Disseminated intravascular coagulation (DIC) is always secondary to some process that leads to pathologic and systemic production of thrombin. These stimuli may either be very brisk, yet brief and limited (such as various obstetrical emergencies), or sustained and chronic (e.g., cancer, chronic aortic aneurysms, and various infections). Liver disease, whether appreciated or occult, increases the susceptibility of the host to DIC, regardless of the initiating process. Thus, DIC can present in a variety of clinical situations, yet it remains that DIC is always the final common pathway that results from that situation; therefore, treatment must be aimed at the underlying cause, not the resulting coagulopathy.
If one has to question seriously whether a patient has acute DIC, the patient probably does not. The clinical features to be outlined below are obvious at the bedside, and laboratory tests are available for confirmation of the suspected diagnosis. DIC should not be viewed as a laboratory diagnosis, rather a clinicopathologic one. Underlying illnesses triggering DIC tend to be obvious (see “Which individuals are most at risk for developing DIC?” below). All these disorders cause excessive production of thrombin by virtue of the injury or death of cells such that tissue factor (TF) is released in excess. Other mediators, especially in infection, are circulating cytokines (including TNF-alpha, interleukin-1, and interleukin-6), which in turn cause cells to release TF.
There is a spectrum of thrombosis and hemostasis in all cases of DIC. Each or both may be encountered in any given patient with DIC. Certain underlying conditions, e.g., the pregnancy-related conditions, may predispose to the bleeding phenotype while others, e.g., adenocarcinomas, are strong inducers of thrombotic DIC.
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The key bedside feature in hemorrhagic DIC is bleeding occurring at multiple sites simultaneously. In a postoperative patient, there is bleeding from all incisions, wounds, and at insertion sites of intravascular devices. Hemorrhage from the nose, gums, and skin (petechiae and ecchymoses) is encountered. Paradoxically, hemorrhagic infarction of the skin (purpura fulminans [PF]) is characteristic of DIC by virtue not of hemorrhage but by microinfarction of skin such as seen in meningococcemia. Postoperative hemorrhage, even should it be serious, if limited to the operative site without any of these other manifestations, is strong mitigating evidence against DIC and implicates some structural local problem in the operative bed; re-exploration of the wound is usually necessary. Thrombosis associated with DIC can occur in venous or arterial beds and in small or mid/large sized vessels, and in the acute or chronic setting. Thrombosis is often the cause of multiorgan failure which patients frequently succumb to.
Beware of other conditions that can mimic disseminated intravascular coagulation:
In a patient with an appropriate initiating cause who presents with hemorrhage, thrombosis, or both, the diagnosis is near certain. However, no single laboratory test can be used to diagnose DIC alone. Therefore, within any acute thrombohemorrhagic emergency, the following should be considered within the differential diagnosis: thrombotic thrombocytopenic purpura (TTP), heparin-induced thrombocytopenia (HIT), hemolytic anemia with elevated liver enzymes and low platelets (HELLP syndrome) in pregnant patients, and thrombotic storm (TS)/catastrophic antiphospholipid syndrome (CAPS) (Table I).
The key is still the clinical context of each patient. Treatment and prognosis are diagnosis-specific, so a timely and correct diagnosis of the underlying condition is important.
If one minimizes or is unaware of the clinical context and thus pays excessive attention only to the laboratory abnormalities, rather than what is seen at the bedside, the two primary laboratory situations with which DIC may be confused are: first, chronic, stable, compensated liver disease; and second, dilutional coagulopathy.
In the first situation, the patient is not hemorrhagic and, typically, is not acutely ill. Confusion results by virtue of the severe liver disease, which itself (without excessive thrombin production) results in prolongations of the prothrombin time (PT), partial thromboplastin time (PTT), thrombin time (TT), accumulation of fibrin degradation products (FDP)/D-dimer, low fibrinogen, and thrombocytopenia due to hypersplenism from portal hypertension. These patients are not in DIC, although their laboratory studies mimic those of DIC. The clinical context is the key.
