Disseminated intravascular coagulation: An uncontrolled explosion of coagulation leading to consumptive coagulopathy

ACHAIKI IATRIKI | 2024; 43(1):23–38

Review

Evgenia Verigou, Krisela-Christina Valera, Theodora Chatzilygeroudi, Argiris Symeonidis


Hematology Division, Dept of Internal Medicine, University of Patras Medical School, University Hospital, Rion of Patras, Greece

Received: 01 Apr 2023; Accepted: 01 Dec 2023

Corresponding author: Evgenia Verigou, General university hospital of Patras, Rion, Greece P.C. 26504, Tel.: +30 6977136286, e-mail: j.verigou@gmail.com

Key words: Disseminated intravascular coagulation, DIC, coagulopathy, thrombosis, sepsis, cancer, hemostasis, intravascular hemolysis, hemolytic microangiopathy

 


Abstract

Disseminated intravascular coagulation (DIC) is the result of an uncontrollable activation of the coagulation cascade that can affect patients of all ages with different underlying diseases and conditions and increases their mortality. Sepsis, cancer, major trauma, and obstetric emergencies are four of the main underlying conditions associated with DIC, followed by vascular malformations, hematological malignancies and entrance of foreign material in the vasculature. Patients exhibit different clinical manifestations from latent DIC (asymptomatic or indolent) to overt DIC with life threatening thrombotic or bleeding complications. The treatment of DIC requires complete understanding of the pathogenetic mechanisms, identification of the underlying causative disease, thorough physical examination and constant laboratory follow up; to evaluate the thrombotic versus bleeding risk of the patient and the severity of their clinical status, and choice of the appropriate supportive measures. The cornerstone of treatment for DIC remains the elimination of the underlying causative factor.

INTRODUCTION

Under normal conditions there are several and complex regulatory mechanisms, securing the preservation of the homeostatic balance between factors with prothrombotic, anti-thrombotic and fibrinolytic properties in the peripheral blood circulation in humans [1]. Following variable causality, a loss of this homeostasis may occur, ultimately leading to an uncontrolled activation of the coagulation cascade at different parts of the vasculature, a condition termed disseminated intravascular coagulation (DIC) [2]. The clinical manifestations of DIC vary greatly and range from absence of any clinical symptom and sign or the appearance of some minor cutaneous ecchymoses to severe symptoms and signs from the central nervous system (CNS), including coma and death [2]. Prognosis relies mainly on the underlying etiology and the prompt and effective management of the emerging condition. Several studies have elucidated various components of the pathogenesis of DIC, providing a solid basis for the application of several and different interventions for the restoration of coagulation and hemostasis pathways [3]. In this review, we aim to summarize long established as well as newer insights in the pathogenesis of DIC and describe the etiology, epidemiology, pathophysiology, diagnostic procedures, clinical manifestations and the supportive measures recommended as treatment options for the patient who suffers from DIC.

EPIDEMIOLOGY

DIC may occur in about 30-50% of patients with sepsis [4] and it is developed at an estimated rate of about 1% among all hospitalized patients [5]. DIC occurs at all ages and in all races, and no particular sex predisposition has been noted. However, many chronic or latent cases may be underdiagnosed or misdiagnosed as manifestations of the underlying condition.

PATHOGENESIS OF DIC

DIC pathogenesis is multifactorial and not yet fully understood. Several deregulated mechanisms and pathways have been described during the past decades, indicating that there are at least five dominant pathogenetic events: 1. Excessive thrombin generation, 2. Immune-mediated (inflammation-mediated) thrombosis, 3. Inappropriate or excessive platelet activation, 4. Deficiency of natural anticoagulants and 5. Defective fibrin degradation [6].

Thrombin generation

Excessive thrombin generation is driven by the increased levels of circulating tissue factor (TF). TF is expressed by activated monocytes, endothelial or neoplastic cells and microparticles (MPs) of monocytes or monocyte -platelet complexes, depending on the underlying disease or condition which generates DIC and plays a crucial role in the activation and perturbation of the coagulation cascade [7,8]. Additionally, MPs from platelets and erythrocytes initiate thrombin generation independently of TF in a FXII‐dependent manner [9].

The sum of these pathways results in a repetitive cycle of upregulation of thrombin production through platelet activation and consequently, the translocation of P selectin and the expression of TF, resulting in increased thrombin generation [10].

Immune-mediated (inflammation- mediated) thrombosis

TF expression is upregulated by immune signaling. Pattern recognition receptors (PRRs) binding pathogen-associated molecular patterns (PAMPs) [11], and/or host-derived DAMPs [12], or activating immunoglobulin Fc receptors are initiative signals for the generation of monocyte TF in infection [13]. Autoactivation of FXII can take place after contact with bacteria-derived long-chain polyphosphates (LC-poly-Ps) and platelet-derived short-chain polyphosphates (SC-poly-P) which initiates coagulation.

