Owing to the development of multiple follicles after the use of ovulation drugs, blood E2 increased, plasma thrombin and fibrin levels increased, antithrombin level decreased, and blood vessel permeability increased, causing body fluid extravasation and increase in blood concentration. The patient was in a hypercoagulable state that could easily lead to deep thrombosis5. A study by Kodama et al.5 found that during the IVF-ET treatment cycle, the activation of the coagulation system occurred within 2 days after HCG injection, whereas the activation of the fibrinolytic system occurred later. The activation of these systems continued after OHSS, and the blood coagulation system returned to normal earlier than the fibrinolysis system. Therefore, the occurrence, development, and outcome of OHSS are accompanied by changes in coagulation function.
D-dimer is the final product of cross-linked fibrin after plasmin action. When blood clotting occurs in the body, thrombin acts on fibrinogen to convert it into cross-linked fibrin, and the fibrinolytic system is activated to degrade cross-linked fibrin to form various fibrin degradation products. Due to cross-linking of the γ chain, two D-fragments containing the connected γ-chains are produced, namely, the formation of D-dimer fragments. Lowe6 pointed out that since D-dimer has good stability in plasma, it can be used as a sensitive and specific marker to confirm the presence of a hypercoagulable state and secondary fibrinolysis in the body. Therefore, D-dimer levels can be used as a significant indicator to observe changes in OHSS coagulation function.
This study found that the plasma D-dimer levels of each group in the early stages of disease increased significantly with the severity of OHSS. This suggested that with the aggravation of symptoms, the activation of coagulation and fibrinolytic systems in the body significantly increased. Moreover, the patients’ risk of developing thrombotic diseases was significantly increased and was consistent with the severity of OHSS symptoms. With the relief of symptoms, the plasma D-dimer levels of patients in the moderate and severe groups became significantly higher than those in the early stages of disease. This result indicated that the coagulation system in the body has gradually returned to normal with the relief of OHSS symptoms, and the fibrinolytic system was continuously activated. The continuous increase in D-dimer levels indicated that the recovery of the fibrinolytic system had a lag period when compared with the symptoms.
Thrombosis is a serious complication of OHSS, which can be fatal. Thrombosis is a small portion of blood clot that forms on the surface of the exfoliation or repair of the inner surface of the cardiovascular system. It is composed of insoluble fibrin, deposited platelets, white blood cells, and trapped red blood cells.
During OHSS, when HCG is injected, the blood coagulation function in the body is activated, but not the fibrinolytic system. A large amount of fibrinogen in the body forms soluble cross-linked fibrin under the action of thrombin. When the delayed fibrinolytic system is activated, the cross-linked fibrin will be degraded while continuing to form, resulting in many D-dimer fragments in the patient’s plasma, and the coagulation and fibrinolytic systems remain relatively balanced in the activated state. When OHSS enters the prognosis period, the coagulation system returns to normal before the fibrinolytic system, and the fibrinolytic system continues to activate, causing the patient’s plasma D-dimer level to further increase. The hysteresis of this activation varies with the severity of OHSS.
The presence of OHSS in patients causes massive neovascularization, leading to massive vascular endothelial damage, increased vascular permeability, and increased blood concentration causing the concentration of platelets, white blood cells, and red blood cells in the blood to exceed the normal range. When the fibrinolytic system fails to activate on time or during clotting during OHSS, the relative balance between the system and fibrinolytic system in the activated state is damaged. This results in a large amount of cross-linked fibrin that cannot be degraded in time, which can easily lead to thrombotic diseases.
A study by Rao et al.7 showed that 74% of the patients who developed thrombosis during IVF treatment had OHSS symptoms. This suggests a change in coagulation function in OHSS patients. Plasma D-dimer is the most valuable indicator for observing the effect of fibrinolysis in vivo. The plasma D-dimer levels of patients in each group in this study were significantly higher than the normal range. Therefore, the large amount of cross-linked fibrin in the body cannot be easily ignored.
Targeted prevention of thrombotic complications in patients with OHSS were according to the following three major conditions of thrombosis: repair the vascular endothelial wound; volume expansion therapy to reduce the concentration of blood cells such as platelets, white blood cells, and red blood cells; and anticoagulation therapy accelerates the degradation of cross-linked fibrin in the blood.
According to the recommendations of the Royal College of Obstetricians and gynecologists8, preventive use of heparin is recommended for OHSS patients. There have been reports9 stating that anticoagulation therapy may be safe for continued pregnancy and embryos. However, there are reports10 suggesting that after the emergence of OHSS, intracranial venous thrombosis still occurs despite the preventive use of heparin.
This study has several limitations. First, selection and surveillance biases in our analysis could not be controlled owing to the retrospective study design of only 140 patients from a single academic institution. Second, although we excluded patients with inflammatory conditions, some hematological biomarkers may have been affected by the presence of unrecognized systemic inflammatory diseases.