In dilutional coagulopathy, the patient’s PT, PTT, TT, and platelet count are all diluted because of massive infusion (several liters) of packed red blood cells, fresh frozen plasma (FFP), or crystalloid solutions which lack platelets and most coagulation factors. These fluids are frequently infused in resuscitative response to structural bleeding such as unligated or ruptured arteries, esophageal varices, or other vessels or wounds in need of structural exploration and repair. Again, thrombin production is neither excessive nor sustained.
Physiologic hemostasis depends on adequate, yet governed, thrombin generation via activation of the coagulation cascade. The foremost physiologic activator of coagulation is tissue factor (TF). TF is constitutively contained in most cells of the body, so that if these cells are stimulated, crushed, damaged, or otherwise injured, proinflammatory cytokines are released and induce TF escape from its intracellular milieu into the local environment. This results in the generation of thrombin through the TF/FVIIa pathway to promote hemostasis within the immediate area. Any excessive TF and its end product, thrombin, escaping the immediate area of injury are neutralized by a variety of mechanisms. Physiologic hemostasis occurs when TF and thrombin generation is sufficient to control hemorrhage, yet not excessive enough to escape neutralization and cause widespread coagulation.
On the other hand, DIC is the pathologic result if production of TF and thrombin are excessive from a massive or sustained underlying stimulus. Accordingly, a functional definition of DIC is the syndrome resulting from overstimulation of physiologic hemostasis, such that TF and thrombin are produced in quantities in excess of the capacity of inhibition – allowing these activators to gain access to the general circulation.
Free, circulating, unbound thrombin is mitigated by four general mechanisms: inhibitors [antithrombin (AT) and thrombomodulin]; clearance by a healthy reticuloendothelial system; dilution of any remaining thrombin by normal blood circulation; and fibrinolysis. Accordingly, enhancers of DIC include perturbations of any of these four mechanisms: absence of inhibitors due to consumption, degradation, or defective synthesis.
Severe systemic infections or sepsis are the most common causes of DIC. Purpura fulminans, a severe form of DIC, is characterized by diffuse microthrombi of the skin leading to hemorrhagic necrosis. This is classically seen in meningococcemia. Extensive acute tissue damage as seen with trauma and hemorrhagic shock are the most immediate triggers of DIC. Many obstetric causes of DIC occur by virtue of TF leakage from the damaged placenta or uterus. Malignancies associated with DIC range from solid tumors that can predispose to the thrombotic phenotype of DIC to hematologic malignancies such as acute promyelocytic leukemia which often present with hemorrhagic DIC. The venom of certain snakes can induce a laboratory coagulopathy similar to DIC, however, despite these abnormal tests patients rarely have hemorrhagic or thrombotic complications.
Processes that may induce DIC:
Trauma
Crush injuries
Central nervous system injuries
Heatstroke
Burns
Hemolytic transfusion reaction
Acute transplant rejection
Malignant solid tumors (e.g., those with Trousseau syndrome)
Leukemias (e.g., acute promyelocytic leukemia)
Cancer chemotherapy
Tumor lysis syndrome
Gram-positive bacteria
Gram-negative bacteria
Spirochetes
Rickettsiae
Protozoa
Fungi
Viruses
Abruptio placentae
Placenta previa, accreta, and percreta
Retained products of conception
Amniotic fluid embolism
Uterine atony
Therapeutic abortion
Toxemia of pregnancy
Acute fatty liver of pregnancy
Shock
Cardiac arrest
Near drowning
Fat embolism
Aortic aneurysm
Giant hemangiomas
Severe allergic/toxic reactions
What other clinical manifestations may help me to diagnose disseminated intravascular coagulation?