Protease-activated receptors (PARs) [14], complement mediators [15,16], P-selectin–mediated leukocyte interactions [17], and recognition of DAMPs [18] contribute to the immune mediated amplification of intravascular TF expression.

Proinflammatory cytokines [19], such as tumor necrosis factor (TNF), interleukin (IL)1-β, and IL-6, all have a procoagulant effect [20], and are overexpressed in DIC.  Preclinical experimental sepsis models have highlighted the prothrombotic effect of proinflammatory cytokines through multiple pathways such as the downregulation of anticoagulant mechanisms [21], the support of endotheliopathies [22], and fibrinolysis modulation [23]. Even though promising, the use of TNF and IL-1 inhibitors in sepsis trials did not affect the incidence of DIC [24,25]. Other components of intravascular coagulation activation (thrombin activity, fibrin deposition and platelet aggregation) include the release of neutrophil extracellular traps (NETs; DNA coated in anti-microbial proteins) into the vasculature which results in microvascular hypoperfusion and end organ damage [26], as well as excessive complement activation. Complement and coagulation pathways interact in various ways. Anaphylatoxins, opsonins, and intermediates of the terminal complement complex are complement mediators with known procoagulant effects such as the inflammatory activation of vascular cells through C3a and C5a anaphylatoxins, or the alteration of endothelial permeability through PARs by C4. C5a induces TF expression by the endothelium, monocytes and neutrophils, and complement can also directly activate platelets, thus co-stimulating the cascade leading to thrombi formation in more than one manner [27].

Platelet activation

Endothelial damage, invading pathogens and sepsis -through either direct contact or circulating proinflammatory molecules- call for an immediate platelet response. Early thrombin generation activates platelets which through the release of pro-inflammatory, procoagulant and vasoactive molecules (prostaglandins, serotonin, adrenaline, PF4) and MPs as well as the exposure of procoagulant membrane phospholipids, aggravate the deregulation of coagulation pathways. Platelets express P-selectin, which further contributes to the inflammatory and procoagulant state in DIC, leading to the formation of microvascular thrombi and ultimately to the decrease of platelet count due to excessive consumption [28].

Deficiency of natural anticoagulants

The etiology of the deficiency of natural anticoagulants (antithrombin and proteins C/S deficiencies) in DIC is multifactorial. The increased consumption of the lately activated coagulation factors, particularly thrombin and fibrinogen, due to the continuous and abnormal activation of the coagulation pathway, the deficient hepatic production, the escape of molecules out of the intravascular space, the proteolytic inactivation of serum antithrombic proteins (mediated through the activity of elastase released by activated neutrophils) as well as the hemodilution occurring when multiple red blood cell transfusion therapy is required, are the main causes. Deficient replenishment of the consumed coagulation factors, resulting from inadequate production by the liver is not uncommon, and is attributed to primary or secondary liver failure, usually accompanying many of the primary causes of DIC. On the contrary, increased TF pathway inhibitor (TFPI) levels have been detected in sepsis-associated DIC, but the inhibitor’s capacity to prevent thrombin generation initiated by TF in the systemic circulation is impaired [29,30,31].

Defective fibrin degradation/ fibrinolysis

Tissue plasminogen activator (t-PA) is a normal anticoagulant, released from endothelial cells upon the generation of traces of fibrin polymers in the circulation and initially activates plasminogen, leading to generation of plasmin, which enzymatically cleaves fibrin polymers and results to the formation of elevated levels of fibrin degradation products and particularly of D-dimers. This defensive process is rapidly reversed, due to the inhibition of t-PA by plasminogen activator inhibitor-1 (PAI-1), which is synthesized in the liver, regulated by immune modulators, and is expressed primarily by endothelial cells but is also released by thrombin-activated platelets. High plasma levels of circulating PAI have been associated with poor prognosis and high mortality in patients with DIC [32]. Another contributing factor to the inhibition of fibrinolysis is the activation of thrombin activatable fibrinolysis inhibitor (TAFI). TAFI activation is thrombomodulin dependent and its exact role in DIC is not fully understood [33,34]. In rare cases fibrinolysis is accelerated leading to a hyperfibrinolytic state and major bleeding manifestations, as seen in DIC related to acute promyelocytic leukemia (APL) [35].

ETIOLOGY

DIC is not a primary disease, but (it is) always a syndrome or a complication, secondary to another underlying disease or condition that induces the inappropriate activation of coagulation.

It is estimated that about 35% of all cases of severe sepsis may be complicated by DIC [36].  Classically, infection by Gram-negative bacteria has mainly been associated with DIC. However, according to published data the incidence of DIC in patients infected by Gram-positive cocci is similar [37]. Systemic infections or infestations caused by other microorganisms, including Neisseriae, fungi or parasites may lead to DIC, as well [37]. For example, high degree of parasitemia, primarily by Falciparum malaria, may be complicated by DIC and has been associated by high mortality rate [38].

