients had overt bleeding diathesis（Fig.2）, and they had received anticoagulation therapy (3 with heparin, 6 with LMWH), after which an obvious improvement and a stable maintenance of the coagulation values and bleeding tendency were observed. The longest follow-up time was 35 months. Warfarin was used instead of LMWH for two patients during the follow-up period. Five of the patients stopped anticoagulation therapy after hospital discharge. Among the five patients, two died because of severe bleeding tendency, one patient was lost to follow up, one patient was stable, and one patient showed deterioration after withdrawal from the therapy but recovered within 1 month after reinstating the heparin treatment.

Discussion

To our knowledge, this study included the largest reported sample of AA patients with chronic DIC, with 22.1% of the patients presenting chronic DIC. In the small proportion of patients with typical DIC (3.8%), the mortality rate was 22.2%. As mentioned above, few previous case reports exist on this type of disease. These studies have reported rates of 43%–67% for AA patients, with typical DIC noted in approximately 4% of the AA patients. Specific mortality rates have not previously been reported for this population [ 10, 11]. Hence, further clinical epidemiological studies are necessary.

The clinical manifestations of AA-DIC are generally nonspecific, making an early diagnosis of this condition challenging. The characteristic features of DIC, including elevations in D-dimer and fibrin degradation products, reductions in fibrinogen concentration and platelet count, and a prolonged prothrombin time, are important indicators for the diagnosis of chronic DIC in patients without bleeding tendencies [ 12]. In the present study, chronic DIC was the initial manifestation in 6 AA patients, and this finding suggests that chronic DIC should be assessed in all AA patients.

Chronic DIC should be suspected, particularly in patients with AA and a mural thrombus, given that the presence of a mural thrombus has been reported to be more common in patients with AA-DIC than in AA patients without DIC [ 13]. This result was supported by the current findings, in which a mural thrombus was present in approximately 78.8% of the patients with AA and DIC. Other indicators of DIC may include a longer disease course or a dissecting aneurysm, which were found in all of our AA patients with typical DIC and have been reported in a previous study [ 14]. Moreover, chronic diseases, such as diabetes, were more common in the AA-DIC group than in the non-DIC group, indicating that diabetes plays an important role in the pathogenesis of chronic DIC [ 15]. In addition, our study showed that the proportions of female patients and those with a family history of AA were higher in the AA-DIC patients than in the non-DIC patients; this novel finding has not been reported to date. Thus, we recommend regular screening for DIC in all AA patients with the “risk factors” mentioned above.

Treatment of the underlying cause and blood replacement therapy are the main therapeutic methods for AA-DIC. An appropriate transfusion of fresh frozen plasma is recommended [ 13]. Furthermore, in patients for whom 2 weeks of conservative therapy is not effective, surgery with aneurysm reconstruction or stent placement is the most effective treatment [ 12, 16]. The majority of DIC manifestations improve following surgery. However, the rate of DIC following surgery was high (36.9%) in the current study, particularly after stent placement. This finding might be related to a coagulation imbalance induced by the graft vessel or the stent itself [ 16, 17]. Therefore, an awareness of chronic DIC is important for the proper diagnosis and management of patients to improve prognosis. Long-term anticoagulation therapy, instead of reoperation, is recommended for patients with DIC after surgery [ 12, 18].

Anticoagulation therapy, such as LMWH in doses of 0.5–1 mg/kg and low-dose heparin, presents an effective success rate of>90% for the postoperative treatment of patients with AA-DIC or patients with surgical contraindications, whereas the use of warfarin does not improve outcomes [ 18– 22]. Some researchers suggest that heparin treatment is appropriate for patients with thrombosis as the main symptom, although cautious use of anticoagulation is recommended for those with a severe bleeding tendency [ 7, 23]. In our study, all AA patients with typical DIC showed manifestations of overt bleeding diathesis, and all these patients received anticoagulation therapy. In this study, heparin and LMWH treatments were safe and effective, but two patients died of disease recurrence after drug withdrawal. Accordingly, anticoagulation therapy remains the primary method of nonsurgical treatment. In recent years, several case reports have described the successful treatment of AA-DIC with recombinant human soluble thrombomodulin and other anti-fibrinolytic or anticoagulant drugs, such as rivaroxaban [ 24– 27].

This study presents some limitations. As s retrospective analysis, the laboratory data during follow-up are incomplete. Furthermore, some amount of bias cannot be avoided as all of the patients were recruited from the same hospital and all were inpatients.

In conclusion, our study showed that chronic DIC might occur at any stage of the AA disease course, even perioperatively. Female gender, advanced age, a longer disease course, dissecting aneurysms, mural thrombi, comorbidities such as diabetes, and a family history of AA were more common in AA-DIC patients than in non-DIC patients. Furthermore, sex, mural thrombosis, aneurysm type, diabetes, and stent surgery might be relative independent risk factors for AA patients who had developed DIC. Therefore, chronic DIC should be considered in patients with AA, particularly in those with the risk factors identified in this study. Further studies with larger sample sizes should be undertaken to confirm the results of this study.

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