Two causes of chronic DIC are abdominal aortic aneurysm (AAA) and malignancy. In AAA, blood in the false channel or large saccular area may clot. This clotting will generate thrombin, which can regain entry into the general circulation because of the aneurysm’s communication. This results in periodic excess of coagulation with resultant worsening of coagulation tests. Further, these vascular lumens can sequester and consume platelets, fibrinogen, and other coagulation factors occasionally leading to ecchymoses and bleeding. Some clinicians have tried to interrupt this process with heparin, and have reported success; however, most authorities think this success would have happened anyway, as this chronic form of DIC waxes and wanes. Patients healthy enough to undergo surgical repair of the AAA do surprisingly well with laboratory markers normalizing quickly after surgical correction.
In the chronic DIC associated with underlying malignancy, patients may develop epistaxis, purpura, or inter-current thrombocytopenia. In patients without a prior diagnosis of a malignancy, these events may eventuate in the discovery of cancer.
In acute fulminant DIC, almost always there are obvious laboratory perturbations of the coagulation system as manifested by any combination of prolongation of the PTT, PT and TT, as well as the production of pathologic amounts of FDP or D-dimer and thrombocytopenia. PT and PTT prolongations reflect consumption of coagulation factors while a prolonged TT is due to elevated fibrin split products and decreased fibrinogen levels (although the latter may actually be normal or elevated as an acute phase reactant). Unfortunately none of the above abnormalities are specific for DIC and therefore DIC remains a clinical diagnosis.
The production of large amounts of FDP/D-dimer is the result of plasminogen being rapidly converted to plasmin, with resultant lysis of fibrin (and even fibrinogen) into FDP. Plasmin is produced by activation of endothelial-bound thrombomodulin by thrombin, resulting in release of tissue plasminogen activator (tPA) and activation of the protein S/protein C system. tPA briskly converts plasminogen into plasmin. In most cases of acute florid DIC, there is concomitant activation of both the coagulation system and the fibrinolytic system, so that free circulating plasmin exists.
Thromboelastography (TEG) and the point of care rapid rotational thromboelastometry (ROTEM) may provide a reasonable estimation of global hemostasis in DIC patients. The advantage over traditional coagulation assays, such as the PTT and PT, is that the TEG/ROTEM provide information regarding platelet function, fibrinolysis, and the overall robustness of the fibrin clot. However, these tests may not be readily available at many institutions.
Accordingly, initial laboratory assessment includes checking platelet count, fibrinogen level, PT, PTT, TT, and estimation of FDP/D-dimer, which are almost universally available. By inspection of the blood smear, one can appreciate thrombocytopenia and occasional schistocytes, neither of which are specific for DIC or the underlying cause of DIC.
The results of more specialized tests that one might obtain often do not return for several days. These include assays for activity of anti-thrombin (AT), plasminogen, protein C or protein S. These rarely improve the diagnosis or management of acute DIC.
The primary effort is to identify and treat the underlying cause that initiates DIC. If it is infectious, appropriate antibiotics need to be initiated; if abscesses are present, these must be drained. Should DIC be a result of a complication of pregnancy (abruptio placentae, placenta previa, retained products of conception), prompt evacuation of the uterus is mandatory. If acute DIC is a complication of trauma, all efforts must be made to intervene aggressively on repairable injuries, and to minimize the DIC-provoking triad of acidosis, hypothermia, and hypotension. If DIC is primarily due to malignancy, one must pursue all practical measures to treat the underlying malignancy.
The likelihood of the patient surviving DIC is primarily determined by the ability to identify and reverse the underlying pathophysiologic mechanism. A tenet of this approach, is that one cannot tolerate timidity (because of coagulopathy) in draining abscesses, evacuating the uterus, or surgical repair of traumatic injury. One cannot hesitate to await correction of the laboratory tests with the infusion of various blood products, as the coagulopathy is the result, not the cause, of the clinical situation. Coagulation tests will not improve unless and until these procedures are done and the inciting pathologic disorder is addressed.