DIC may emerge in the course of all types of neoplastic disorders, including hematological malignancies as well as solid tumors. In these diseases the coagulation cascade is activated as a result of the membrane surface expression of procoagulant factors by tumor cells. Τhe incidence of DIC in cancer is not precisely known and may depend on the diagnostic criteria used. In some published series, particularly in patients with metastatic adenocarcinoma or in those with lymphoproliferative diseases, the reported incidence rises up to 20% in consecutive cases [39]. In these patients the risk of thrombosis is clearly greater than that of bleeding, but in severe cases, thromboembolism can be seen in conjunction with bleeding manifestations [40].

Severe trauma is another clinical condition commonly associated with DIC. Systemic cytokine patterns in patients with severe trauma have been shown to be virtually identical to those observed in septic patients [41].  In several cases it might be difficult to differentiate DIC from the coagulopathy induced by massive blood loss and by the dilutional coagulopathy manifested as a result of massive transfusion or infusion of large volumes of crystalloids that may occur in the first hours following a major trauma.

Pregnancy is also associated with a risk for hemorrhagic events and obstetrical syndromes that may develop into DIC. During pregnancy, DIC is a rare and unique entity. It is always secondary to an underlying disease or complication and subsides only when the underlying disease resolves. DIC can result from complications unrelated to pregnancy such as sepsis or trauma, but it is also associated with specific pregnancy complications including: 1) acute peripartum hemorrhage (uterine atony, cervical and vaginal lacerations, and uterine rupture), 2) placental abruption; 3) pre-eclampsia/ eclampsia/HELLP syndrome; 4) retained stillbirth; 5) septic abortion and intrauterine infection; 6) amniotic fluid embolism; and 7) acute fatty liver of pregnancy [42].

DIC is also associated with liver pathology. The physiology of the hemostatic system is intricately linked to normal liver function and overly complicated derangements of hemostasis occur in patients with severe liver disease and liver transplantation. The hemostatic abnormalities in patients with hepatic failure or in those that have undergone liver surgery are similar to those in DIC and it is difficult to distinguish whether or not DIC contributes to hemostatic derangements associated with hepatic pathology [43].

For other underlying conditions (Table 1), DIC is a relatively infrequent complication. In most situations, the severity of the associated systemic inflammatory response in combination with specific circumstances, such as concomitant infections, will determine whether severe systemic coagulation activation will occur.

CLINICAL MANIFESTATIONS

Clinical features

The presenting symptoms of patients with DIC vary from asymptomatic patients to severe multiorgan dysfunction related to thrombotic and/or bleeding events and related thrombotic microangiopathy and hemolysis.

Observed clinical manifestations mainly depend on the nature and severity of the underlying disease and the grade of deregulation of coagulation pathways and so DIC may present as either Latent/chronic/compensated or overt. In latent, chronic or compensated DIC the hemostatic dysfunction is often subtle and/or compensated and the clinical presentation is often subacute. In such cases it is common that the thrombotic risk is greater than the bleeding risk, whereas in overt DIC bleeding disorders are a more characteristic finding. Clinical manifestations of patients with DIC are the result of multi-organ dysfunction due to either microvascular thrombosis and hemolytic anemia or thrombotic or bleeding events (DVT, PE, etc.). Common findings are summarized in Table 2.

Classification of clinical DIC types

Classifying DIC types based on differences in pathogenesis is important in order to understand the diversity of DIC and to make early diagnosis of DIC and plan for treatment. A major pathogenetic factor in DIC is marked activation of coagulation and is common to all DIC types, but other aspects of the pathogenesis (especially the degree of fibrinolytic activation) differ considerably depending on the underlying disease. PAI regulates the degree of fibrinolytic activity and is a crucial factor in characterizing DIC [35].

Suppressed-fibrinolytic-type DIC (DIC
with suppressed fibrinolysis)

DIC with suppressed fibrinolysis is typically seen in sepsis. The fibrinolytic inhibitory factor PAI is markedly increased and therefore fibrinolysis is strongly suppressed, the dissolution of multiple microthrombi is more difficult, and as a result of microcirculatory impairment, severe organ dysfunction may occur. However, bleeding complications are relatively mild [35].

Enhanced-fibrinolytic-type DIC (DIC
with enhanced fibrinolysis)

DIC with enhanced fibrinolysis is typically seen in APL, abdominal aortic aneurysm, and prostate cancer and is associated with excessive fibrinolysis corresponding to coagulation activation. Fibrinolysis is strongly activated, with no elevation in PAI, thrombi are more easily dissolved, and bleeding symptoms tend to be severe. Organ dysfunction is less common [35].

Balanced- fibrinolytic-type DIC (DIC
with balanced fibrinolysis)

DIC with balanced fibrinolysis is common in solid cancers in which case bleeding and organ symptoms are relatively uncommon except in advanced cases.

