Obstetric hemorrhage is a major cause of maternal morbidity and mortality. Acquired coagulopathy can develop rapidly in severe obstetric hemorrhage(1). Disseminated intravascular coagulation (DIC) was frequently found in combination with primary post-partum hemorrhage (PPH), and the outcome was worse in these patients than in those without DIC(2).
Disseminated intravascular coagulation is an acquired syndrome characterized by systemic activation of coagulation, potentially leading to thrombotic obstruction of small and midsize vessels, thereby contributing to organ dysfunction. At the same time, ongoing consumption of platelets and coagulation proteins results in thrombocytopenia and in low concentrations of clotting factors, which may cause severe bleeding(3).
Activation and peripheral consumption of clotting factors and platelets may occur antepartum and postpartum. Pregnant patients may develop disseminated intravascular coagulation. Its pathophysiological mechanisms are complex and dependent on the underlying pathology, making the clinical and biological expression of quite variable DIC(4), possibly resulting in massive maternal hemorrhage.
The accurate diagnosis of critical obstetric hemorrhage is important due to the maternal and fetal morbidity and mortality. In order to make the optimal evaluation of coagulopathy with bleeding in obstetric, this mini-review aims at discussing aspects regarding the clinical manifestations and laboratory assays of coagulopathy associated with hemorrhage.
Disseminated intravascular coagulation
According to the definition of the International Society of Thrombosis and Hemostasis scientific subcommittee, DIC is an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature which, if sufficiently severe, can produce organ dysfunction(5,6).
Several important themes in the pathophysiology of DIC exist. The first is the central part played by the generation of thrombin in vivo. The second is the fact that mechanisms fueling and perpetuating the generation of thrombin are pathogenic in its dissemination. The third one is the parallel and concomitant activation of the inflammatory cascade with regard to the links between inflammation and coagulation. The fourth one is represented by the importance of the endothelial microvasculature in this process(7).
The clinical presentation of disseminated intravascular coagulation is highly variable and depends on the dynamic balance between clot formation in the microvasculature and the degree of consumption of coagulation factors, inhibitors and platelets. Based on the severity and stage, DIC is categorized as non-overt (early, compensated phase) and overt (decompensated). Disseminated intravascular coagulation can present either acute or chronic, and it can be subclinical. In general, DIC patients can suffer from both bleeding and thrombosis, although thrombosis is not often readily apparent, because clot formation primarily involves the microvasculature, manifesting as organ failure(8).
The diagnosis is based on the presence of ≥1 known underlying conditions causing DIC plus abnormal global coagulation tests: decreased platelet count, increased prothrombin time, elevated fibrin-related maker (D-dimer/fibrin degradation products) and decreased fibrinogen(9).
Clinical conditions associated with DIC in obstetrics
The incidence of disseminated intravascular coagulation during pregnancy is not well defined and ranges from 0.03% to 0.35%(6,10).
Any pathophysiology disrupting the trophoblasts can lead to a large release of tissue factor (TF), activating the coagulation cascade, causing inflammatory responses which can eventually lead to DIC(11).
Obstetric patients often present early and severe coagulation disorders(12). Consumption coagulopathy or DIC has been described in association with postpartum hemorrhage, placental abruption; amniotic fluid embolism; preeclampsia/HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), fetal demise; and septic abortion(10). Other prevalent causes of obstetrical DIC include sepsis, intrauterine infection and acute fatty liver of pregnancy(11).
The poor maternal outcome was observed when disseminated intravascular coagulation was presented during delivery. One study reported that the highest rate of intrauterine fetal death was noted in patients who had placental abruption(11); however, ultrasound and other examination techniques offer a relatively rapid diagnosis of placental abruption(13).
The analysis of the amniotic fluid embolism registry and Maternal Death Evaluation Committee recognize “DIC type (uterine type) amniotic fluid embolism (AFE)” as a cause of critical obstetric hemorrhage (COH) and recently it was raised “the concern that AFE is implicated in massive obstetric haemorrhage”(13,14).
COH is a collective term for obstetric hemorrhage related to the life of the pregnant patients, where there is a critical situation requiring rapid transfusion (not only red blood cell [RBC] concentrate, but also fresh frozen plasma [FFP] or platelet concentrate) and intensive team management(14).
DIC (uterine)-type AFE shows consumption coagulopathy and uterine relaxation, which are difficult to distinguish from early-stage postpartum hemorrhage. In non-AFE PPH, the amount of needed coagulation factors generally correlates with the amount of bleeding, whereas in DIC (uterine)-type AFE, severe coagulopathy should be anticipated from the early stages(13).
Scoring systems of DIC to facilitate earlier detection and treatment
In order to facilitate the diagnosis and management of DIC, scoring systems were developed by the Japanese Association for Acute Medicine (JAAM) and the International Society on Thrombosis and Haemostasis (ISTH)(10). The ongoing problem with scoring systems is that they are difficult to apply as pregnancy physiologically alters the clotting factors of the body(11).
For patients who have obstetrical complications that put them at risk for DIC, Erez et al. developed a pregnancy modified DIC score by using platelet count, fibrinogen concentrations and the PT difference (the differences between the PT values of patients and the laboratory controls in seconds), adjusted to the reference ranges of pregnancy(6,10).
The validity of the DIC score, created by Erez et al., was compared to the ISTH score (based on four components: platelet count, fibrinogen, prothrombin time, and fibrin related marker). Jonard and co-workers concluded that the pregnancy-specific DIC score by Erez et al. seems highly discriminant in the subset of patients admitted to the ICU after delivery for an acute specific complication. The ISTH score is not recommended in pregnant patients because of its poor sensitivity(15).