There is meager evidence, at best, to support the notion that blood products (packed red blood cells, fresh-frozen plasma [FFP], cryoprecipitate or platelet concentrates) are sufficient to overcome this process. Some transfused patients do improve, yet it is more likely that in the meantime the cause was self-limited, such as a brief septicemia episode or an obstetrical complication prior to successful evacuation of the uterus. Thus, evidence for the benefit of transfusing blood products is illusory. Because it has recently been determined that the chief cause of transfusion-related death is transfusion-related acute lung injury (TRALI) (about 35% fatal), there is increasing evidence that FFP transfusion presents a real risk; thus, routine and massive infusion of FFP is becoming less acceptable.
Patients with active bleeding or high risk for bleeding requiring invasive procedures/surgeries should be considered for transfusion of blood products. In general, maintaining a platelet count of 50,000-75,000/mm3 and hematocrit level of 25%-35% is logical. It is usually advised to maintain fibrinogen levels of 50-100mg/dl, with cryoprecipitate infusion being the preferred blood product for providing fibrinogen.
If the patient is improving, this will usually be evident by improvement in the clinical situation; accordingly, a patient in shock and with acidosis will have a return of blood pressure and a correction of acidemia. One could serially measure the PT, PTT, TT, D-dimer and platelet count daily and find some encouragement as these results improve; however, a firmer prognosis is derived from successful treatment for the underlying cause. The platelet count and disappearance of schistocytes on peripheral blood smear may lag several days behind obvious improvement. Rely on bedside observations for signs of recovery.
Evidence that other blood products (AT concentrates or recombinant activated factor VII) are efficacious is limited, and neither of these should be viewed as standard of care. Activated protein C infusion had shown some initial success in decreasing mortality in patients with severe sepsis, however it was withdrawn from the market in 2011 based upon updated data from the PROWESS-SHOCK trial in which a statistically significant reduction in 28-day all-cause mortality was not shown. While antifibrinolytics are effective in treating bleeding, these agents are not routinely recommended in DIC, especially in the setting of organ failure or thrombosis. In DIC complicated by hyperfibrinolysis, antifibrinolytics may be given if severe bleeding does not respond to standard replacement therapy. Efficacy of any product will probably be more a function of the specific cause of DIC, rather than the final common pathway represented by the manifestations of DIC. Thus, what might work for pneumococcal sepsis in a post-splenectomy patient with DIC should not be expected to be the agent of choice in a case of DIC associated with an ABO mismatched transfusion reaction. Currently, there is no consensus about the use of any of these products. Recombinant FVIIa (rFVIIa) is often used as a final option in patients with uncontrolled bleeding. If pathologic and widespread thrombin activation is felt to be the culprit in DIC then use of rFVIIa has no role and in fact could be detrimental in the DIC patient.
If circulating thrombin is the prime initiator of DIC, should one consider infusion of heparin to neutralize thrombin? Although logical, no studies have shown that heparin infusion improves survival when all cases of DIC are considered. Based on limited data, some authorities recommend aggressive heparin infusion in cases where the primary bedside manifestation is thrombosis, particularly of the skin such as seen in pneumococcemia or meningococcemia; however, no series of patients with those diseases has established that infusion of heparin is unequivocally efficacious. In fact, other evidence indicates that infusion of heparin in most cases of acute DIC actually increases hemorrhagic death. Since patients with DIC are at high risk for VTE, prophylaxis with UFH, low-molecular weight heparin, and/or mechanical strategies should strongly be considered.
Unfortunately, acute fulminant DIC has a mortality of about 65-85%. Survivors are young and healthy enough to resist the insult, especially when the cause is identified and quickly reversed, so that excessive thrombin production is abrogated. At the forefront of this group are the obstetrical catastrophes. Aggressive obstetrical care with prompt delivery has greatly lowered morbidity and mortality. On the other end of the spectrum, mortality is extremely high in diseases that are not easily reversible and are near end-stage. These latter include sepsis in patients with refractory leukemias and lymphomas, as well as other neoplastic diseases for which efficacious therapeutic options may be inadequate. Any case of DIC will fare much worse in the face of concurrent hepatic dysfunction.