Phenotypic classification of DIC

Moreover, the 2014 International Society of Thrombosis and Hemostasis (ISTH) harmonized guidelines distinguish DIC types based on clinical phenotype [35,44].

Asymptomatic type DIC

Non-symptomatic DIC is seen in variable underlying diseases and is associated with low grade fibrinolysis and/or hypercoagulation.

Bleeding type DIC

In this form of DIC the predominant mechanism is hyperfibrinolysis and is typically seen in leukemias, obstetric complications and aortic aneurysms.

Massive bleeding type DIC

Massive bleeding type DIC occurs when hypercoagulation and hyperfibrinolysis are equally met and is observed in patients who exhibit marked consumption of coagulation factors and excessive bleeding after major surgery or in those with obstetric complications. It can be fatal if not acutely and effectively managed.

Organ failure type DIC

Organ failure type DIC occurs when hypercoagulation is remarkable and dominant and the main symptom is organ failure due to microthrombi. This form of DIC is often observed in patients with infection, particularly sepsis.

DIAGNOSIS

Laboratory tests

There is no single laboratory test that can establish or rule out the diagnosis of DIC. Thus, it is of utmost importance to assess thoroughly the clinical presentation of the patient, taking into account the underlying condition and all available laboratory results.  Moreover, since DIC is an evolving process, laboratory test values are a snapshot of this dynamic state and must be regarded as such. In addition, in some cases the underlying causative condition or even unrelated co-morbidities of the patient might affect laboratory values assessed for the evaluation of DIC severity. Hematologic malignancies that affect the platelet number regardless of DIC severity or coagulation time prolongation in preexisting hepatic dysfunction are representative examples. However, a combination of tests, when performed regularly in a patient with a clinical condition known to be associated with DIC, can be used to diagnose the disorder with reasonable certainty in most cases.

Laboratory studies used in diagnosis and evaluation of the prothrombin time (PT), activated partial thromboplastin time (aPTT) or platelet count, provide important evidence of the grade of coagulation factor consumption and activation. The laboratory abnormalities detected, in decreasing order of frequency, are thrombocytopenia, elevated fibrin degradation products, prolonged PT, prolonged aPTT, and low fibrinogen.

Platelet count

Low platelets or a rapidly progressing thrombocytopenia is a key finding in DIC. Moderate (< 100,000/ mm3) to severe thrombocytopenia (50,000/ mm3) is seen in the majority of patients and those with <50,000 have a 4-5-fold increase in bleeding complications compared to those with a normal platelet count.  It is a sensitive but not specific finding of DIC. Thrombocytopenia is seen in about 98 % of cases, with a platelet count of <50,000/ mm3 in about half of the cases. On the other hand, as mentioned above a low or decreasing platelet count is not specific for DIC since conditions associated with DIC such as acute leukemia and sepsis can also present with thrombocytopenia in the absence of DIC.

Fibrin degradation products and D-dimers

Fibrin degradation product (FDP) is a measure of increased fibrinolytic activity, which is also increased in DIC. FDPs may be detected by specific enzyme-linked immunoabsorbent assays or by latex agglutination assays. FDPs and D-dimers should not be considered as stand-alone tests, but as a useful indicator of DIC when there is an elevation in D-dimer levels with concomitant falls in the platelet count and changes in coagulation times. The specificity of elevated levels of FDPs is limited and many other conditions, such as trauma, recent surgery, inflammation, or venous thromboembolism are associated with elevated FDPs. Soluble fibrin monomer measurements offer theoretical advantages in DIC in reflecting thrombin activity on fibrinogen and are one of the best parameters for detection of developing DIC. However, a major problem remains, that of reliable quantification, with wide discordance reported.

PT and aPTT

Both PT and aPTT are reported prolonged in about 50 % of DIC cases and this is attributed to the consumption of coagulation factors. Prolongation of PT and aPTT can also be detected in impaired synthesis of coagulation factors and in massive bleeding [44,45]. At the same time, at least in half the patients with DIC, PT and aPTT are found normal or even shortened due to the presence of circulating activated clotting factors like thrombin or Xa. Thus, a normal PT or aPTT does not exclude DIC and repeated monitoring is required [46].

Fibrinogen

Measurement of fibrinogen has been widely advocated as a useful tool for the diagnosis of DIC but in fact is not helpful in most cases [47]. Fibrinogen acts as an acute –phase reactant and despite ongoing consumption, plasma levels can remain well within the normal range for a prolonged period. In a consecutive series of patients, the sensitivity of a low fibrinogen level for the diagnosis of DIC was only 28% and hypofibrinogenemia was detected in very severe cases of DIC only [47]. Fibrinogen levels can be normal in as many as 57% of patients [48].