The European guidelines recommend fibrinogen threshold levels of 1.5-2 g/L relating to perioperative bleeding and trauma. In pregnant patients, the normal levels of fibrinogen at delivery are higher than in non-pregnant patients (3.5-6.5 g/L versus 2-4.5 g/L), attributable to normal physiological changes in hemostasis during pregnancy, creating a state of hypercoagulability. For this reason, the exact fibrinogen threshold for intervention during postpartum hemorrhage (PPH) is unclear. However, low fibrinogen levels (<2 g/L) during delivery are predictive of progression to severe PPH(16).
On the other hand, low fibrinogen levels are a common and prognostically important feature of conditions associated with hyperfibrinolytic DIC, such as amniotic fluid embolism(5). One study reported that the blood loss/fibrinogen (B/F) ratio, significantly higher in the DIC-type AFE, could be used to differentiate PPH from DIC-type AFE, facilitating the optimal replacement of coagulation factors during the early stages(13).
The use of point of care systems based on thromboelastography (TEG) and rotational thromboelastometry (ROTEM) allows the individualized administration of blood components (fresh plasma and platelets) and of coagulation factor concentrates where necessary and in adequate amounts(12).
Recommendations for the treatment of DIC and bleeding
The prompt treatment of the underlying disorder and the elimination of the trigger mechanism are the cornerstone therapeutic approaches(5,9). In some cases, particularly those associated with placental abruption and intrauterine death, disseminated intravascular coagulation will resolve completely within hours of the resolution of the underlying condition(5). In patients with DIC and active bleeding, the administration of cryoprecipitate or CFCs (i.e., FC) appears to be superior to fresh frozen plasma (FFP) as first-line treatment. The European guidelines now suggest FC as the first-line treatment for major bleeding accompanied by hypofibrinogenaemia(16).
Inefficacious administration of non-RBC components (fresh frozen plasma and platelets) to treat massive obstetric hemorrhage (MOH) is associated with an increased risk of dilutional coagulopathy. The management of MOH is now structured with massive transfusion protocols (MTPs), including early intervention and the use of fixed ratios of non-RBC:RBC components; however, protocols vary(17).
The use of tranexamic acid in postpartum hemorrhage is fully established, but in obstetric DIC, where suppressed fibrinolysis may be dominating, caution is advised(8).
The timing of use of recombinant FVIIa (rFVIIa) in relation to a peripartum hysterectomy has been the subject of debate. An early hysterectomy is recommended for severe bleeding as a result of placenta accreta or uterine rupture. In patients with uterine atony who have ongoing bleeding in spite of correction of coagulopathy, hypothermia, acidosis and hypocalcaemia, it may be reasonable to consider a trial of rFVIIa before a hysterectomy, in order to avoid the sterility(18).
If PPH is not controlled by pharmacological treatments and possibly with intrauterine balloon, invasive treatments by arterial embolization or surgery are recommended(19).
Transarterial embolization (TAE) might be one of the best strategies in the management of refractory PPH, not only to prevent DIC, but also to avoid the sterility and significant morbidity of emergent peripartum hysterectomy. However, one study from Taiwan highly recommended the use of surgical blockage of uterine feeding vessel (BUFV) in place of using TAE in the management of patients with refractory PPH, based on their better outcomes and avoidance of maternal death(20).
In patients with massive PPH and coagulopathy, thromboprophylaxis is recommended to start as soon as feasible after bleeding has been controlled(21).
Discussion and conclusions
In the event of coagulopathy associated with massive blood loss, it is essential to confirm the bleeding point and perform appropriate hemostasis procedures(22).
The etiology of the coagulopathy of PPH relates to varying proportions of dilutional coagulopathy, localized consumption, disseminated consumption and/or increased fibrinolysis. It is unusual to develop an early coagulopathy when bleeding is caused by atony or trauma(21). Early coagulopathy leading to DIC promptly is associated with placenta abruptio, amniotic fluid embolism, severe pregnancy-induced hypertension, HELLP syndrome, and dead fetus syndrome(21,22).
Disseminated intravascular coagulation is a dynamic situation that requires a continuous assessment of the clinical and laboratory parameters(6). The classical clinical signs (tachycardia and hypotension) or important blood loss are misleading in pregnancy, due to the notorious increase in plasmatic volume, and might not manifest until bleeding becomes very abundant(12).
Obstetric DIC is often undiagnosed until a late stage, leading to adverse maternal outcomes, including massive blood product transfusion, hysterectomy and maternal mortality(10). The goal is on recognizing a non-overt stage rather than an overt and late stage of DIC(7). Thus, the early identification of patients at risk for obstetrical bleeding that requires blood products transfusion can be a key step in reducing, at least partially, the rate of preventable maternal deaths due to hemorrhage(23).
In conclusion, disseminated intravascular coagulation is the dynamic coagulation/fibrinolysis disorder that can proceed from compensated to decompensated phases. DIC is a critical step of disease progression that is important to monitor over time. Overt-DIC diagnostic criteria have been used clinically for more than 20 years, but may not be adequate to detect the compensated phase of DIC, and due to different underlying causes, there is no “one size fits all criteria”. Individualized criteria for heterogeneous conditions continue to be proposed to facilitate the diagnosis(24), because critical challenges remain in this field(13).
Conflict of interest: none declared
Financial support: none declared
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