As a general rule, the easier it is to detect and treat the cause, the better the outcome. Progressive end-organ failure is the most common cause of death. Hepatic function is often compromised and rapidly becomes worse. Renal failure quickly ensues, followed by cardiac, pulmonary and central nervous system failure.
“What if” scenarios.
Trousseau’s syndrome is an extreme form of chronic DIC due to malignancy. It is notorious because of its difficult-to-control hypercoagulability with recurrent thrombosis, which is usually the cause of death. Survival depends on extremely aggressive anticoagulation and, when possible, treatment of the underlying cancer. This can be achieved occasionally using unfractionated heparin, low molecular weight heparin, or fondaparinux. Higher doses of these agents may need to be administered because of their abbreviated half-lives in vivo in these specific scenarios. The shortened half-lives are due to the constant production of thrombin by procoagulant substances produced and secreted by the tumor. These patients’ hypercoagulability is generally resistant to warfarin therapy.
What’s the evidence?
Mant, MJ, King, EG.. “Severe acute DIC”. Am J Med.. vol. 67. 1979. pp. 557-563. [A classic paper describing clinical and laboratory features of severe, acute DIC.]
Sack, GH, Levin, J, Bell, WR.. “Trousseau’s syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical pathologic and therapeutic features”. Medicine.. vol. 56. 1977. pp. 1-37. [Another classic article describing Trousseau’s syndrome and other types of chronic DIC associated with neoplasms.]
Mandernach, M, Kitchens, CS., Kitchens, CS, Kessler, CM, Konkle, B. “Disseminated intravascular coagulation”. Consultative Hemostasis and Thrombosis. 2013. [This book chapter reviews the pathophysiology of DIC.]
Kitchens, CS.. “Thrombocytopenia and thrombosis in disseminated intravascular coagulation (DIC). Hematology 2009”. the American Society of Hematology Education Book. 2009. pp. 240-246. [Detailed update on DIC.]
Cosgriff, N, Moore, EE, Sauaia, A. “Predicting life-threatening coagulopathy in the massively transfused trauma patient; hypothermia and acidosis revisited”. J Trauma.. vol. 42. 1997. pp. 857-862. [Explains the roles of hypothermia and acidosis in DIC of trauma.]
Toh, C-H, Hoots, WK. “The scoring system of the Scientific and Standardization Committee on Disseminated Intravascular Coagulation of the Internal Society of Thrombosis and Haemostasis; a 5-year overview”. J Thromb Haemost.. vol. 5. 2007. pp. 604-606. [Validates a simple DIC scoring system based on laboratory findings, if used in the correct clinical context.]
Dempfle, CE.. “Coagulopathy of sepsis”. Thromb Haemost.. vol. 91. 2004. pp. 213-224. [Recent discussions of possible role of newer products such (e.g., antithrombin concentrate and recombinant activated protein C).]
Varki, A.. “Trousseau’s syndrome: Multiple definitions and multiple mechanisms”. Blood.. vol. 110. 2007. pp. 1723-1729. [Comprehensive review of pathophysiology and management.]
Kitchens, CS, Erkan, D, Brandäo, LR. “Thrombotic Storm revisited: Preliminary diagnostic criteria suggested by the Thrombotic Storm Study Group”. Am J Med.. vol. 124. 2011. pp. 269-269. [Description of the concept of thrombotic storm.]
Ranieri, M, Thompson, T, Barie, P. “Drotrecogin Alfa (Activated) in Adults with Septic Shock”. N Engl J Med. vol. 366. 2012. pp. 2055-2064. [PROWESS-SHOCK trial which led to withdrawal of activated protein C as a therapeutic agent.]
Taylor, FB, Toh, C-H, Hoots, WK. “Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation”. Thromb Haemost. vol. 86. 2001. pp. 1327-1330. [Scoring system for DIC.]
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