Blood film

The evaluation of the blood film of a patient with DIC can confirm the platelet count when there is doubt, identify pathological cells (e.g. leukemic or lymphomatic cells) in case of underlying hematological malignancy and detect fragmented red blood cells. Fragmented red blood cells are the result of hemolysis due to thrombotic microangiopathy, and although reported in patients with DIC, rarely constitute > 10% of the red blood cells. The finding of fragments is neither sensitive nor specific to DIC. When they are seen in increased numbers, other potential diagnoses, such as thrombotic thrombocytopenic purpura and other causes of thrombotic microangiopathy should be considered.

Specialized tests

In a specialized setting, molecular markers for activation of coagulation or fibrin formation may be the most sensitive assays for DIC [6]. A number of clinical studies show that the presence of soluble fibrin in plasma has a 90-100% sensitivity for DIC but, unfortunately, a relatively low specificity. The dynamics of DIC can also be judged by measuring activation markers that are released upon the conversion of the coagulation factor zymogen to an active protease, such as prothrombin activation fragment F1+2. Indeed, these markers are markedly elevated in patients with DIC, but again, the specificity is not adequate.

Levels of antithrombin activity decrease in severe sepsis [49] and are associated with poor survival [50]. The Japanese Association for Thrombosis and Hemostasis (JSTH) proposed in 2018 new DIC diagnostic criteria which include antithrombin activity [51]. Previously, in 2016 Iba et al had proposed a revision of the Japanese Association for Acute Medicine (JAAM) DIC diagnostic criteria using antithrombin activity [52].

Evidence also suggests that serum levels of thrombomodulin, a marker for endothelial cell damage, correlate well with the clinical course of DIC, the development of multiple organ dysfunction syndrome (MODS), and mortality in septic patients. Thrombomodulin is elevated in DIC, and this elevation not only correlates well with the severity of DIC but also can serves as a marker for early identification and monitoring of DIC [53].

Thromboelastography (TEG) is a point-of-care test that evaluates the entire process of clot formation and dissolution. TEG has been reported as useful in the diagnosis of coagulation abnormalities in sepsis patients and may be associated with clinical prognosis [54]. The advantage of this test is that it enables bedside performance and can be used in acute care settings.

Scoring Systems

Multiple scoring systems have been developed in Japan, Italy and the United Kingdom for the diagnosis of DIC. The major concern that arises with the use of these scoring systems is their ability to diagnose non-overt DIC, as well as initial stages of acute DIC.

 The scoring system of The International Society on Thrombosis and Hemostasis (ISTH) is widely used for the diagnosis of overt DIC [55,56,57,58] (Table 3). It is a five-step diagnostic algorithm to calculate a DIC score based on simple laboratory results. For a diagnosis of DIC, a score of ≥5 is required regardless of the etiology of DIC. The score has a sensitivity of 93% and specificity of 98% [59,60] and a strong correlation between an increasing score and mortality has been reported. The severity of DIC according to this scoring system is a strong predictor for mortality in sepsis [61].

As concern pregnancy, none of these scores is adjusted for the physiologic hemostatic changes occurring in pregnancy. Based, on this consideration Erez et al. [62], developed a pregnancy modified DIC score by using only three components of the ISTH DIC score (platelet count, fibrinogen concentrations and the PT difference) (Table 4) and showed that at a cutoff of ≥26 points had a sensitivity of 88%, a specificity of 96%, a positive likelihood ratio of 22, and a negative likelihood ratio of 0.125 for the diagnosis of DIC.

Differential Diagnosis

The differential diagnosis of DIC is broad and includes other causes of consumptive coagulopathies, such as trauma and major surgery. In addition, severe liver disease can result in markedly reduced production of coagulation factors and inhibitors. Thrombocytopenia may also occur in this setting secondary to splenic sequestration, resulting in an overall clinical picture quite similar to DIC.

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are thrombotic microangiopathies that share similar clinical features with DIC, but in contrast to DIC, the mechanism of thrombosis is not via the TF/factor VIIa pathway. Results of blood coagulation assays in TTP and HUS are normal [63] and thrombosis arises from direct platelet activation, usually as a result of widespread endothelial damage or an inherited or acquired impairment of ADAMTS13, a protease that normally cleaves von Willebrand factor (vWF), which results in ultra-large vWF polymers (ULVWF) that agglutinate platelets, leading to thrombosis and shearing of red blood cells [64]. Moreover, TTP and HUS are associated with microangiopathic hemolytic anemia, whereas in DIC hemolysis is not a feature.

Other thrombotic microangiopathies include chemotherapy-induced or stem cell transplant–associated microangiopathy and HIV-induced TTP [65].

Thrombocytopenia is present in both DIC and immune thrombocytopenia (ITP). However, ITP is distinct from DIC in terms of its pathophysiologic mechanism and does not involve coagulation activation, microangiopathic hemolytic anemia or presence of typical schistocytes in blood films.

Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) is another clinical entity with a presentation similar to that of DIC but microangiopathic hemolytic anemia is absent, and the history of heparin administration is a weighing factor for differential diagnosis. A subgroup of patients who have received heparin develop antibodies against platelet antigens (PF4) which leads to thrombocytopenia derived from platelet destruction and in some cases thrombosis as a result of platelet activation. In HITTS, the plasma PT, the aPTT, and the fibrinogen levels are normal [66].

MANAGEMENT

General principles of DIC management

Managing thrombotic and hemorrhagic risk in DIC is a challenge for the clinical physician. Replacement of deficient hemostatic components is not a straightforward decision to make in most cases and the synchronous configuration of both thrombotic and fibrinolytic pathways demands a complex therapeutic algorithm. Multiple factors should be taken under consideration, such as the etiology of DIC, the thrombotic versus hemorrhagic manifestations or risk of the specific patient, laboratory test values, co-morbidities, and estimated time to treatment of underlying etiologic condition.

DIC is always secondary to an underlying condition and thus the cornerstone of management is the treatment of etiology [67]. This is more profound in obstetrical DIC, where the coagulation disorder is often resolved by the removal of the placenta. Similarly, in cases of infectious sepsis, appropriate antibiotics and/or surgical drainage are necessary [4] whereas in cancer patients, treatment should not be delayed [68].

Prophylactic and therapeutic anticoagulation

Based on the previous knowledge of the partial inhibition of coagulation activation [69] by heparin, its benefit in DIC was early investigated. Heparin use results in restraining excess effects of thrombin [70] and improving laboratory values [71]. Although critically ill patients and patients with sepsis have been found to benefit from prophylactic use of heparin [72,73] and its use has been standard of care, there is no large randomized trial demonstrating the clinical impact of heparin use in patients with DIC. A meta-analysis of trials of anticoagulant therapy in patients with sepsis, showed a significant reduction in mortality in the population with sepsis associated DIC who received any of the examined treatments as compared to those who did not receive any anticoagulant treatment [74].

Choice of heparin has been a debatable issue. A small, randomized trial showed that low molecular weight heparin (LMWH) is superior to unfractionated heparin (UFH) for treating DIC [75] and thus it is more commonly suggested, except in cases with high risk of bleeding and renal failure, where UFH is preferred due to its easier reversibility [76]. In general, thromboprophylaxis is indicated in DIC, but should be paused or avoided in bleeding or high- bleeding risk patients or if platelet count drops below the threshold of 20 x 109/l [58].

Cancer-mediated prothrombotic state is well clinically established. Cancer patients with DIC are at substantial risk of several types of thrombosis, not only due to pathogenetic mechanisms described, but also to other contributing factors, such as recent surgery, immobilization, advanced age, indwelling catheters that may favor thrombosis, and chemotherapy- induced endothelial damage. Therefore, thrombosis prevention with unfractionated or LMW heparin has become customary in patients with malignancies and signs of a procoagulant condition [77].

APL is a high bleeding risk hematological malignancy, and the concern of hemorrhagic death does not allow indiscriminate use of anticoagulation [78]. As a result, caution is advised regarding thromboprophylaxis, and prophylactic platelet transfusion is suggested to maintain platelet counts above 30 x 109/l [79].

As obstetric DIC primarily manifests with bleeding, the role of UFH or LMWH is unclear and should be reserved for patients in whom thrombosis is the dominant manifestation, such as amniotic fluid embolism or mismatched blood transfusion [58,80].

Optimal timing for the initiation of pharmacological thromboprophylaxis is often difficult for trauma DIC, but it is generally suggested within 24 hours after bleeding control or at 48 hours of hospitalization to reduce venous thromboembolism (VTE) risk [81]. Therapeutic heparin use in DIC is restricted to patients with VTE or severe thrombotic manifestations, such as acral ischemia, and the use of LMWH is preferred to UFH [57,58,82]. In patients with thrombosis and concomitant bleeding, a vena cava filter should be considered in parallel with platelet and FFP transfusion strategies, permitting the use of therapeutic LMWH [83].

Direct oral anticoagulants (DOACs) specifically inhibit thrombin and factor X, hence theoretically their use in DIC would be reasonable. Nevertheless, current literature data consists only of case reports [84].

Platelet transfusion

Platelet or plasma transfusion should not be started based on laboratory results alone. Platelet transfusion is recommended under the threshold of 50 x109/l in DIC patients with major bleeding, such as in a perioperative period, obstetric DIC complicated by postpartum hemorrhage. In severe trauma with concomitant ongoing bleeding or trauma brain injury, maintenance of a platelet count above 100 x109/l is advised [85].

In cancer-DIC or patients with minor or no bleeding, a markedly lower threshold of 20 x109/l for platelet transfusion is advised [58,83]. In APL patients, given the high risk of hemorrhagic mortality during early induction, ISTH suggests a higher transfusion threshold of platelet count < 30 ×109/L [79].

In patients undergoing surgery or invasive procedures, transfusions of one to two doses of platelets are suggested if the platelet count is less than 30 x109/l in APL, and less than 20 x109/l in other malignancies [76].

Plasma /Cryoprecipitate /Fibrinogen concentrate transfusions.

To support coagulopathy in patients with DIC and active bleeding or prolonged aPTT and/or PT values (> 1.5 times normal), fresh frozen plasma transfusions are indicated (15-30ml/kg) [32,58]. Careful clinical and laboratory monitoring is required for dose adjustments. For patients in danger for volume overload, smaller volumes of prothrombin complex concentrates (PCC) might be of use. However, most PCC contain the vitamin K-dependent FII, FVII, FIX and FX, but lack important coagulation factors, e.g. FV, and no specific dosing strategies exist [58,82].

Generally, it is well established that fibrinogen levels <100 mg/dL is a critical threshold to treat hypofibrinogenemia [86]. As far as DIC is concerned, in bleeding patients and fibrinogen levels <150 mg/dL and in women with concomitant postpartum hemorrhage with fibrinogen levels <200mg/dL, administration of fibrinogen is indicated either as fibrinogen concentrate or as cryoprecipitate. Administering fibrinogen concentrate 30 mg/kg, the level of fibrinogen will increase 100 mg/dL, whereas for cryoprecipitate, two pools are recommended to increase fibrinogen levels [32,58].

In trauma induced DIC with substantial bleeding, where fibrinolysis is mostly prominent, either plasma transfusion is recommended to maintain PT and APTT <1.5 times the normal control or treatment with fibrinogen concentrate or cryoprecipitate if significant bleeding accompanied by a plasma fibrinogen level of less than <150 mg/dL. Initial fibrinogen supplementation of 3–4 g fibrinogen concentrate is equivalent to 15–20 single donor units of cryoprecipitate. In a massive bleeding setting, plasma (FFP or pathogen-inactivated plasma) is advised in a plasma–RBC (red blood cell) ratio of at least 1:2 [85].

FVIIa binds to TF at the site of endothelial damage and their complex is necessary to initiate hemostasis [87]. In concentrations higher than normal, FVIIa can activate FX on activated platelets as well, leading to an excess thrombin production [88]. In patients with severe overt DIC and hemorrhage refractory to FFP, PCCs and platelet concentrates, treatment with recombinant FVIIa (rFVIIa) is an additional option. This option is exceptionally used in the management of obstetrical DIC secondary to placental abruption or amniotic fluid embolism with severe peripartum hemorrhage or major bleeding and traumatic coagulopathy persistent despite all other attempts to control bleeding and best-practice use of conventional hemostatic measures [89]. Treatment with rFVIIa is commonly at a dose of 90-100 μg/kg. However, this treatment should be used with caution and in selected cases because of the increased thromboembolic risk [90].

Anticoagulant factor concentrates.

The use of different agents restoring dysfunctional anticoagulant pathways in patients with DIC, has been the center of attention early on. Antithrombin concentrate has been available for more than 30 years, but large multicenter studies have failed to demonstrate survival benefit [4,91].

Clinical efficacy of activated protein C (APC) in sepsis was assessed in a large, randomized trial [92] and a post hoc analysis demonstrated its benefit specifically in patients with overt DIC [61]. Nevertheless, afterwards, the ADRESS study, showed that in patients with low mortality risk (APACHE score <25 or single organ failure), APC had no significant benefit and resulted in more severe bleeding episodes [93]. With the increasing uncertainty about efficacy and the concerns about bleeding risk, the PROWESS-SHOCK trial was initiated to reexamine the risk-benefit profile of the drug. This trial, involving 1697 patients, failed to show any benefit in mortality compared to a placebo, even in patients with severe protein C deficiency. Following these results, the product was withdrawn from the market worldwide [6].

Thrombomodulin forms a complex with thrombin and subsequently inhibits its activity. Thrombomodulin recombinant soluble form (recTM) is extensively studied in Japan, for DIC associated with sepsis or cancer [58]. In a recent randomized trial, including 816 patients with mean APACHE II score approximately 22 in both drug and placebo groups, only minor reduction in mortality was demonstrated, though with notably no increase in bleeding risk [94].

TFPI inhibits factor Xa directly and is the main inhibitor of the TF/FVII catalytic complex and thus it would be an excellent target for DIC treatment. Nevertheless, the phase 3 multicenter OPTIMIST trial failed to show a survival benefit in patients with severe sepsis receiving recombinant TFPI compared to placebo [95].

Anti-fibrinolytics

As suppression of fibrinolysis is a contributing factor in sepsis DIC, the use of anti-fibrinolytics is generally not reasonable [32]. Although these agents were advocated for the treatment of hyperfibrinolytic DIC of APL before the era of all-trans retinoic acid, a larger retrospective study did not demonstrate clinical benefit [96]. Moreover, the PETHEMA group study failed to identify a clear reduction on hemorrhagic incidents with systematic tranexamic acid prophylaxis along with induction therapy but demonstrated a higher incidence of thrombotic events [97]. In summary, antifibrinolytic agents are not routinely recommended even for hyperfibrinolytic DIC and may be deleterious in the other types. However, if therapy resistant bleeding dominates the picture in hyperfibrinolytic DIC, tranexamic acid may be considered [76]. Especially in severely bleeding trauma patients, tranexamic acid is only found to be beneficial if administered within 3 hours after injury [85].

The treatment algorithm of DIC is depicted in figure 1 and molecular targets of therapeutic interventions in figure 2.

Figure 1. DIC treatment algorithm.

Figure 2. DIC pathophysiology. Pathophysiology of DIC is characterized by: 1. Excess thrombin generation driven by TF, 2. Consumptive coagulopathy and deficiency of natural anticoagulants (protein C, S), 3. Platelet activation enhanced by endothelial damage, pathogens and proinflammatory molecules 4. Defective fibrin degradation and 5. Immune-mediated thrombosis. Therapeutic measures target distinct parts of these pathways. Heparin, LMWH, DOACs, TFPI and rTM act by inhibiting excess thrombin and activated factor Xa. Platelets, FFPs, CCPs and fibrinogen partially restore consumptive coagulopathy in patients with high bleeding risk. APC used to substitute protein C is currently withdrawn from the market. rFVIIa binding to TF to initiate hemostasis, is only used in DIC with persistent bleeding.

Prognosis

Prognosis of patients with DIC depends on the severity of the coagulopathy and on the status of the underlying condition that led to the manifestation of DIC. Assigning numerical figures to DIC-specific morbidity and mortality is difficult. The following are examples of mortality rates for diseases complicated by DIC:

Idiopathic purpura fulminans associated with DIC have a mortality rate of 18%.

Septic abortion complicated by clostridial infection and septic shock associated with severe DIC has a mortality rate of 50%.

In the setting of major trauma, the presence of DIC approximately doubles the mortality rate [50,98].

In general, if the underlying condition is self-limited or can be appropriately managed, DIC will disappear, and coagulation will be gradually restored. A patient with acute hemorrhagic DIC that is associated with metastatic gastric carcinoma most probably has a lethal condition that does not alter patient demise, regardless of the applied treatment. On the other hand, a patient with acute DIC associated with placental abruption needs quick recognition and obstetric treatment; in this case DIC will be resolved with the treatment of the obstetric catastrophe.

DIC has been shown to be an independent predictor of mortality in patients with sepsis and severe trauma [99-103). The presence of DIC may increase the risk of death by a factor of 1.5 to 2.0 according to numerous studies. A study utilizing the JAAM diagnostic criteria for DIC, showed that septic patients with DIC had a higher mortality than trauma patients with DIC did (34.7% vs 10.5%) [104].

DISCUSSION

DIC is a common, multifactorial, complex consumptive coagulopathy, endangering patients of all races, gender and ages with different underlying conditions and increasing their mortality. Sepsis, cancer, major trauma, and obstetric emergencies are four of the main underlying conditions associated with DIC. Clinical approach demands understanding of the pathogenetic mechanisms, identification of the underlying causative factor, thorough physical examination, and regular laboratory tests to evaluate the thrombotic versus bleeding risk of the patient and the severity of their clinical status, and choice of the appropriate supportive measures.

 Thrombin generation, deficiency of natural anticoagulants, platelet activation, defective fibrinolysis and immune-mediated thrombosis are the major pathogenetic mechanisms. The grade of dysregulation of these pathways and the capability of repairing mechanisms to restore coagulation balance will define the spectrum of clinical manifestations exhibited by patients with different underlying conditions and lead to distinct phenotypes. These different subtypes of DIC phenotype are one of the reasons that this clinical entity is a challenge for the physician in terms of diagnosis but also management.

Laboratory tests are mandatory for the diagnosis and regular follow up is needed to assess both the grade of the coagulopathy as well as the effectiveness of treatment.  Different scoring systems assess the probability and/or severity of DIC and can be easily incorporated in routine clinical practice. Current therapeutic interventions are mostly supportive and difficult to manage due to simultaneous existence of both bleeding and thrombotic risk, limited availability of real time evaluation of measurements depicting the severity of coagulopathy and the multifactorial pathogenesis of DIC which stimulates a vicious cycle. This explains why no single treatment option has proven to be adequate to restrict the phenomenon once initiated. Our interventions should be carefully justified and there should be constant re-evaluation of clinical and laboratory parameters to guide our therapeutic strategy.

Conflict of interest disclosure: None to declare.

Declaration of funding sources: None to declare.

Author contributions: E.V. contributed to the conceptualization and design of the review, conducted literature review, and drafted the manuscript. C.V and T.C. conducted literature review, created figures and tables, and contributed to the writing of specific sections. A.S. provided critical feedback on the manuscript and revised the content. All authors read and approved the final manuscript.

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